Breast Cancer, part 2

A pooled analysis of cardiac safety in 598 cancer patients treated with pertuzumab was performed using data supplied by Roche and Genentech.[14][Level of evidence C2]

Sources: 14 · Level of evidence C2

A pooled analysis of cardiac safety in 598 cancer patients treated with pertuzumab was performed using data supplied by Roche and Genentech.[14][Level of evidence C2]

Asymptomatic left ventricular systolic dysfunction was observed in 6.9% of patients receiving pertuzumab alone (n = 331; 95% CI, 4.5%–10.2%), 3.4% of patients receiving pertuzumab in combination with a non–anthracycline-containing chemotherapy (n = 175; 95% CI, 1.3%–7.3%), and 6.5% of patients receiving pertuzumab in combination with trastuzumab (n = 93; 95% CI, 2.4%–13.5%).

Symptomatic heart failure was observed in one patient (0.3%) who received pertuzumab alone, two patients (1.1%) who received pertuzumab in combination with a non–anthracycline-containing chemotherapy, and one patient (1.1%) who received pertuzumab in combination with trastuzumab.

A meta-analysis of randomized trials (n = 6) that evaluated the administration of anti-HER2 monotherapy (trastuzumab or lapatinib or pertuzumab) versus dual anti-HER2 therapy (trastuzumab plus lapatinib or trastuzumab plus pertuzumab) was performed.[15][Level of evidence C2]

Sources: 15 · Level of evidence C2

A meta-analysis of randomized trials (n = 6) that evaluated the administration of anti-HER2 monotherapy (trastuzumab or lapatinib or pertuzumab) versus dual anti-HER2 therapy (trastuzumab plus lapatinib or trastuzumab plus pertuzumab) was performed.[15][Level of evidence C2]

LVEF decline was observed in 3.1% of the patients who received monotherapy (95% CI, 2.2%–4.4%) and 2.9% of the patients who received dual therapy (95% CI, 2.1%–4.1%).

Symptomatic heart failure was observed in 0.88% of the patients who received monotherapy (95% CI, 0.47%–1.64%) and 1.49% of the patients who received dual therapy (95% CI, 0.98%–2.23%).

Long-term follow-up of the ATLAS trial (NCT00003016) included toxicity data. Compared with 5 years, 10 years of tamoxifen therapy increased the risk of the following:[16]

Sources: ATLAS · 16

Long-term follow-up of the ATLAS trial (NCT00003016) included toxicity data. Compared with 5 years, 10 years of tamoxifen therapy increased the risk of the following:[16]

Pulmonary embolus: relative risk (RR), 1.87 (95% CI, 1.13–3.07; P = .01).

Stroke: RR, 1.06 (95% CI, 0.83–1.36).

Ischemic heart disease: RR, 0.76 (95% CI, 0.6–0.95; P = .02).

Endometrial cancer: RR, 1.74 (95% CI, 1.30–2.34; P = .0002). Notably, the cumulative risk of endometrial cancer during years 5 to 14 from breast cancer diagnosis was 3.1% for women who received 10 years of tamoxifen versus 1.6% for women who received 5 years of tamoxifen. The mortality rate for years 5 to 14 was 12.2% for women who received 10 years of tamoxifen versus 15% for women who received 5 years of tamoxifen, for an absolute mortality reduction of 2.8%.

Chest wall: Local chest wall recurrence after mastectomy is often a sign of widespread disease, but, in a subset of patients, it may be the only site of recurrence. For patients in this subset, surgery and/or radiation therapy may be curative.[8,9] Patients with chest wall recurrences of less than 3 cm, axillary and internal mammary node recurrence (not supraclavicular, which has a poorer survival), and a greater-than-2-year disease-free interval before recurrence have the best chance for prolonged survival.[9] The 5-year disease-free survival (DFS) rate in one series of such patients was 25%, with a 10-year rate of 15%.[10] The locoregional control rate was 57% at 10 years. Systemic therapy should be considered in patients with locoregional recurrence.

Sources: 8 · 9 · 9 · 10

Breast: In the Chemotherapy as Adjuvant for Locally Recurrent Breast Cancer (CALOR [NCT00074152]) trial, patients with a history of breast-conserving surgery or mastectomy with clear margins and complete excision of an isolated local recurrence of their breast cancer were randomly assigned to receive either chemotherapy of the physician's choice or no chemotherapy. The study was closed early because of poor accrual. The original sample size for a hazard ratio (HR) of 0.74 was 977 patients (347 DFS events) and was revised subsequently to 265 patients (HR, 0.6; 124 DFS events), with only 162 enrolled at the time of study closure.[11][Level of evidence B1]

Sources: CALOR · 11 · Level of evidence B1

Breast: In the Chemotherapy as Adjuvant for Locally Recurrent Breast Cancer (CALOR [NCT00074152]) trial, patients with a history of breast-conserving surgery or mastectomy with clear margins and complete excision of an isolated local recurrence of their breast cancer were randomly assigned to receive either chemotherapy of the physician's choice or no chemotherapy. The study was closed early because of poor accrual. The original sample size for a hazard ratio (HR) of 0.74 was 977 patients (347 DFS events) and was revised subsequently to 265 patients (HR, 0.6; 124 DFS events), with only 162 enrolled at the time of study closure.[11][Level of evidence B1]

In ER-negative patients, the HR for DFS for chemotherapy versus no chemotherapy was 0.29 (95% confidence interval [CI], 0.13–0.67; 10-year DFS, 70% vs. 34%), whereas in ER-positive patients, the HR was 1.07 (95% CI, 0.57–2.00; 10-year DFS, 50% vs. 59%). The interaction between chemotherapy and ER status with respect to DFS was significant (P = .013).[12]

Sources: 12

This trial supports consideration of adjuvant chemotherapy after complete resection of isolated locoregional recurrence of breast cancer in patients with ER-negative tumors.

Hormone therapy (tamoxifen, aromatase inhibitors, selective estrogen receptor [ER] degraders).

HER2-targeted therapy.

CDK4/6 inhibitors.

mTOR inhibitors.

PIK3CA inhibitors.

Chemotherapy.

Immunotherapy.

Surgery for patients with limited symptomatic metastases.

Radiation therapy for patients with limited symptomatic metastases.

Bone-modifying therapy for patients with bone metastases.

PALOMA-2 (NCT01740427) confirmed the results of the phase II PALOMA-1 trial.[10] This phase III, double-blind trial compared placebo plus letrozole with palbociclib plus letrozole as initial therapy for ER-positive postmenopausal patients with advanced disease (n = 666). The primary end point was investigator-assessed progression-free survival (PFS).[11]

Sources: PALOMA-2 · 10 · 11

PALOMA-2 (NCT01740427) confirmed the results of the phase II PALOMA-1 trial.[10] This phase III, double-blind trial compared placebo plus letrozole with palbociclib plus letrozole as initial therapy for ER-positive postmenopausal patients with advanced disease (n = 666). The primary end point was investigator-assessed progression-free survival (PFS).[11]

The median PFS was 24.8 months in the palbociclib-plus-letrozole group compared with 14.5 months in the placebo-plus-letrozole group (hazard ratio [HR], 0.58; 95% confidence interval [CI], 0.46–0.72; P < .001).[11][Level of evidence B1]

Sources: 11 · Level of evidence B1

Overall survival (OS) data are not yet mature.

Patients who received palbociclib experienced more frequent cytopenias (66.4% grade 3 to 4 in palbociclib-treated patients vs. 1.4% in placebo-treated patients). Other common adverse events included nausea, arthralgia, fatigue, and alopecia. The most common grade 3 to 4 adverse events other than neutropenia included leukopenia (24.8% vs. 0%), anemia (5.4% vs. 1.8%), and fatigue (1.8% vs. 0.5%).

The phase III placebo-controlled MONALEESA-2 trial (NCT01958021) randomly assigned 668 patients to receive either first-line ribociclib plus letrozole or placebo plus letrozole.[12,13]

Sources: MONALEESA-2 · 12 · 13

The phase III placebo-controlled MONALEESA-2 trial (NCT01958021) randomly assigned 668 patients to receive either first-line ribociclib plus letrozole or placebo plus letrozole.[12,13]

The primary end point (investigator-assessed PFS) was met. A preplanned interim analysis was performed after 243 patients had disease progression or died, and median duration of follow-up was 15.3 months. After 18 months, the PFS rate was 63.0% (95% CI, 54.6%–70.3%) in the ribociclib group and 42.2% (95% CI, 34.8%–49.5%) in the placebo group.[12]

Sources: 12

OS was a secondary end point. A protocol-specified final analysis of OS was published after 400 deaths and a median follow-up of 6.6 years. Patients who received ribociclib plus letrozole had a significant OS benefit compared with patients who received placebo plus letrozole. Median OS was 63.9 months in the ribociclib group and 51.4 months in the placebo group (HRdeath, 0.76; 95% CI, 0.63–0.93; two-sided P = .008).[14][Level of evidence A1]

Sources: 14 · Level of evidence A1

Grade 3 to 4 neutropenia occurred in 63.8% of patients in the ribociclib group and 1.2% of patients in the placebo group. Grade 1 to 2 nausea, infection, fatigue, and diarrhea were also noted. Grade 3 to 4 hepatobiliary toxic effects occurred in 14.4% of patients who received ribociclib and 4.8% of patients who received placebo. Prolonged QTcF interval occurred in 4.5% of patients in the ribociclib group and 2.1% of patients in the placebo group.

Ribociclib has also been tested in combination with fulvestrant in postmenopausal patients with HER2-negative hormone receptor–positive, recurrent or metastatic breast cancer. The MONALEESA-3 trial (NCT02422615) included patients receiving first-line or second-line therapy. This phase III, placebo-controlled trial randomly assigned 726 patients in a 2:1 ratio to receive ribociclib plus fulvestrant or placebo plus fulvestrant.[15]

Sources: MONALEESA-3 · 15

Ribociclib has also been tested in combination with fulvestrant in postmenopausal patients with HER2-negative hormone receptor–positive, recurrent or metastatic breast cancer. The MONALEESA-3 trial (NCT02422615) included patients receiving first-line or second-line therapy. This phase III, placebo-controlled trial randomly assigned 726 patients in a 2:1 ratio to receive ribociclib plus fulvestrant or placebo plus fulvestrant.[15]

The primary end point (investigator-assessed PFS) was met. At the time of final analysis for PFS, the median PFS for the ribociclib group was 20.5 months versus 12.8 months in the placebo group (HR, 0.593; 95% CI, 0.480–0.732; P < .001).[15][Level of evidence B1]

Sources: 15 · Level of evidence B1

OS was superior in the ribociclib group (HR, 0.724; 95% CI, 0.568–0.924; P = .004). The result crossed the prespecified stopping boundary (P = .011) for superior efficacy. Results were similar in all subgroups.[16][Level of evidence A1]

Sources: 16 · Level of evidence A1

Adverse events were similar to those in other studies of CDK4/6 inhibitors.

Ribociclib has also been tested in combination with fulvestrant in postmenopausal patients with HER2-negative hormone receptor–positive, recurrent or metastatic breast cancer. The MONALEESA-3 trial (NCT02422615) included patients receiving first-line or second-line therapy. This phase III, placebo-controlled trial randomly assigned 726 patients in a 2:1 ratio to receive ribociclib plus fulvestrant or placebo plus fulvestrant.[15] › Adverse events were similar to those in other studies of CDK4/6 inhibitors.

Grade 3 to 4 neutropenia occurred in 53.4% of patients in the ribociclib group and 0.0% of patients in the placebo group.

The rate of febrile neutropenia was 1.0% in the ribociclib group and 0% in the placebo group.

An increase in QTcF interval of more than 60 milliseconds from baseline was observed in 6.5% of patients in the ribociclib arm and 0.4% in the placebo arm.

Ribociclib was also assessed in the first-line setting in a study conducted solely in premenopausal or perimenopausal women receiving either tamoxifen or a nonsteroidal aromatase inhibitor (AI) plus goserelin.[17] In the MONALEESA-7 trial (NCT02278120), 672 premenopausal patients with HER2-negative hormone receptor–positive, recurrent or metastatic breast cancer, who had not received endocrine therapy for advanced disease, were randomly assigned in a 1:1 ratio to ribociclib or placebo.

Sources: 17 · MONALEESA-7

Ribociclib was also assessed in the first-line setting in a study conducted solely in premenopausal or perimenopausal women receiving either tamoxifen or a nonsteroidal aromatase inhibitor (AI) plus goserelin.[17] In the MONALEESA-7 trial (NCT02278120), 672 premenopausal patients with HER2-negative hormone receptor–positive, recurrent or metastatic breast cancer, who had not received endocrine therapy for advanced disease, were randomly assigned in a 1:1 ratio to ribociclib or placebo.

The primary end point (investigator-assessed PFS) was met. At the time of final analysis for PFS, the median PFS for the ribociclib group was 23.8 months versus 13.0 months in the placebo group (HR, 0.55; 95% CI, 0.44–0.69; P < .0001).[17][Level of evidence A3]

Sources: 17 · Level of evidence A3

OS was a secondary end point. The combination of ribociclib plus endocrine therapy was associated with longer OS than was endocrine therapy alone (42-month OS, 70.2% vs. 46%; HRdeath, 0.71; 95% CI, 0.54−0.95; P = .01).[18][Level of evidence A1] The survival benefit was observed both in patients who received an AI plus goserelin and in those who received tamoxifen, but it was not statistically significant in the much-smaller tamoxifen group.

Sources: 18 · Level of evidence A1

Adverse events were similar to those in other studies of CDK4/6 inhibitors.

Ribociclib was also assessed in the first-line setting in a study conducted solely in premenopausal or perimenopausal women receiving either tamoxifen or a nonsteroidal aromatase inhibitor (AI) plus goserelin.[17] In the MONALEESA-7 trial (NCT02278120), 672 premenopausal patients with HER2-negative hormone receptor–positive, recurrent or metastatic breast cancer, who had not received endocrine therapy for advanced disease, were randomly assigned in a 1:1 ratio to ribociclib or placebo. › Adverse events were similar to those in other studies of CDK4/6 inhibitors.

Grade 3 to 4 neutropenia occurred in 61% of patients in the ribociclib group and 4% of patients in the placebo group.

The rate of febrile neutropenia was 2.0% in the ribociclib group and 1.0% in the placebo group.

An increase in QTcF interval of more than 60 milliseconds from baseline was observed in 10.0 % of patients in the ribociclib arm and 2.0% in the placebo arm. Sixty-millisecond increases were more common in patients receiving tamoxifen (16% on ribociclib and 7% on placebo).

MONARCH 3 (NCT02246621) was a randomized, double-blind, phase III trial that evaluated first-line abemaciclib or placebo plus a nonsteroidal AI in 493 postmenopausal women with HER2-negative hormone receptor–positive, advanced breast cancer.[19]

Sources: MONARCH 3 · 19

MONARCH 3 (NCT02246621) was a randomized, double-blind, phase III trial that evaluated first-line abemaciclib or placebo plus a nonsteroidal AI in 493 postmenopausal women with HER2-negative hormone receptor–positive, advanced breast cancer.[19]

The primary end point, investigator-assessed PFS, was met. After a median follow-up of 17.8 months, the PFS was not reached in the abemaciclib arm and was reached at 14.7 months in the placebo arm (HR, 0.54; 95% CI, 0.41–0.72; P = .000021).

In the final analysis of OS, there was a nonsignificant difference in median survival (median OS, 66.8 months [abemaciclib arm] vs. 53.7 months [placebo arm]; HR, 0.804; 95% CI, 0.637–1.015; P = .066).[20][Level of evidence B1]

Sources: 20 · Level of evidence B1

The side effect profile of abemaciclib differs from the other CDK4/6 inhibitors. Diarrhea was the most frequent adverse event in the abemaciclib arm, although most of the diarrhea cases were grade 1.

Neutropenia was more common in the abemaciclib arm; however, only 21.1% of participants experienced grade 3 to 4 neutropenia.

PALOMA-3 (NCT01942135) was a double-blind, phase III trial of 521 patients with HER2-negative hormone receptor–positive, advanced breast cancer who had relapsed after or progressed on previous endocrine therapy and were randomly assigned to receive either fulvestrant plus placebo or fulvestrant plus palbociclib. Premenopausal and postmenopausal patients were eligible. Premenopausal patients received goserelin.[5][Level of evidence A3]

Sources: PALOMA-3 · 5 · Level of evidence A3

PALOMA-3 (NCT01942135) was a double-blind, phase III trial of 521 patients with HER2-negative hormone receptor–positive, advanced breast cancer who had relapsed after or progressed on previous endocrine therapy and were randomly assigned to receive either fulvestrant plus placebo or fulvestrant plus palbociclib. Premenopausal and postmenopausal patients were eligible. Premenopausal patients received goserelin.[5][Level of evidence A3]

The final PFS analysis showed a median PFS of 9.5 months on the palbociclib-fulvestrant arm versus 4.6 months on the placebo-fulvestrant arm (HR, 0.46; 95% CI, 0.36–0.59; P < .0001).[21][Level of evidence A3]

Sources: 21 · Level of evidence A3

Cytopenias, particularly neutropenia, were much more frequent on the palbociclib-containing arm, but febrile neutropenia was very uncommon (1%) in both groups. Patients receiving palbociclib had more-frequent fatigue, nausea, and headache.

A prespecified analysis of OS was made after 310 patients had died. A 6.9 month difference in median OS favoring the palbociclib-fulvestrant arm (34.9 months vs. 28.0 months) was found, which did not reach statistical significance (HR, 0.81; 95% CI, 0.64–1.03; P = .09).[22]

Sources: 22

In a preplanned subgroup analysis, improved OS was observed in patients who had demonstrated sensitivity to hormone therapy (HR, 0.72; 95% CI, 0.55−0.94), whereas in patients without sensitivity, OS was not improved in the palbociclib group (HR, 1.14; 95% CI, 0.71−1.84; P = .12 for interaction).

The MONARCH 2 study (NCT02107703) tested abemaciclib (CDK4/6 inhibitor) in a phase III, placebo-controlled trial that randomly assigned 669 patients with HER2-negative, hormone receptor–positive, advanced breast cancer (with previous progression on endocrine therapy) to receive abemaciclib plus fulvestrant or placebo plus fulvestrant.[23]

Sources: MONARCH 2 · 23

The MONARCH 2 study (NCT02107703) tested abemaciclib (CDK4/6 inhibitor) in a phase III, placebo-controlled trial that randomly assigned 669 patients with HER2-negative, hormone receptor–positive, advanced breast cancer (with previous progression on endocrine therapy) to receive abemaciclib plus fulvestrant or placebo plus fulvestrant.[23]

The primary end point (investigator-assessed PFS) was met, with median duration of follow-up of 19.5 months. The median PFS was 16.4 months for the abemaciclib-fulvestrant arm versus 9.3 months for the placebo-fulvestrant arm (HR, 0.55; 95% CI, 0.45–0.68; P < .001).[23][Level of evidence B1]

Sources: 23 · Level of evidence B1

OS data are mature and demonstrate an improvement in OS for patients receiving abemaciclib, and showed a median OS of 46.7 months for abemaciclib plus fulvestrant versus 37.3 months for placebo (HR, 0.757; 95% CI, 0.606–0.945; P = .01).[24][Level of evidence A1]

Sources: 24 · Level of evidence A1

Adverse events included diarrhea in the abemaciclib group (86.4%) and in the placebo group (24.7%), neutropenia (46% and 4%), nausea (45.1% and 22.9%), fatigue (39.9% and 26.9%), and abdominal pain (35.4% and 15.7%).

The MONARCH 2 study (NCT02107703) tested abemaciclib (CDK4/6 inhibitor) in a phase III, placebo-controlled trial that randomly assigned 669 patients with HER2-negative, hormone receptor–positive, advanced breast cancer (with previous progression on endocrine therapy) to receive abemaciclib plus fulvestrant or placebo plus fulvestrant.[23] › Adverse events included diarrhea in the abemaciclib group (86.4%) and in the placebo group (24.7%), neutropenia (46% and 4%), nausea (45.1% and 22.9%), fatigue (39.9% and 26.9%), and abdominal pain (35.4% and 15.7%).

These events were mostly grade 1 to 2. Grade 1 to 2 diarrhea occurred in 73% of the patients in the abemaciclib group and in 24.2% of the placebo group. Anti-diarrheal medicine effectively managed this symptom in most cases, according to the study report.

Grade 3 diarrhea occurred in 13.4% of patients in the abemaciclib group and 0.4% of patients in the placebo group. No grade 4 diarrhea was reported.

Grade 3 to 4 neutropenia occurred in 25.5% of patients in the abemaciclib group and 1.7% of patients in the placebo group. Febrile neutropenia was reported in six patients in the abemaciclib arm.

The global, double-blind, placebo-controlled postMONARCH trial (NCT05169567), reported in abstract form, included 368 patients with HER2-negative ER-positive advanced breast cancer. Patients were randomly assigned in a 1:1 ratio to receive either abemaciclib plus fulvestrant or fulvestrant alone. Eligible patients had (1) disease progression during initial therapy for metastatic breast cancer, which included a CDK4/6 inhibitor and aromatase inhibitor (99% of patients), or (2) disease relapse during or after adjuvant therapy for early breast cancer with a CDK4/6 inhibitor plus endocrine therapy. The CDK inhibitor was palbociclib in 59% of patients, ribociclib in 33% of patients, and abemaciclib in 8% of patients. No other prior treatment was permitted for metastatic disease. The primary end point was investigator-assessed PFS.[25]

Sources: postMONARCH · 25

The global, double-blind, placebo-controlled postMONARCH trial (NCT05169567), reported in abstract form, included 368 patients with HER2-negative ER-positive advanced breast cancer. Patients were randomly assigned in a 1:1 ratio to receive either abemaciclib plus fulvestrant or fulvestrant alone. Eligible patients had (1) disease progression during initial therapy for metastatic breast cancer, which included a CDK4/6 inhibitor and aromatase inhibitor (99% of patients), or (2) disease relapse during or after adjuvant therapy for early breast cancer with a CDK4/6 inhibitor plus endocrine therapy. The CDK inhibitor was palbociclib in 59% of patients, ribociclib in 33% of patients, and abemaciclib in 8% of patients. No other prior treatment was permitted for metastatic disease. The primary end point was investigator-assessed PFS.[25]

The 6-month PFS rate was 50% in the abemaciclib-plus-fulvestrant group and 37% in the fulvestrant-alone group (HR, 0.73; 95% CI, 0.57–0.95).[25][Level of evidence B1]

Sources: 25 · Level of evidence B1

Overall response rate, a secondary end point, was 17% in the abemaciclib-plus-fulvestrant group and 7% in the fulvestrant-alone group.

Single-agent abemaciclib was approved by the FDA for use in HER2-negative hormone receptor–positive breast cancer with disease progression on or after endocrine therapy and chemotherapy on the basis of results of the MONARCH 1 trial (NCT02102490).[26] Abemaciclib is the only CDK4/6 inhibitor approved as a single agent. MONARCH 1 was a single-arm phase II study of single-agent abemaciclib in 132 women with HER2-negative hormone receptor–positive, advanced breast cancer that had progressed on at least one line of previous endocrine therapy and at least two lines of previous chemotherapy. The study population was heavily pretreated, and most participants had visceral disease. Patients who had previous CDK inhibitors were excluded. The primary end point was investigator-assessed objective response rate.

Sources: MONARCH 1 · 26

Single-agent abemaciclib was approved by the FDA for use in HER2-negative hormone receptor–positive breast cancer with disease progression on or after endocrine therapy and chemotherapy on the basis of results of the MONARCH 1 trial (NCT02102490).[26] Abemaciclib is the only CDK4/6 inhibitor approved as a single agent. MONARCH 1 was a single-arm phase II study of single-agent abemaciclib in 132 women with HER2-negative hormone receptor–positive, advanced breast cancer that had progressed on at least one line of previous endocrine therapy and at least two lines of previous chemotherapy. The study population was heavily pretreated, and most participants had visceral disease. Patients who had previous CDK inhibitors were excluded. The primary end point was investigator-assessed objective response rate.

The objective response rate was 19.7% at 12 months (95% CI, 13.3%–27.5%).

The clinical benefit rate was 42.4%.

Median PFS was 6.0 months (95% CI, 4.2–7.5).

The most common adverse event was diarrhea, which occurred in 90.2% of the participants. However, the majority was grade 1 to 2, and only 19.7% of participants experienced grade 3 diarrhea. There was no grade 4 diarrhea.

Neutropenia occurred in 97.7% of participants; however, the majority was grade 1 to 2, and only 26.9% of participants experienced grade 3 to 4 neutropenia.

The Breast Cancer Trial of Oral Everolimus (BOLERO-2 [NCT00863655]) was a randomized, phase III, placebo-controlled trial in which patients with hormone receptor–positive metastatic breast cancer that is resistant to nonsteroidal aromatase inhibition were randomly assigned to receive either the mTOR inhibitor everolimus plus exemestane, or placebo plus exemestane.[27][Level of evidence B1]

Sources: BOLERO-2 · 27 · Level of evidence B1

The Breast Cancer Trial of Oral Everolimus (BOLERO-2 [NCT00863655]) was a randomized, phase III, placebo-controlled trial in which patients with hormone receptor–positive metastatic breast cancer that is resistant to nonsteroidal aromatase inhibition were randomly assigned to receive either the mTOR inhibitor everolimus plus exemestane, or placebo plus exemestane.[27][Level of evidence B1]

At the interim analysis, median PFS was 6.9 months for everolimus plus exemestane and 2.8 months for placebo plus exemestane (HR, 0.43; 95% CI, 0.35–0.54; P < .001).

The addition of everolimus to exemestane was more toxic than was placebo plus exemestane, with the most-common grade 3 or 4 adverse events being stomatitis (8% vs. 1%), anemia (6% vs. <1%), dyspnea (4% vs. 1%), hyperglycemia (4% vs. <1%), fatigue (4% vs. 1%), and pneumonitis (3% vs. 0%).

OS differences were not significant after further follow-up.[28]

Sources: 28

TAMRAD (NCT01298713) was an open-label, randomized, phase II trial comparing tamoxifen with tamoxifen plus everolimus in postmenopausal women whose disease had progressed after receiving an AI in the adjuvant or metastatic setting. The trial randomly assigned 57 women to receive tamoxifen and 54 women to receive the combination therapy.[29]

Sources: TAMRAD · 29

TAMRAD (NCT01298713) was an open-label, randomized, phase II trial comparing tamoxifen with tamoxifen plus everolimus in postmenopausal women whose disease had progressed after receiving an AI in the adjuvant or metastatic setting. The trial randomly assigned 57 women to receive tamoxifen and 54 women to receive the combination therapy.[29]

Median time to progression was 8.6 months in the combination group and 4.5 months in the tamoxifen group (HR, 0.54; 95% CI, 0.56−0.81; P = .002).

Toxicities were greater on the everolimus arm and similar to those in the BOLERO2 trial.

In an exploratory analysis, OS was 32.9 months in the tamoxifen group and not reached in the combination group (HR, 0.45; 95% CI, 0.24−0.81; P = .007).[29][Level of evidence A1]

Sources: 29 · Level of evidence A1

PrE0102 (NCT01797120) was a double-blind, randomized, phase II trial comparing fulvestrant with fulvestrant plus everolimus in postmenopausal women whose disease had progressed after receiving an AI in the adjuvant or metastatic setting. Sixty-six women were randomly assigned to the combination arm and 65 to fulvestrant alone.[30]

Sources: PrE0102 · 30

PrE0102 (NCT01797120) was a double-blind, randomized, phase II trial comparing fulvestrant with fulvestrant plus everolimus in postmenopausal women whose disease had progressed after receiving an AI in the adjuvant or metastatic setting. Sixty-six women were randomly assigned to the combination arm and 65 to fulvestrant alone.[30]

Median PFS was 10.3 months on the combination arm and 5.1 months on the fulvestrant-alone arm (HR, 0.61; 95% CI, 0.40−0.92; P = .02).[30][Level of evidence B1]

Sources: 30 · Level of evidence B1

Toxicities were similar to those in previous studies.

The was no observed difference in OS between the arms.

The single-arm SWISH trial (NCT02069093) assessed the efficacy of a dexamethasone oral solution (0.5 mg per 5 mL) in the prevention of stomatitis in women receiving exemestane plus everolimus.[31] The incidence of grade 2 or worse stomatitis was 2% in the 85 evaluable patients in this study compared with 33% in the BOLERO-2 trial.

Sources: SWISH · 31

The phase III, randomized, double-blind CAPITELLO-291 trial (NCT04305496) enrolled women and men with HER2-negative ER-positive advanced breast cancer. Patients had disease relapse or progression during or after treatment with an aromatase inhibitor, with or without previous CDK4/6 inhibitor therapy. The trial included 708 patients: 289 patients (40.8%) had PIK3CA/AKT/PTEN pathway alterations and 489 (69.1%) received a prior CDK4/6 inhibitor for advanced breast cancer. Patients were randomly assigned in a 1:1 ratio to receive either capivasertib plus fulvestrant or placebo plus fulvestrant. The dual primary end point was investigator-assessed PFS which was measured both in the overall population and in patients with PIK3CA/AKT/PTEN pathway–altered tumors.[32]

Sources: CAPITELLO-291 · 32

The phase III, randomized, double-blind CAPITELLO-291 trial (NCT04305496) enrolled women and men with HER2-negative ER-positive advanced breast cancer. Patients had disease relapse or progression during or after treatment with an aromatase inhibitor, with or without previous CDK4/6 inhibitor therapy. The trial included 708 patients: 289 patients (40.8%) had PIK3CA/AKT/PTEN pathway alterations and 489 (69.1%) received a prior CDK4/6 inhibitor for advanced breast cancer. Patients were randomly assigned in a 1:1 ratio to receive either capivasertib plus fulvestrant or placebo plus fulvestrant. The dual primary end point was investigator-assessed PFS which was measured both in the overall population and in patients with PIK3CA/AKT/PTEN pathway–altered tumors.[32]

In the overall population, the median PFS was 7.2 months in the capivasertib-fulvestrant group versus 3.6 months in the placebo-fulvestrant group (HR, 0.60; 95% CI, 0.51–0.71; P < .001).[32][Level of evidence B1]

Sources: 32 · Level of evidence B1

In the PIK3CA/AKT/PTEN pathway-altered population, the median PFS was 7.3 months in the capivasertib-fulvestrant group and 3.1 months in the placebo-fulvestrant group (HR, 0.50; 95% CI, 0.38–0.65; P < .001).

In patients who received capivasertib and fulvestrant, the most frequent grade 3 or higher adverse events were rash (12.1%) and diarrhea (9.3%). Grade 3 or higher rash and diarrhea occurred in 0.3% of patients who received placebo and fulvestrant. Adverse events sometimes led to treatment discontinuation. This occurred in 13.0% of the capivasertib-fulvestrant group and 2.3% of the placebo-fulvestrant group.

SOLAR-1 (NCT02437318) was a randomized phase III trial comparing alpelisib plus fulvestrant with placebo plus fulvestrant. The trial included 572 postmenopausal women with HER2-negative hormone receptor–positive advanced breast cancer who had received previous endocrine therapy.[33][Level of evidence B1] PIK3CA variants were confirmed in 341 participants. The primary end point was PFS in the cohort of patients with PIK3CA variants. The FDA approved alpelisib for use in combination with fulvestrant in advanced PIK3CA-mutated, HER2-negative hormone receptor–positive breast cancer after previous endocrine therapy.

Sources: SOLAR-1 · 33 · Level of evidence B1

SOLAR-1 (NCT02437318) was a randomized phase III trial comparing alpelisib plus fulvestrant with placebo plus fulvestrant. The trial included 572 postmenopausal women with HER2-negative hormone receptor–positive advanced breast cancer who had received previous endocrine therapy.[33][Level of evidence B1] PIK3CA variants were confirmed in 341 participants. The primary end point was PFS in the cohort of patients with PIK3CA variants. The FDA approved alpelisib for use in combination with fulvestrant in advanced PIK3CA-mutated, HER2-negative hormone receptor–positive breast cancer after previous endocrine therapy.

In this cohort, median PFS was 11 months in the alpelisib-plus-fulvestrant arm compared with 5.7 months in the placebo-plus-fulvestrant arm (HRprogression or HRdeath, 0.65; 95% CI, 0.50−0.85; P < .001).

PFS did not differ between arms in the cohort of participants without PIK3CA variants (median PFS, 7.4 months in the alpelisib-plus-fulvestrant arm vs. 5.6 months in the placebo-plus-fulvestrant arm).

OS in the cohort with PIK3CA variants was a secondary end point. OS data are not yet mature.

Very few study participants had received previous CDK4/6 inhibitor therapy.

Common toxicities associated with alpelisib included hyperglycemia, diarrhea, nausea, anorexia, and rash. Careful monitoring and management of hyperglycemia are required during alpelisib use.

A randomized, open-label, phase III trial (EMERALD [NCT03778931]) enrolled patients with ER-positive HER2-negative metastatic breast cancer. Eligible patients had previously received one or two lines of endocrine therapy, a CDK4/6 inhibitor, and no more than one line of chemotherapy. A total of 477 patients were randomly assigned in a 1:1 ratio to receive either elacestrant 400 mg orally once daily or standard-of-care endocrine monotherapy. Primary end points were PFS by blinded independent central review in all patients and in patients with detectable ESR1 variants. ESR1 variants were found in 47.8% of patients, and 43.4% of patients had received two prior endocrine therapies. Twenty-nine percent of patients in the elacestrant arm and 31% of patients in the standard-of-care arm had received prior fulvestrant therapy. Less than 5% of patients in either arm had received prior mTOR inhibitor therapy.[34]

Sources: EMERALD · 34

A randomized, open-label, phase III trial (EMERALD [NCT03778931]) enrolled patients with ER-positive HER2-negative metastatic breast cancer. Eligible patients had previously received one or two lines of endocrine therapy, a CDK4/6 inhibitor, and no more than one line of chemotherapy. A total of 477 patients were randomly assigned in a 1:1 ratio to receive either elacestrant 400 mg orally once daily or standard-of-care endocrine monotherapy. Primary end points were PFS by blinded independent central review in all patients and in patients with detectable ESR1 variants. ESR1 variants were found in 47.8% of patients, and 43.4% of patients had received two prior endocrine therapies. Twenty-nine percent of patients in the elacestrant arm and 31% of patients in the standard-of-care arm had received prior fulvestrant therapy. Less than 5% of patients in either arm had received prior mTOR inhibitor therapy.[34]

PFS was prolonged in the elacestrant arm in all patients (HR, 0.70; 95% CI, 0.55–0.88; P = .002) and in elacestrant-treated patients with ESR1 variants (HR, 0.55; 95% CI, 0.39–0.77; P = .0005). Among all patients, 6-month PFS rates were 34.3% for patients in the elacestrant arm and 20.4% for patients in the standard-of-care arm. In patients with ESR1 variants, 6-month PFS rates were 40.8% for patients in the elacestrant arm and 19.1% for patients in the standard-of-care arm. Similarly, for all patients, 12-month PFS rates were 22.3% for patients in the elacestrant arm and 9.4% for patients in the standard-of-care arm. For patients with ESR1 variants, 12-month PFS rates were 26.8% for patients in the elacestrant arm and 8.2% for patients in the standard-of-care arm.[34][Level of evidence B1]

Sources: 34 · Level of evidence B1

The most common adverse events observed with elacestrant versus standard-of-care therapy included nausea (35.0% vs. 18.8%), fatigue (19.0% vs. 18.8%), vomiting (19.0% vs. 8.3%), decreased appetite (14.8% vs. 9.2%), and arthralgia (14.3% vs. 16.2%). Grade 3 or 4 adverse events occurred in 64 patients (27.0%) who received elacestrant and 47 patients (20.5%) who received standard-of-care therapy. The most common grade 3 or 4 adverse events in the elacestrant arm were nausea (six patients, 2.5%), back pain (six patients, 2.5%), and increased alanine aminotransferase (five patients, 2.1%). The most common grade 3 or 4 adverse events in the standard-of-care arm were nausea, fatigue, diarrhea, and increased aspartate aminotransferase (each occurring in two patients, 0.9%). Adverse events led to treatment discontinuation in 15 patients (6.3%) in the elacestrant arm and 10 patients (4.4%) in the standard-of-care arm.

A meta-analysis evaluated patients with metastatic disease who were randomly assigned to receive either an AI as their first or second hormone therapy, or standard therapy (tamoxifen or a progestational agent).[40][Level of evidence A1]

Sources: 40 · Level of evidence A1

A meta-analysis evaluated patients with metastatic disease who were randomly assigned to receive either an AI as their first or second hormone therapy, or standard therapy (tamoxifen or a progestational agent).[40][Level of evidence A1]

Patients who received an AI as either their first or second hormone therapy for metastatic disease and were randomly assigned to receive a third-generation drug (anastrozole, letrozole, exemestane, or vorozole) lived longer (HRdeath, 0.87; 95% CI, 0.82–0.93) than those who received standard therapy (tamoxifen or a progestational agent).

FALCON (NCT01602380) was a phase III, double-blind, randomized trial that compared fulvestrant (500 mg) with anastrozole (1 mg) in patients with advanced or metastatic receptor-positive breast cancer who had not received previous endocrine therapy.[41] The trial randomly assigned 230 patients to receive fulvestrant and 232 patients to receive anastrozole.

Sources: FALCON · 41

FALCON (NCT01602380) was a phase III, double-blind, randomized trial that compared fulvestrant (500 mg) with anastrozole (1 mg) in patients with advanced or metastatic receptor-positive breast cancer who had not received previous endocrine therapy.[41] The trial randomly assigned 230 patients to receive fulvestrant and 232 patients to receive anastrozole.

Median PFS was 16.6 months in the fulvestrant group and 13.8 months in the anastrozole group (HR, 0.797; 95% CI, 0.637−0.999; P = .049).[41][Level of evidence B1]

Sources: 41 · Level of evidence B1

The frequency of adverse events was similar in the two groups, and there was no difference in quality of life.

OS results were not reported.

Two randomized trials that enrolled 400 and 451 patients whose disease had progressed after they received tamoxifen demonstrated that fulvestrant yielded results similar to those of anastrozole in terms of its impact on PFS.[42,43] The proper sequence of these therapies is not known.[44,45]

Sources: 42 · 43 · 44 · 45

EFECT (NCT00065325) was a phase III, double-blind, randomized trial that compared fulvestrant given in a loading-dose regimen (500 mg day 0, 250 mg days 14 and 28, and 250 mg every 28 days thereafter) with exemestane (25 mg) in women who had developed progressive disease after previous nonsteroidal AI (anastrozole or letrozole) therapy.[46] The trial randomly assigned 351 women to receive fulvestrant and 342 women to receive exemestane.

Sources: EFECT · 46

EFECT (NCT00065325) was a phase III, double-blind, randomized trial that compared fulvestrant given in a loading-dose regimen (500 mg day 0, 250 mg days 14 and 28, and 250 mg every 28 days thereafter) with exemestane (25 mg) in women who had developed progressive disease after previous nonsteroidal AI (anastrozole or letrozole) therapy.[46] The trial randomly assigned 351 women to receive fulvestrant and 342 women to receive exemestane.

Median time to progression was 3.7 months in both groups (HR, 0.93; 95% CI, 0.819−1.133; P = .65).[46][Level of evidence B1]

Sources: 46 · Level of evidence B1

The frequency of adverse events was similar in both groups, and there was no difference in quality of life.

OS results were not reported.

CONFIRM (NCT00099437) was a double-blind phase III trial that compared two doses of fulvestrant (500 mg vs. 250 mg, each given in a loading-dose schedule) in 736 women whose disease had progressed on previous endocrine therapy.[47]

Sources: CONFIRM · 47

CONFIRM (NCT00099437) was a double-blind phase III trial that compared two doses of fulvestrant (500 mg vs. 250 mg, each given in a loading-dose schedule) in 736 women whose disease had progressed on previous endocrine therapy.[47]

PFS was significantly better on the higher-dose arm (HR, 0.80; 95% CI, 0.68–0.94; P = .006).[47][Level of evidence B1]

Sources: 47 · Level of evidence B1

Adverse events and quality of life were similar on the two arms.

The SWOG-0226 trial (NCT00075764), which enrolled 707 patients, demonstrated a statistically significant difference in PFS (HR, 0.80; 95% CI, 0.68–0.94; P = .007) and OS (HR, 0.81; 95% CI, 0.65–1.00; P = .05).[48][Level of evidence A1]

Sources: SWOG-0226 · 48 · Level of evidence A1

In an analysis done after 5 more years of follow-up, the observed benefits of combined therapy were still present, and the level of significance with respect to OS was greater (HR, 0.82; 95% CI, 0.69–0.98; P = .03).[50][Level of evidence A1]

Sources: 50 · Level of evidence A1

In contrast, the FACT trial, which enrolled 514 patients, found no difference in either disease-free survival (DFS) (HR, 0.99; 95% CI, 0.81–1.20; P = .91) or OS (HR, 1.0; 95% CI, 0.76–1.32; P = 1.00).[49][Level of evidence A1]

Sources: 49 · Level of evidence A1

The global phase III TROPiCS-02 trial (NCT03901339) randomly assigned 543 patients to receive either sacituzumab govitecan or physician’s choice chemotherapy (eribulin, vinorelbine, capecitabine, or gemcitabine). Patients had locally recurrent inoperable or metastatic breast cancer that was endocrine-resistant, chemotherapy-treated, hormone receptor–positive, and HER2-negative. Patients had received three median lines of chemotherapy for advanced disease, and 99% of patients had previously received a CDK4/6 inhibitor. The primary end point was PFS by blinded independent central review.[52][Level of evidence B1]

Sources: TROPiCS-02 · 52 · Level of evidence B1

The global phase III TROPiCS-02 trial (NCT03901339) randomly assigned 543 patients to receive either sacituzumab govitecan or physician’s choice chemotherapy (eribulin, vinorelbine, capecitabine, or gemcitabine). Patients had locally recurrent inoperable or metastatic breast cancer that was endocrine-resistant, chemotherapy-treated, hormone receptor–positive, and HER2-negative. Patients had received three median lines of chemotherapy for advanced disease, and 99% of patients had previously received a CDK4/6 inhibitor. The primary end point was PFS by blinded independent central review.[52][Level of evidence B1]

An analysis noted a 34% reduction in the risk of progression or death (HR, 0.66; 95% CI, 0.53–0.83; P = .0003). The median PFS was 5.5 months in the sacituzumab govitecan group and 4.0 months in the chemotherapy group. The PFS at 6 and 12 months was 46% and 21% for patients who received sacituzumab govitecan and 30% and 7% for patients who received chemotherapy.

Median OS data are not mature.

Key grade 3 or higher treatment-related adverse events were neutropenia (occurring in 51% of patients who received sacituzumab govitecan and 38% of patients who received chemotherapy) and diarrhea (occurring in 9% of patients who received sacituzumab govitecan and 1% of patients who received chemotherapy). One patient in the sacituzumab govitecan group died of a treatment-related adverse event (septic shock related to neutropenic colitis).

The objective response rate by blinded independent central review was 21% in the sacituzumab govitecan group and 14% in the chemotherapy group. The clinical benefit rate was higher with sacituzumab govitecan than with chemotherapy (34% vs. 22%).

The DESTINY-Breast04 trial (NCT03734029) randomly assigned 557 women in a 2:1 ratio to receive either trastuzumab deruxtecan or the physician’s choice of chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel). Patients had received one or two prior lines of chemotherapy. The primary end point was PFS in the hormone receptor–positive group (88.7% of patients). The secondary end points were PFS in the total population, OS in the total population, and OS in the hormone receptor–positive group.[54][Level of evidence A1]

Sources: DESTINY-Breast04 · 54 · Level of evidence A1

The DESTINY-Breast04 trial (NCT03734029) randomly assigned 557 women in a 2:1 ratio to receive either trastuzumab deruxtecan or the physician’s choice of chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel). Patients had received one or two prior lines of chemotherapy. The primary end point was PFS in the hormone receptor–positive group (88.7% of patients). The secondary end points were PFS in the total population, OS in the total population, and OS in the hormone receptor–positive group.[54][Level of evidence A1]

In the hormone receptor–positive cohort, the median PFS was 10.1 months for patients who received trastuzumab deruxtecan and 5.4 months for patients who received the physician’s choice of chemotherapy (HRdisease progression or death, 0.51; P < .001). The OS was 23.9 months for patients who received trastuzumab deruxtecan and 17.5 months for patients who received the physician's choice of chemotherapy (HRdeath, 0.64; P = .003).

Among all patients, the median PFS was 9.9 months in the trastuzumab deruxtecan group and 5.1 months in the physician’s choice group (HRdisease progression or death, 0.50; P < .001). The OS was 23.4 months in the trastuzumab deruxtecan group and 16.8 months in the physician's choice group (HRdeath, 0.64; P = .001).

Drug-related interstitial lung disease or pneumonitis occurred in 12.1% of the patients who received trastuzumab deruxtecan; 0.8% had grade 5 events.

The phase III, randomized, open-label DESTINY-Breast06 trial (NCT04494425) included patients with ER-positive metastatic breast cancer with low HER2 expression (with a score of 1+ or 2+ on IHC analysis and negative results on in situ hybridization) or ultralow HER2 expression (with a score of 0 on IHC analysis with membrane staining). These patients previously received one or more lines of endocrine-based therapy and no previous chemotherapy for metastatic breast cancer. The trial randomly assigned 866 patients in a 1:1 ratio to receive either trastuzumab deruxtecan or the physician’s choice of chemotherapy. A total of 713 patients had HER2-low disease and 153 patients had HER2-ultralow disease. The primary end point was PFS.[55]

Sources: DESTINY-Breast06 · 55

The phase III, randomized, open-label DESTINY-Breast06 trial (NCT04494425) included patients with ER-positive metastatic breast cancer with low HER2 expression (with a score of 1+ or 2+ on IHC analysis and negative results on in situ hybridization) or ultralow HER2 expression (with a score of 0 on IHC analysis with membrane staining). These patients previously received one or more lines of endocrine-based therapy and no previous chemotherapy for metastatic breast cancer. The trial randomly assigned 866 patients in a 1:1 ratio to receive either trastuzumab deruxtecan or the physician’s choice of chemotherapy. A total of 713 patients had HER2-low disease and 153 patients had HER2-ultralow disease. The primary end point was PFS.[55]

In patients with HER2-low disease, the median PFS was 13.2 months (95% CI, 11.4–15.2) in the trastuzumab deruxtecan group and 8.1 months (95% CI, 7.0–9.0) in the chemotherapy group (HR, 0.62; 95% CI, 0.51–0.74; P < .001).[55][Level of evidence B1]

Sources: 55 · Level of evidence B1

Grade 3 or higher adverse events occurred in 52.8% of patients in the trastuzumab deruxtecan group and 44.4% of patients in the chemotherapy group. Interstitial lung disease occurred in 49 patients (11.3%; three events had grade 5 severity) and pneumonitis occurred in one patient (0.2%; grade 2).

Patients were randomly assigned in a 2:1 ratio to receive either pembrolizumab (200 mg every 3 weeks) and chemotherapy (nab-paclitaxel, paclitaxel, or gemcitabine plus carboplatin) or placebo and chemotherapy. Randomization was stratified by the type of on-study chemotherapy (taxane or gemcitabine/carboplatin), PD-L1 expression at baseline (CPS ≥1 or <1), and previous treatment with the same class of chemotherapy in the neoadjuvant or adjuvant setting (yes or no). Dual primary efficacy end points were PFS and OS assessed in the PD-L1 CPS of 10 or more, PD-L1 CPS of 1 or more, and ITT populations. Of the 847 patients assigned to treatment, 566 patients received pembrolizumab and chemotherapy and 281 patients received placebo and chemotherapy.[56,57]

Sources: 56 · 57

Patients were randomly assigned in a 2:1 ratio to receive either pembrolizumab (200 mg every 3 weeks) and chemotherapy (nab-paclitaxel, paclitaxel, or gemcitabine plus carboplatin) or placebo and chemotherapy. Randomization was stratified by the type of on-study chemotherapy (taxane or gemcitabine/carboplatin), PD-L1 expression at baseline (CPS ≥1 or <1), and previous treatment with the same class of chemotherapy in the neoadjuvant or adjuvant setting (yes or no). Dual primary efficacy end points were PFS and OS assessed in the PD-L1 CPS of 10 or more, PD-L1 CPS of 1 or more, and ITT populations. Of the 847 patients assigned to treatment, 566 patients received pembrolizumab and chemotherapy and 281 patients received placebo and chemotherapy.[56,57]

At the second interim analysis, the median follow-up was 25.9 months in the pembrolizumab-and-chemotherapy group and 26.3 months in the placebo-and-chemotherapy group. Among patients with CPS of 10 or more, the median PFS was 9.7 months with pembrolizumab and chemotherapy and 5.6 months with placebo and chemotherapy (HRprogression or death, 0.65; 95% CI, 0.49–0.86; one-sided P = .0012 [primary objective met]). Among patients with CPS of 1 or more, the median PFS was 7.6 months with pembrolizumab and chemotherapy and 5.6 months with placebo and chemotherapy (HR, 0.74; 0.61–0.90; one-sided P = .0014 [not significant]). Among the ITT population, the median PFS was 7.5 months and 5.6 months (HR, 0.82; 0.69–0.97 [not tested]). The pembrolizumab treatment effect increased with PD-L1 enrichment.

Based on the PFS data, the FDA approved pembrolizumab and chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10).

At time of final analysis, the median follow-up was 44.1 months. In the group with a CPS of at least 10, the median OS was 23 months in the pembrolizumab-and-chemotherapy group and 16.1 months in the placebo-and-chemotherapy group (HR, 0.73; 95% CI, 0.55–0.95; two-sided P = .0185 [significant]). In the group with a CPS of at least 1, the median survival was not significantly altered (17.6 vs. 16 months; P = .1125).

Grade 3 to 5 treatment-related adverse events occurred in 68.1% of patients in the pembrolizumab group and 66.9% of patients in the placebo group. Two deaths occurred in the pembrolizumab group (acute kidney injury and pneumonia). There were no deaths in the placebo group. Grade 3 to 4 immune-mediated adverse events occurred in 5.3% of patients in the pembrolizumab group, none of which led to death.

IMpassion130 reported PFS data with a median follow-up of 12.9 months.[58]

Sources: 58

IMpassion130 reported PFS data with a median follow-up of 12.9 months.[58]

In the ITT population, PFS was improved with the addition of atezolizumab (median PFS, 7.2 months vs. 5.5 months; HR, 0.80; 95% CI, 0.69–0.92; P = .0025).

In the PD-L1–positive population, PFS was improved with the addition of atezolizumab (median PFS, 7.5 months vs. 5 months; HR, 0.62; 95% CI, 0.49–0.78; P < .001).

Adverse events occurred as expected. Adverse events that were potentially immune-related were more frequent in the atezolizumab arm.

The primary PFS analysis from IMpassion131 revealed that adding atezolizumab to paclitaxel did not improve investigator-assessed PFS in the PD-L1–positive population. The median PFS was 6.0 months for patients who received atezolizumab and paclitaxel compared with 5.7 months for patients who received placebo and paclitaxel (HR, 0.82; 95% CI, 0.60–1.12; P = .20).[60]

Sources: 60

The primary PFS analysis from IMpassion131 revealed that adding atezolizumab to paclitaxel did not improve investigator-assessed PFS in the PD-L1–positive population. The median PFS was 6.0 months for patients who received atezolizumab and paclitaxel compared with 5.7 months for patients who received placebo and paclitaxel (HR, 0.82; 95% CI, 0.60–1.12; P = .20).[60]

The final OS results showed no difference between the treatment arms. The median OS was 22.1 months for patients who received atezolizumab and paclitaxel compared with 28.3 months for patients who received placebo and paclitaxel in the PD-L1–positive population (HR, 1.11; 95% CI, 0.76–1.64).

Results in the ITT population were consistent with the PD-L1–positive population. The safety profile was consistent with known effects of each study drug.

In a phase I/II trial, 108 women with TNBC who received at least two previous chemotherapy regimens (median, three) were treated with sacituzumab govitecan at a dose of 10 mg/kg intravenously on days 1 and 8 of a 21-day cycle.[61][Level of evidence C3]

Sources: 61 · Level of evidence C3

In a phase I/II trial, 108 women with TNBC who received at least two previous chemotherapy regimens (median, three) were treated with sacituzumab govitecan at a dose of 10 mg/kg intravenously on days 1 and 8 of a 21-day cycle.[61][Level of evidence C3]

A response rate of 33.3% (95% CI, 24.6%–43.1%) was observed.

The median duration of response was 7.7 months (95% CI, 4.9–10.8).

The main toxicity was neutropenia, and four deaths occurred during treatment.[61][Level of evidence C3]

Sources: 61 · Level of evidence C3

The FDA granted accelerated approval to sacituzumab govitecan for patients with metastatic TNBC after at least two previous lines of therapy.

A phase III randomized trial (ASCENT [NCT02574455]) confirmed the efficacy of sacituzumab govitecan in patients with metastatic TNBC that was relapsed or refractory to two or more previous chemotherapy regimens. The trial randomly assigned 468 women without brain metastases to receive either sacituzumab govitecan or the physician's choice of single-agent chemotherapy (eribulin, vinorelbine, capecitabine, or gemcitabine). The primary end point was PFS. All patients had previous taxane exposure. Patients received sacituzumab govitecan at a dose of 10 mg/kg intravenously on days 1 and 8 of each 21-day cycle.[62]

Sources: ASCENT · 62

A phase III randomized trial (ASCENT [NCT02574455]) confirmed the efficacy of sacituzumab govitecan in patients with metastatic TNBC that was relapsed or refractory to two or more previous chemotherapy regimens. The trial randomly assigned 468 women without brain metastases to receive either sacituzumab govitecan or the physician's choice of single-agent chemotherapy (eribulin, vinorelbine, capecitabine, or gemcitabine). The primary end point was PFS. All patients had previous taxane exposure. Patients received sacituzumab govitecan at a dose of 10 mg/kg intravenously on days 1 and 8 of each 21-day cycle.[62]

In the chemotherapy arm, 54% of patients received eribulin, 20% received vinorelbine, 13% received capecitabine, and 12% received gemcitabine.

The median PFS was 5.6 months (95% CI, 4.3–6.3; 166 events) in the sacituzumab govitecan arm and 1.7 months (95% CI, 1.5–2.6; 150 events) in the chemotherapy arm (HRdisease progression or death, 0.41; 95% CI, 0.32–0.52; P < .001).[62][Level of evidence A1]

Sources: 62 · Level of evidence A1

The median OS was 12.1 months (95% CI, 10.7–14.0) in the sacituzumab govitecan arm and 6.7 months (95% CI, 5.8–7.7) in the chemotherapy arm (HRdeath, 0.48; 95% CI, 0.38–0.59; P < .001).

The overall response rate was 35% in the sacituzumab govitecan arm and 5% in the chemotherapy arm.

Key treatment-related adverse events of grade 3 or higher occurred more often in patients who received sacituzumab govitecan than patients who received chemotherapy: neutropenia (51% vs. 33%), leukopenia (10% vs. 5%), diarrhea (10% vs. <1%), anemia (8% vs. 5%), and febrile neutropenia (6% vs. 2%).

KEYNOTE-119 (NCT02555657) was a phase III, randomized, open-label, multicenter, international trial that enrolled patients with metastatic TNBC. Patients had received one or two previous systemic treatments for metastatic disease and had previous treatment with an anthracycline or taxane. The trial randomly assigned 622 patients to receive intravenous pembrolizumab 200 mg once every 3 weeks for 35 cycles (pembrolizumab group), or to the investigator's choice of single-drug chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine). The primary end point was OS as assessed in each of the following groups: patients with a PD-L1 CPS of 10 or more, patients with a CPS of 1 or more, and all patients.[63]

Sources: KEYNOTE-119 · 63

KEYNOTE-119 (NCT02555657) was a phase III, randomized, open-label, multicenter, international trial that enrolled patients with metastatic TNBC. Patients had received one or two previous systemic treatments for metastatic disease and had previous treatment with an anthracycline or taxane. The trial randomly assigned 622 patients to receive intravenous pembrolizumab 200 mg once every 3 weeks for 35 cycles (pembrolizumab group), or to the investigator's choice of single-drug chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine). The primary end point was OS as assessed in each of the following groups: patients with a PD-L1 CPS of 10 or more, patients with a CPS of 1 or more, and all patients.[63]

In patients with a PD-L1 CPS of 10 or more, the median OS was 12.7 months (95% CI, 9.9–16.3) in the pembrolizumab group and 11.6 months (95% CI, 8.3–13.7) in the chemotherapy group (HR, 0.78; 95% CI, 0.57–1.06; log-rank P = .057).[63][Level of evidence A1]

Sources: 63 · Level of evidence A1

In patients with a CPS of 1 or more, the median OS was 10.7 months (95% CI, 9.3–12.5) in the pembrolizumab group and 10.2 months (95% CI, 7.9–12.6) in the chemotherapy group (HR, 0.86; 95% CI, 0.69–1.06; log-rank P = .073).

Among all patients, the median OS was 9.9 months (95% CI, 8.3–11.4) in the pembrolizumab group and 10.8 months (95% CI, 9.1–12.6) in the chemotherapy group (HR, 0.97; 95% CI, 0.82–1.15).

In a phase III trial, patients with metastatic disease were randomly assigned to receive either chemotherapy alone (doxorubicin and cyclophosphamide or paclitaxel) or the same chemotherapy plus trastuzumab.[66][Level of evidence A1]

Sources: 66 · Level of evidence A1

In a phase III trial, patients with metastatic disease were randomly assigned to receive either chemotherapy alone (doxorubicin and cyclophosphamide or paclitaxel) or the same chemotherapy plus trastuzumab.[66][Level of evidence A1]

Patients treated with chemotherapy plus trastuzumab had an OS advantage over those who received chemotherapy alone (25.1 months vs. 20.3 months, P = .05).[66][Level of evidence A1]

Sources: 66 · Level of evidence A1

In one randomized study of patients with metastatic breast cancer treated with trastuzumab, paclitaxel, and carboplatin, patients tolerated the combination well and had a longer time to disease progression, compared with those treated with trastuzumab and paclitaxel alone.[68][Level of evidence B1]

Sources: 68 · Level of evidence B1

However, no difference in OS, time to disease progression, or response rate was shown in the Breast Cancer International Research Group’s phase III trial (BCIRG-007 [NCT00047255]) that compared carboplatin and docetaxel plus trastuzumab versus docetaxel plus trastuzumab as first-line chemotherapy for metastatic HER2-overexpressing breast cancer.[69][Level of evidence A1]

Sources: BCIRG-007 · 69 · Level of evidence A1

The phase III CLEOPATRA trial (NCT00567190) assessed the efficacy and safety of pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel, in the first-line HER2-positive metastatic setting.[70,71][Level of evidence A1]

Sources: CLEOPATRA · 70 · 71 · Level of evidence A1

The phase III CLEOPATRA trial (NCT00567190) assessed the efficacy and safety of pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel, in the first-line HER2-positive metastatic setting.[70,71][Level of evidence A1]

With a median follow-up of 50 months, the median OS was 40.8 months in the control group versus 56.5 months in the pertuzumab group (HR favoring pertuzumab group, 0.68; 95% CI, 0.56–0.84; P < .001). Median PFS per investigator assessment was improved by 6.3 months by the addition of pertuzumab (HR, 0.68; 95% CI, 0.58–0.80).

Median OS was 56.5 months in the pertuzumab group compared with 40.8 months in the placebo group (HR, 0.68; 95% CI, 0.57–0.84; P < .001).[71] Eight-year landmark OS rates were 37% with the addition of pertuzumab, compared with 23% in the placebo group.[72]

Sources: 71 · 72

The toxicity profile was similar in both treatment groups, with no increase in cardiac toxic effects seen in the pertuzumab combination arm.

The phase III EMILIA or TDM4370g study (NCT00829166) was a randomized open-label trial that enrolled 991 patients with HER2-overexpressing, unresectable, locally advanced or metastatic breast cancer who were previously treated with trastuzumab and a taxane.[73][Level of evidence A1] Patients were randomly assigned to receive either T-DM1 or lapatinib plus capecitabine.

Sources: EMILIA · 73 · Level of evidence A1

The phase III EMILIA or TDM4370g study (NCT00829166) was a randomized open-label trial that enrolled 991 patients with HER2-overexpressing, unresectable, locally advanced or metastatic breast cancer who were previously treated with trastuzumab and a taxane.[73][Level of evidence A1] Patients were randomly assigned to receive either T-DM1 or lapatinib plus capecitabine.

Median PFS was 9.6 months with T-DM1 versus 6.4 months with lapatinib plus capecitabine (HR, 0.65; 95% CI, 0.55–0.77; P < .001).

Median OS was longer with T-DM1 versus lapatinib plus capecitabine (29.9 months vs. 25.9 months; HR, 0.75 [95% CI, 0.64–0.88]).[74]

Sources: 74

The incidences of thrombocytopenia and increased serum aminotransferase levels were higher in patients who received T-DM1, whereas the incidences of diarrhea, nausea, vomiting, and palmar-plantar syndrome were higher in patients who received lapatinib plus capecitabine.

Further evidence of T-DM1’s activity in metastatic HER2-overexpressed breast cancer was shown in a randomized phase II study of T-DM1 versus trastuzumab plus docetaxel.[75][Level of evidence B1] This trial randomly assigned 137 women with HER2-overexpressed breast cancer in the first-line metastatic setting.

Sources: 75 · Level of evidence B1

Further evidence of T-DM1’s activity in metastatic HER2-overexpressed breast cancer was shown in a randomized phase II study of T-DM1 versus trastuzumab plus docetaxel.[75][Level of evidence B1] This trial randomly assigned 137 women with HER2-overexpressed breast cancer in the first-line metastatic setting.

At median follow-up of 14 months, median PFS was 9.2 months with trastuzumab plus docetaxel and 14.2 months with T-DM1 (HR, 0.59; 95% CI, 0.36–0.97).

Preliminary OS results were similar between treatment arms.

T-DM1 had a favorable safety profile compared with trastuzumab plus docetaxel, with fewer grade 3 adverse events (46.4% vs. 90.9%), adverse events leading to treatment discontinuations (7.2% vs. 40.9%), and serious adverse events (20.3% vs. 25.8%).

Evidence of activity of T-DM1 in heavily pretreated patients with metastatic, HER2-overexpressed breast cancer who had received previous trastuzumab and lapatinib was shown in the randomized phase III TH3RESA study (NCT01419197) of T-DM1 versus physician’s choice of treatment.[76][Level of evidence A1] This trial randomly assigned 602 patients in a 2:1 ratio (404 patients assigned to T-DM1 and 198 patients assigned to physician’s choice) and allowed crossover to T-DM1.

Sources: TH3RESA · 76 · Level of evidence A1

Evidence of activity of T-DM1 in heavily pretreated patients with metastatic, HER2-overexpressed breast cancer who had received previous trastuzumab and lapatinib was shown in the randomized phase III TH3RESA study (NCT01419197) of T-DM1 versus physician’s choice of treatment.[76][Level of evidence A1] This trial randomly assigned 602 patients in a 2:1 ratio (404 patients assigned to T-DM1 and 198 patients assigned to physician’s choice) and allowed crossover to T-DM1.

At a median follow-up of 7.2 months in the T-DM1 group and 6.5 months in the physician’s-choice group, median PFS was 6.2 months in the T-DM1 group and 3.3 months in the physician’s-choice group (HR, 0.528; 95% CI, 0.422–0.661; P < .0001).

OS was significantly longer with trastuzumab emtansine versus the treatment of physician’s choice (median OS, 22.7 months vs. 15.8 months; HR, 0.68; 95% CI, 0.54–0.85; P = .0007).[77]

Sources: 77

The role of T-DM1 as first-line treatment of metastatic HER2-overexpressed breast cancer was evaluated in the phase III MARIANNE trial (NCT01120184).[78][Level of evidence B1] This study randomly assigned 1,095 patients to receive either trastuzumab plus taxane, T-DM1 plus placebo, or T-DM1 plus pertuzumab.

Sources: MARIANNE · 78 · Level of evidence B1

The role of T-DM1 as first-line treatment of metastatic HER2-overexpressed breast cancer was evaluated in the phase III MARIANNE trial (NCT01120184).[78][Level of evidence B1] This study randomly assigned 1,095 patients to receive either trastuzumab plus taxane, T-DM1 plus placebo, or T-DM1 plus pertuzumab.

The median PFS for these treatment groups was 13.7 months for the trastuzumab-plus-taxane group, 14.1 months for the T-DM1-plus-placebo group, and 15.2 months for the T-DM1-plus-pertuzumab group.

There was no significant difference in PFS with T-DM1 plus placebo compared with trastuzumab plus taxane (HR, 0.91; 97.5% CI, 0.73–1.13), or with T-DM1 plus pertuzumab compared with trastuzumab plus taxane (HR, 0.87; 97.5% CI, 0.69–1.08).

Therefore, neither T-DM1 plus placebo nor T-DM1 plus pertuzumab showed PFS superiority over trastuzumab plus taxane.

A phase III, multicenter, open-label, randomized trial (DESTINY-Breast03 [NCT03529110]) compared the efficacy and safety of trastuzumab deruxtecan with trastuzumab emtansine. The study included 524 patients with HER2-positive metastatic breast cancer previously treated with a taxane and trastuzumab. PFS was the primary end point.[79] This trial led to a change in the standard of care for patients with HER2-positive metastatic breast cancer, such that patients with prior taxane/trastuzumab therapy proceed to trastuzumab deruxtecan, rather than trastuzumab emtansine, for second-line therapy.

Sources: DESTINY-Breast03 · 79

A phase III, multicenter, open-label, randomized trial (DESTINY-Breast03 [NCT03529110]) compared the efficacy and safety of trastuzumab deruxtecan with trastuzumab emtansine. The study included 524 patients with HER2-positive metastatic breast cancer previously treated with a taxane and trastuzumab. PFS was the primary end point.[79] This trial led to a change in the standard of care for patients with HER2-positive metastatic breast cancer, such that patients with prior taxane/trastuzumab therapy proceed to trastuzumab deruxtecan, rather than trastuzumab emtansine, for second-line therapy.

At 12 months, 75.8% of patients who received trastuzumab deruxtecan were alive without disease progression, compared with 34.1% of patients who received trastuzumab emtansine (HR, 0.28; 95% CI, 0.22–0.37; P < .001).

Secondary end points were OS, overall response rate, and safety. A total of 94.1% of patients who received trastuzumab deruxtecan were alive at 12 months, compared with 85.9% of patients who received trastuzumab emtansine (HRdeath, 0.55; 95% CI, 0.36–0.86). The overall response rate was 79.7% versus 34.2%, favoring trastuzumab deruxtecan. Grade 3 to 4 drug-related adverse events occurred in 45.1% of patients who received trastuzumab deruxtecan and 38.9% of patients who received trastuzumab emtansine. Interstitial lung disease and pneumonitis occurred in 10.5% of patients who received trastuzumab deruxtecan and 1.9% of patients who received trastuzumab emtansine; none of these events were grade 4 to 5.

The primary PFS analysis from the phase III SOPHIA study (NCT02492711) led to the FDA approval of margetuximab with chemotherapy in patients with HER2-positive metastatic breast cancer who have received as least two previous anti-HER2 regimens, at least one of which was for metastatic disease. The open-label SOPHIA trial randomly assigned 536 patients in the ITT population to receive either margetuximab or trastuzumab. Both groups received investigator's choice of chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine). Eligible patients had disease progression after two or more previous anti-HER2 therapies and one to three lines of therapy for metastatic disease. All patients had received previous trastuzumab, all but one had received previous pertuzumab, and 91.2% had received prior ado-trastuzumab emtansine. The sequential primary end points were PFS by central review followed by OS.[80,81][Level of evidence B1]

Sources: SOPHIA · 80 · 81 · Level of evidence B1

The primary PFS analysis from the phase III SOPHIA study (NCT02492711) led to the FDA approval of margetuximab with chemotherapy in patients with HER2-positive metastatic breast cancer who have received as least two previous anti-HER2 regimens, at least one of which was for metastatic disease. The open-label SOPHIA trial randomly assigned 536 patients in the ITT population to receive either margetuximab or trastuzumab. Both groups received investigator's choice of chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine). Eligible patients had disease progression after two or more previous anti-HER2 therapies and one to three lines of therapy for metastatic disease. All patients had received previous trastuzumab, all but one had received previous pertuzumab, and 91.2% had received prior ado-trastuzumab emtansine. The sequential primary end points were PFS by central review followed by OS.[80,81][Level of evidence B1]

Margetuximab improved primary PFS over trastuzumab with a 24% relative risk reduction (HR, 0.76; 95% CI, 0.59–0.98; P = .03) (median PFS, 5.8 months vs. 4.9 months, favoring margetuximab).

The median follow-up was 20.2 months. The median OS in the ITT population was not statistically different between the two treatment groups: 21.6 months in the margetuximab group and 21.9 months in the trastuzumab group (HR, 0.95; 95% CI, 0.77–1.17; P = .620).

Grade 3 or higher adverse events that occurred in at least 5% of patients included decreased neutrophil count and anemia in both groups, fatigue in the margetuximab group, and febrile neutropenia in the trastuzumab group.

The HER2CLIMB trial (NCT02614794) compared trastuzumab, capecitabine, and tucatinib with trastuzumab, capecitabine, and placebo in 632 patients who had previously been treated with trastuzumab, pertuzumab, and trastuzumab emtansine. Patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients with and without brain metastases were included. The primary end point was PFS.[82][Level of evidence A1]

Sources: HER2CLIMB · 82 · Level of evidence A1

The HER2CLIMB trial (NCT02614794) compared trastuzumab, capecitabine, and tucatinib with trastuzumab, capecitabine, and placebo in 632 patients who had previously been treated with trastuzumab, pertuzumab, and trastuzumab emtansine. Patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients with and without brain metastases were included. The primary end point was PFS.[82][Level of evidence A1]

The median PFS was 7.8 months in the tucatinib combination group and 5.6 months in the placebo combination group (HR, 0.54; 95% CI, 0.42–0.71; P < .001)

In an interim analysis conducted at the time of the PFS analysis, median OS was 21.9 months in the tucatinib combination group and 17.4 months in the placebo combination group (HR, 0.66; 95% CI, 0.50–0.88; P = .005)

Patients with and without brain metastases benefited from the tucatinib combination.

Grade 3 adverse events including diarrhea, palmar-plantar erythrodysesthesia syndrome, and elevated aminotransferase levels were more common in the tucatinib combination group but occurred in fewer than 15% of patients.

In the phase III NALA trial (NCT01808573), neratinib and capecitabine were compared with lapatinib and capecitabine in 621 patients with HER2-positive metastatic breast cancer who received two or more HER2-directed regimens in the metastatic setting. PFS and OS were co-primary end points. Secondary end points were time to intervention for metastatic central nervous system (CNS) disease and duration of response. Patients with stable or asymptomatic CNS disease were included.[83][Level of evidence B1]

Sources: NALA · 83 · Level of evidence B1

In the phase III NALA trial (NCT01808573), neratinib and capecitabine were compared with lapatinib and capecitabine in 621 patients with HER2-positive metastatic breast cancer who received two or more HER2-directed regimens in the metastatic setting. PFS and OS were co-primary end points. Secondary end points were time to intervention for metastatic central nervous system (CNS) disease and duration of response. Patients with stable or asymptomatic CNS disease were included.[83][Level of evidence B1]

Patients who received neratinib and capecitabine had significantly improved PFS (HR, 0.76; 95% CI, 0.63–0.93). OS between the two arms was not different.

The cumulative incidence of intervention for CNS disease was 22.8% (95% CI, 15.5%–30.9%) for patients who received neratinib versus 29.2% (95% CI, 22.5%–36.1%) for patients who received lapatinib.

Duration of response was 8.5 months for patients who received neratinib versus 5.6 months for patients who received lapatinib.

Diarrhea, nausea, palmar-plantar erythrodysesthesia, and vomiting were the most common adverse events, with grade 3 diarrhea occurring in 24.4% of patients who received neratinib. Antidiarrheal medications were required in the neratinib arm and used by 98.3% of those patients.

Quality-of-life scores were similar between the two groups.

A nonblinded randomized trial (GSK-EGF100151 [NCT00078572]) compared the combination of capecitabine and lapatinib with capecitabine alone in 324 patients with locally advanced or metastatic disease that progressed after therapies that included anthracyclines, taxanes, and trastuzumab.[84][Level of evidence A1]

Sources: GSK-EGF100151 · 84 · Level of evidence A1

A nonblinded randomized trial (GSK-EGF100151 [NCT00078572]) compared the combination of capecitabine and lapatinib with capecitabine alone in 324 patients with locally advanced or metastatic disease that progressed after therapies that included anthracyclines, taxanes, and trastuzumab.[84][Level of evidence A1]

Median time-to-disease progression in the lapatinib-plus-capecitabine arm was 8.4 months compared with 4.4 months in the capecitabine-alone arm (HR, 0.49; 95% CI, 0.34–0.71; P < .001).

There was no difference in OS (HR, 0.92; 95% CI, 0.58–1.46; P = .72).[84][Level of evidence A1]

Sources: 84 · Level of evidence A1

Patients on combination therapy were more likely to develop diarrhea, rash, and dyspepsia. For more information, see the Diarrhea section in Gastrointestinal Complications.

Sources: Diarrhea

No data are available on quality of life or treatment after disease progression.

In the BOLERO-3 trial, 569 patients with HER2-positive, trastuzumab-resistant, breast cancer, who had received previous taxane therapy, were randomly assigned to receive either everolimus plus trastuzumab plus vinorelbine, or placebo plus trastuzumab plus vinorelbine.[85][Level of evidence B1]

Sources: 85 · Level of evidence B1

In the BOLERO-3 trial, 569 patients with HER2-positive, trastuzumab-resistant, breast cancer, who had received previous taxane therapy, were randomly assigned to receive either everolimus plus trastuzumab plus vinorelbine, or placebo plus trastuzumab plus vinorelbine.[85][Level of evidence B1]

At median follow-up of 20.2 months, median PFS was 7.0 months in the everolimus group versus 5.78 months in the placebo group (HR, 0.78; 95% CI, 0.65–0.95; P = .0067).

Serious adverse events were reported in 117 patients (42%) in the everolimus group and 55 patients (20%) in the placebo group.

Final OS outcomes for this trial have not yet been reported.

The OlympiAD trial (NCT02000622) was a randomized, open-label, phase III trial that randomly assigned 302 patients, in a 2:1 ratio, to receive olaparib (300 mg bid) or standard therapy (either single-agent capecitabine, eribulin, or vinorelbine).[86] All patients had received anthracycline and taxane previously in either the adjuvant or metastatic setting, and those with hormone receptor–positive disease had also received endocrine therapy previously.

Sources: OlympiAD · 86

The OlympiAD trial (NCT02000622) was a randomized, open-label, phase III trial that randomly assigned 302 patients, in a 2:1 ratio, to receive olaparib (300 mg bid) or standard therapy (either single-agent capecitabine, eribulin, or vinorelbine).[86] All patients had received anthracycline and taxane previously in either the adjuvant or metastatic setting, and those with hormone receptor–positive disease had also received endocrine therapy previously.

Median PFS was significantly longer in the olaparib group than in the standard therapy group (7.0 months vs. 4.2. months; HRdisease progression or death, 0.58; 95% CI, 0.43–0.80; P < .001).[86][Level of evidence A1]

Sources: 86 · Level of evidence A1

OS did not differ between the two treatment groups with median time to death (HRdeath, 0.90; 95% CI, 0.63–1.29; P = .57).

Olaparib was less toxic than standard therapy, with a rate of grade 3 or higher adverse events of 36.6% in the olaparib group and 50.5% in the standard therapy group, with anemia, nausea, vomiting, fatigue, headache, and cough occurring more frequently with olaparib; neutropenia, palmar-plantar erythrodysesthesia, and liver-function test abnormalities occurred more commonly with chemotherapy.

Of note, subset analysis suggested that PFS improvement with olaparib appeared greater in the TNBC subgroup (HR, 0.43; 95% CI, 0.29–0.63) than in the hormone receptor–positive subgroup (HR, 0.82; 95% CI, 0.55–1.26).

The EMBRACA trial (NCT01945775) was a randomized, open label, phase III trial that assigned 431 patients with germline BRCA1 or BRCA2 pathogenic variants and locally advanced or metastatic breast cancer in a 2:1 ratio to talazoparib (1 mg PO qd) or standard single-agent chemotherapy of the physician’s choice (eribulin, capecitabine, gemcitabine, or vinorelbine).[87] All patients had received previous treatment with an anthracycline, taxane, or both. Patients had received three or fewer lines of cytotoxic chemotherapy for advanced breast cancer. Previous platinum therapy in the setting of early breast cancer was permitted if it was completed at least 6 months before progressive disease or if there was no objective progression while on platinum therapy in the advanced-disease setting. Hormone receptor–positive and hormone receptor–negative patients were enrolled.

Sources: EMBRACA · 87

The EMBRACA trial (NCT01945775) was a randomized, open label, phase III trial that assigned 431 patients with germline BRCA1 or BRCA2 pathogenic variants and locally advanced or metastatic breast cancer in a 2:1 ratio to talazoparib (1 mg PO qd) or standard single-agent chemotherapy of the physician’s choice (eribulin, capecitabine, gemcitabine, or vinorelbine).[87] All patients had received previous treatment with an anthracycline, taxane, or both. Patients had received three or fewer lines of cytotoxic chemotherapy for advanced breast cancer. Previous platinum therapy in the setting of early breast cancer was permitted if it was completed at least 6 months before progressive disease or if there was no objective progression while on platinum therapy in the advanced-disease setting. Hormone receptor–positive and hormone receptor–negative patients were enrolled.

Median PFS was significantly longer in the talazoparib group than in the standard therapy group (8.6 months vs. 5.6 months; HRdisease progression or death, 0.54; 95% CI, 0.41–0.71; P < .001).

Benefits were observed in all subgroups, although CIs were wide in the subgroup of patients who had received previous platinum therapy.

Median OS did not differ between the two groups (22.3 months vs. 19.5 months; HRdeath, 0.76; 95% CI, 0.55–1.06; P = .11), although survival data are not yet mature.

The primary toxicity observed with talazoparib was myelosuppression, especially anemia.

Patient-reported outcome data demonstrated more favorable effects of talazoparib than standard chemotherapy on quality-of-life measures.[88]

Sources: 88

The FDA approved pembrolizumab for the treatment of metastatic solid tumors with a TMB of at least 10 Mut/Mb, based on the KEYNOTE-158 trial.[90]

Sources: 90

The FDA approved pembrolizumab for the treatment of metastatic solid tumors with a TMB of at least 10 Mut/Mb, based on the KEYNOTE-158 trial.[90]

KEYNOTE-158 (NCT02628067) was a multicohort, open-label, nonrandomized, phase II multinational study. Patients had metastatic solid malignancies, treated with at least one previous line of therapy. Participants received pembrolizumab 200 mg intravenously every 3 weeks for up to 35 cycles. TMB was assessed in formalin-fixed paraffin-embedded tumor samples using the FoundationOne CDx assay. A total of 105 of 805 evaluable patients had high TMB (≥10 Mut/Mb).

Sources: KEYNOTE-158

The primary outcome was objective response rate. Objective responses were observed in 30 of 102 patients (29%) in the TMB-high group and 43 of 688 patients (6%) in the non-TMB-high group. Grade 3 to 5 treatment-related adverse events occurred in 16 patients. One patient died of pneumonia that was assessed by the investigator to be treatment related.

The TAPUR study (NCT02693535) was a phase II basket trial done to identify the efficacy of commercially available targeted agents in patients with advanced cancers and genomic alterations known to be drug targets. TAPUR results from patients with metastatic breast cancer and high TMB have been reported. The primary end point was disease control (objective response or stable disease for ≥16 weeks).[91][Level of evidence C3]

Sources: TAPUR · 91 · Level of evidence C3

The TAPUR study (NCT02693535) was a phase II basket trial done to identify the efficacy of commercially available targeted agents in patients with advanced cancers and genomic alterations known to be drug targets. TAPUR results from patients with metastatic breast cancer and high TMB have been reported. The primary end point was disease control (objective response or stable disease for ≥16 weeks).[91][Level of evidence C3]

The study enrolled 28 patients with metastatic breast cancer and high TMB. TMB ranged from 9 to 37 Mut/Mb.

Disease control was noted in 37% of patients, with objective response noted in 21% of patients.

The median PFS was 10.6 weeks and the median OS was 30.6 weeks.

Anthracyclines.

Anthracyclines.

Doxorubicin.

Epirubicin.

Liposomal doxorubicin.[93-96]

Sources: 93 · 96

Mitoxantrone.

Taxanes.

Taxanes.

Paclitaxel.[97,98]

Sources: 97 · 98

Docetaxel.

Albumin-bound nanoparticle paclitaxel (ABI-007 or Abraxane).[99,100]

Sources: 99 · 100

Alkylating agents.

Alkylating agents.

Cyclophosphamide.

Fluoropyrimidines.

Fluoropyrimidines.

Capecitabine.[101-103]

Sources: 101 · 103

Fluorouracil (5-FU).

Antimetabolites.

Antimetabolites.

Methotrexate.

Vinca alkaloids.

Vinca alkaloids.

Vinorelbine.[104]

Sources: 104

Vinblastine.

Vincristine.

Platinum.

Platinum.

Carboplatin.

Cisplatin.

Other.

Other.

Gemcitabine.[105]

Sources: 105

Mitomycin.

Eribulin mesylate.[106,107]

Sources: 106 · 107

Ixabepilone.[108]

Sources: 108

AC: Doxorubicin and cyclophosphamide.[109]

Sources: 109

EC: Epirubicin and cyclophosphamide.[110]

Sources: 110

Docetaxel and doxorubicin.[111]

Sources: 111

CAF: Cyclophosphamide, doxorubicin, and 5-FU.[112]

Sources: 112

CMF: Cyclophosphamide, methotrexate, and 5-FU.[113]

Sources: 113

Doxorubicin and paclitaxel.[114,115]

Sources: 114 · 115

Docetaxel and capecitabine.[116]

Sources: 116

Vinorelbine and epirubicin.[117]

Sources: 117

Capecitabine and ixabepilone.[118]

Sources: 118

Carboplatin and gemcitabine.[119]

Sources: 119

Gemcitabine and paclitaxel.[120]

Sources: 120

Rate of disease progression.

Presence or absence of comorbid medical conditions.

Physician/patient preference.

Patient preference and goals of treatment.

Presence of toxicities from previous therapies.

Availability of alternative treatment options.

Advanced age.

Previous chest-wall radiation therapy.

Previous anthracycline exposure.

Hypertension and known underlying heart disease.

Diabetes.

The 3-year OS was 67.9% in the systemic therapy group and 68.4% in the locoregional therapy group (HR, 1.11; 90% CI, 0.82–1.52; P = .57). The median OS was 53.1 months (95% CI, 47.9–not estimable) in the systemic therapy group and 54.9 months (95% CI, 46.7–not estimable) in the locoregional therapy group.

Locoregional disease progression was less frequent in patients who received locoregional therapy (3-year locoregional progression rate, 16.3% vs. 39.8%; P < .001).

Fungating/painful breast lesions (mastectomy).

Parenchymal brain or vertebral metastases with spinal cord compression.

Pathological (or impending) fractures.

Pleural or pericardial effusions.

Painful bony metastases.

Unresectable central nervous system metastases (i.e., brain, meninges, and spinal cord).

Bronchial obstruction.

Fungating/painful breast or chest wall lesions.

After surgery for decompression of intracranial or spinal cord metastases.

After fixation of pathological fractures.

Micropapillary.

Papillary.

Solid.

Cribriform.

Comedo.

Breast-conserving surgery or mastectomy plus radiation therapy with or without tamoxifen.

Total mastectomy with or without tamoxifen.

Of the 818 women enrolled in the NSABP-B-17 trial, 80% were diagnosed by mammography, and 70% of the patients' lesions were 1 cm or smaller. Results were reported at the 12-year actuarial follow-up interval.[7]; [9][Level of evidence B1]

Sources: 7 · 9 · Level of evidence B1

Of the 818 women enrolled in the NSABP-B-17 trial, 80% were diagnosed by mammography, and 70% of the patients' lesions were 1 cm or smaller. Results were reported at the 12-year actuarial follow-up interval.[7]; [9][Level of evidence B1]

The overall rate of in-breast tumor recurrence was reduced from 31.7% to 15.7% when radiation therapy was delivered (P < .005).

Radiation therapy reduced the occurrence of invasive cancer from 16.8% to 7.7% (P = .001) and recurrent DCIS from 14.6% to 8.0% (P = .001).

Nine pathological features were evaluated for their ability to predict for in-breast recurrence, but only comedo necrosis was a significant predictor for recurrence.

Similarly, of the 1,010 patients enrolled in the EORTC-10853 trial, mammography detected lesions in 71% of the women. Results were reported at a median follow-up of 10.5 years.[9][Level of evidence B1]In both studies, the effect of radiation therapy was consistent across all assessed risk factors.

Sources: 9 · Level of evidence B1

Similarly, of the 1,010 patients enrolled in the EORTC-10853 trial, mammography detected lesions in 71% of the women. Results were reported at a median follow-up of 10.5 years.[9][Level of evidence B1]In both studies, the effect of radiation therapy was consistent across all assessed risk factors.

The overall rate of in-breast tumor recurrence was reduced from 26% to 15% (P < .001), with a similarly effective reduction of invasive recurrence rates (13% to 8%, P = .065) and noninvasive recurrence rates (14% to 7%, P = .001).

In this analysis, parameters associated with an increased risk of in-breast recurrence included age 40 years or younger, palpable disease, intermediate or poorly differentiated DCIS, cribriform or solid growth pattern, and indeterminate margins. Elsewhere, margins of less than 1 mm have been associated with an unacceptable local recurrence rate, even with radiation therapy.[10]

Sources: 10

The benefit of administering radiation therapy has been confirmed in a systematic review of four randomized trials (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.41–0.58; P < .00001). In this study, the number needed to treat with radiation therapy was nine women to prevent one ipsilateral breast recurrence.[11]

Sources: 11

A large national clinical trial by the Radiation Therapy Oncology Group (RTOG-9804 [NCT00003857]) comparing breast-conserving surgery and tamoxifen with or without radiation therapy was closed because of poor accrual (636 of planned 1,790 patients accrued). Patients with good-risk DCIS (defined as mammographically detected low- or intermediate-grade DCIS, measuring <2.5 cm with margins of ≥3 mm) were enrolled.[12]

Sources: RTOG-9804 · 12

A large national clinical trial by the Radiation Therapy Oncology Group (RTOG-9804 [NCT00003857]) comparing breast-conserving surgery and tamoxifen with or without radiation therapy was closed because of poor accrual (636 of planned 1,790 patients accrued). Patients with good-risk DCIS (defined as mammographically detected low- or intermediate-grade DCIS, measuring <2.5 cm with margins of ≥3 mm) were enrolled.[12]

The 15-year cumulative incidence of in-breast recurrence was 7.1% (95% CI, 4.0%–11.5%) with radiation therapy versus 15.1% (95% CI, 10.8%–20.2%) with observation (HR, 0.36; 95% CI, 0.20–0.66; P = .0007). On multivariable analysis, only radiation therapy (HR, 0.34; 95% CI, 0.19–0.64; P = .0007) and tamoxifen use (HR, 0.45; 95% CI, 0.25–0.78; P = .0047) were associated with reduced in-breast recurrence.[13]

Sources: 13

In NSABP-B-24, 1,804 women were randomly assigned to receive breast-conserving surgery, radiation therapy (50 Gy), and placebo or breast-conserving surgery, radiation therapy, and tamoxifen (20 mg qd for 5 years).[21] Positive or unknown surgical margins were present in 23% of patients. Approximately 80% of the lesions measured 1 cm or smaller, and more than 80% were detected mammographically. Breast cancer events were defined as the presence of new ipsilateral disease, contralateral disease, or metastases.

Sources: 21

In NSABP-B-24, 1,804 women were randomly assigned to receive breast-conserving surgery, radiation therapy (50 Gy), and placebo or breast-conserving surgery, radiation therapy, and tamoxifen (20 mg qd for 5 years).[21] Positive or unknown surgical margins were present in 23% of patients. Approximately 80% of the lesions measured 1 cm or smaller, and more than 80% were detected mammographically. Breast cancer events were defined as the presence of new ipsilateral disease, contralateral disease, or metastases.

Women in the tamoxifen group had fewer breast cancer events at 5 years than did those treated with a placebo (8.2% vs. 13.4%; P = .009).[21][Level of evidence B1]

Sources: 21 · Level of evidence B1

With tamoxifen, ipsilateral invasive breast cancer decreased from 4.2% to 2.1% at 5 years (P = .03).

Tamoxifen also decreased the incidence of contralateral breast neoplasms (invasive and noninvasive) from 0.8% per year to 0.4% per year (P = .01).

The benefit of tamoxifen extended to patients with positive or uncertain margins.[22] For more information, see Breast Cancer Prevention.

Sources: 22 · Breast Cancer Prevention

No survival advantage was demonstrated for the use of tamoxifen.

In the NSABP-B35 double-blind study, 3,104 postmenopausal women with DCIS who were treated with breast-conserving surgery were randomly assigned to receive either adjuvant tamoxifen or anastrozole, in addition to adjuvant radiation therapy.

In the NSABP-B35 double-blind study, 3,104 postmenopausal women with DCIS who were treated with breast-conserving surgery were randomly assigned to receive either adjuvant tamoxifen or anastrozole, in addition to adjuvant radiation therapy.

The use of anastrozole was associated with significantly fewer breast cancer events (HR, 0.73; P = .023) but no improvement in survival.[23][Level of evidence B1]

Sources: 23 · Level of evidence B1

The Second International Breast Cancer Intervention Study (IBIS II DCIS [NCT00078832]) enrolled 2,980 postmenopausal women in a double-blind comparison of tamoxifen with anastrozole as adjuvant therapy. All of the women had breast-conserving surgery, and 71% of them had radiation therapy.[24]

Sources: IBIS II DCIS · 24

The Second International Breast Cancer Intervention Study (IBIS II DCIS [NCT00078832]) enrolled 2,980 postmenopausal women in a double-blind comparison of tamoxifen with anastrozole as adjuvant therapy. All of the women had breast-conserving surgery, and 71% of them had radiation therapy.[24]

No difference in the rate of breast cancer recurrence in favor of anastrozole was found (HR, 0.89; 95% CI, 0.64–1.23; P = .49), and there was no difference in survival.

Surgery for Breast Cancer Learn about surgery to treat breast cancer and access more information about lumpectomy and mastectomy, the two main types of surgery used.

Sources: Surgery for Breast Cancer

Radiation for Breast Cancer You may receive radiation therapy as part of your breast cancer treatment. Learn about the types of radiation therapy and possible side effects.

Sources: Radiation for Breast Cancer

Chemotherapy for Breast Cancer Not everyone with breast cancer will get chemotherapy. Learn about who gets chemo and why and find a list of drugs that may be prescribed.

Sources: Chemotherapy for Breast Cancer

Hormone Therapy for Breast Cancer Hormone therapy helps lower the risk of recurrence of certain types of breast cancer. Learn about types of hormone therapy, common side effects, and more.

Sources: Hormone Therapy for Breast Cancer

Immunotherapy for Breast Cancer Immunotherapy may be used to treat triple-negative breast cancer. Learn about immunotherapy, when it is given, and common side effects.

Sources: Immunotherapy for Breast Cancer

Targeted Therapy for Breast Cancer Targeted therapy is a treatment for certain types of breast cancer. Learn about types of targeted therapy, common side effects, and more.

Sources: Targeted Therapy for Breast Cancer

Breast Cancer Treatment by Stage The stage of breast cancer is an important factor in determining which type of treatment may work best for you. Learn more about treatment options for breast cancer by stage.

Sources: Breast Cancer Treatment by Stage

Breast Cancer During Pregnancy Learn about breast cancer during pregnancy, including challenges in detection and options for treatment in women who are pregnant or breastfeeding.

Sources: Breast Cancer During Pregnancy

Ductal Carcinoma in Situ (DCIS) DCIS is diagnosed when abnormal cells are found in the milk ducts of the breast. Learn more about DCIS, including treatment options and prognosis.

Sources: Ductal Carcinoma in Situ (DCIS)

Inflammatory Breast Cancer Treatment Inflammatory breast cancer treatments may include surgery, radiation therapy, chemotherapy, and more. Learn about the different ways inflammatory breast cancer can be treated.

Sources: Inflammatory Breast Cancer Treatment

Triple-Negative Breast Cancer Treatment Triple-negative breast cancer treatments may include surgery, chemotherapy, and more. Learn about the different ways triple-negative breast cancer can be treated.

Sources: Triple-Negative Breast Cancer Treatment

Paget Disease of the Breast Paget disease of the breast involves the nipple and areola. Learn about symptoms, diagnosis, and treatment of this rare type of breast cancer.

Sources: Paget Disease of the Breast

the type of breast cancer you have

whether you have started menopause

Sources: menopause

whether you are pregnant

your age and general health

your preferences

Surgery. Lumpectomy (breast-conserving surgery) is often used, but mastectomy may be recommended if the tumor is large or cancer is found in multiple areas of the breast or chest. The surgeon may also remove the underarm lymph node closest to the tumor in a procedure called sentinel lymph node biopsy. Learn more about Breast Cancer Surgery and Sentinel Lymph Node Biopsy.

Sources: Lumpectomy · mastectomy · lymph node · sentinel lymph node biopsy · Breast Cancer Surgery · Sentinel Lymph Node Biopsy

Radiation therapy. After surgery, you will likely have radiation therapy to the breast or the chest wall where the breast was removed to reduce the chance of breast cancer returning in the breast or the chest wall. However, you may not need radiation therapy if you have a mastectomy. Learn more about Radiation Therapy for Breast Cancer.

Sources: Radiation Therapy for Breast Cancer

Chemotherapy. You are more likely to receive chemotherapy if the tumor is high grade, in the lymph nodes, HER2-positive, or triple-negative. Whether chemotherapy is given before or after surgery depends on the size and location of the tumor and other factors. Learn more about Chemotherapy for Breast Cancer.

Sources: high grade · HER2 · triple-negative · Chemotherapy for Breast Cancer

Hormone therapy. If the cancer tests positive for estrogen receptor and/or progesterone receptor, or when the hormone receptor status of the cancer is unknown, you may receive hormone therapy as part of your treatment. Hormone therapy for breast cancer may begin before or after surgery. If you are premenopausal, you might also have treatment to stop the ovaries from making hormones. Learn more about Hormone Therapy for Breast Cancer.

Sources: estrogen receptor · progesterone receptor · hormone receptor status · Hormone Therapy for Breast Cancer

Immunotherapy. This cancer treatment is only used to treat triple-negative breast cancer. Learn about this type of cancer and how it is treated at Triple-Negative Breast Cancer and Immunotherapy for Breast Cancer.

Sources: Triple-Negative Breast Cancer · Immunotherapy for Breast Cancer

Targeted therapy. If biomarker tests suggest that the cancer is HER2-positive, hormone-receptor positive, or has a BRCA1 or BRCA2 mutation, you may receive targeted therapy. Targeted therapy for breast cancer may be given at different times in your treatment. It might be started before or after surgery. It can also be given even if surgery is not recommended for you. Learn more about Targeted Therapy for Breast Cancer.

Sources: biomarker tests · Targeted Therapy for Breast Cancer

high-grade breast cancer (grade 3)

Sources: high-grade

breast cancer that has spread to the lymph nodes

Sources: lymph nodes

triple-negative breast cancer

Sources: triple-negative breast cancer

inflammatory breast cancer

Sources: inflammatory breast cancer

high-grade breast cancer (grade 3)

breast cancer that has spread to the lymph nodes

a large breast cancer

HER2-positive breast cancer

Sources: HER2-positive

triple-negative breast cancer

inflammatory breast cancer

anthracyclines, such as doxorubicin, liposomal doxorubicin, and epirubicin

Sources: anthracyclines · doxorubicin · liposomal doxorubicin · epirubicin

capecitabine

Sources: capecitabine

cyclophosphamide

Sources: cyclophosphamide

eribulin

Sources: eribulin

fluorouracil (5-FU)

Sources: fluorouracil (5-FU)

gemcitabine

Sources: gemcitabine

ixabepilone

Sources: ixabepilone

methotrexate

Sources: methotrexate

platinum agents, such as cisplatin or carboplatin

Sources: cisplatin · carboplatin

taxanes, such as paclitaxel, docetaxel, and albumin-bound paclitaxel

Sources: taxanes · paclitaxel · docetaxel · albumin-bound paclitaxel

HER2-positive breast cancer may be treated with both chemotherapy and targeted therapy, such as trastuzumab and pertuzumab. Learn more about these drugs at Targeted Therapy for Breast Cancer.

Sources: targeted therapy · trastuzumab · pertuzumab · Targeted Therapy for Breast Cancer

Triple-negative breast cancer may be treated with both chemotherapy and the immunotherapy drug pembrolizumab. Learn more about Triple-Negative Breast Cancer Treatment.

Sources: immunotherapy · pembrolizumab · Triple-Negative Breast Cancer Treatment

Hormone receptor–positive breast cancer may be treated with both chemotherapy and hormone therapy. Learn more about Hormone Therapy for Breast Cancer.

Sources: Hormone receptor–positive · hormone therapy · Hormone Therapy for Breast Cancer

goserelin

Sources: goserelin

leuprolide

Sources: leuprolide

anastrozole

Sources: anastrozole

letrozole

Sources: letrozole

exemestane

Sources: exemestane

Selective estrogen receptor modulators (SERMs) bind to estrogen receptors. In breast cells, SERMs block the effects of estrogen, but in some other cells, such as bone, SERMs act like estrogen. SERMs used to treat breast cancer include:

Selective estrogen receptor modulators (SERMs) bind to estrogen receptors. In breast cells, SERMs block the effects of estrogen, but in some other cells, such as bone, SERMs act like estrogen. SERMs used to treat breast cancer include:

tamoxifen, which is used in both premenopausal and postmenopausal women

Sources: tamoxifen

toremifene, which is used only in postmenopausal women

Sources: toremifene

Selective estrogen receptor degraders (SERDs), sometimes called pure antiestrogens, bind strongly to estrogen receptors. In addition to blocking the effects of estrogen, they destroy estrogen receptors. Fulvestrant is a SERD approved to treat breast cancer. It is used only in postmenopausal women.

Sources: Fulvestrant

tamoxifen

toremifene

fulvestrant

anastrozole

letrozole

exemestane

quinidine, which is used to treat abnormal heart rhythms

diphenhydramine, which is an antihistamine

Sources: diphenhydramine · antihistamine

cimetidine, which is used to reduce stomach acid

Sources: cimetidine