Trastuzumab

The Herceptin Adjuvant (HERA) (BIG-01-01 [NCT00045032]) trial examined the efficacy of trastuzumab as adjuvant treatment for HER2-positive breast cancer if used after completion of the primary treatment. For most patients, primary treatment consisted of an anthracycline-containing chemotherapy regimen given preoperatively or postoperatively, with or without locoregional radiation therapy. Trastuzumab was given every 3 weeks starting within 7 weeks of the completion of primary treatment.[128][Level of evidence A1] Patients were randomly assigned to one of three study arms:Of the patients in the group comparing 1 year of trastuzumab versus observation, the median age was 49 years, about 33% had node-negative disease, and nearly 50% had hormone receptor–negative disease.[129]The following results were observed for patients assigned to 1 year of trastuzumab versus patients assigned to observation:The following results were observed for patients assigned to 1 year of trastuzumab versus patients assigned to 2 years of trastuzumab:Symptomatic cardiac events occurred in 1% of the patients who received trastuzumab and in 0.1% of the observation group.

The Herceptin Adjuvant (HERA) (BIG-01-01 [NCT00045032]) trial examined the efficacy of trastuzumab as adjuvant treatment for HER2-positive breast cancer if used after completion of the primary treatment. For most patients, primary treatment consisted of an anthracycline-containing chemotherapy regimen given preoperatively or postoperatively, with or without locoregional radiation therapy. Trastuzumab was given every 3 weeks starting within 7 weeks of the completion of primary treatment.[128][Level of evidence A1] Patients were randomly assigned to one of three study arms:Of the patients in the group comparing 1 year of trastuzumab versus observation, the median age was 49 years, about 33% had node-negative disease, and nearly 50% had hormone receptor–negative disease.[129]The following results were observed for patients assigned to 1 year of trastuzumab versus patients assigned to observation:The following results were observed for patients assigned to 1 year of trastuzumab versus patients assigned to 2 years of trastuzumab:Symptomatic cardiac events occurred in 1% of the patients who received trastuzumab and in 0.1% of the observation group.

Observation (n = 1,693).

The Herceptin Adjuvant (HERA) (BIG-01-01 [NCT00045032]) trial examined the efficacy of trastuzumab as adjuvant treatment for HER2-positive breast cancer if used after completion of the primary treatment. For most patients, primary treatment consisted of an anthracycline-containing chemotherapy regimen given preoperatively or postoperatively, with or without locoregional radiation therapy. Trastuzumab was given every 3 weeks starting within 7 weeks of the completion of primary treatment.[128][Level of evidence A1] Patients were randomly assigned to one of three study arms:Of the patients in the group comparing 1 year of trastuzumab versus observation, the median age was 49 years, about 33% had node-negative disease, and nearly 50% had hormone receptor–negative disease.[129]The following results were observed for patients assigned to 1 year of trastuzumab versus patients assigned to observation:The following results were observed for patients assigned to 1 year of trastuzumab versus patients assigned to 2 years of trastuzumab:Symptomatic cardiac events occurred in 1% of the patients who received trastuzumab and in 0.1% of the observation group.

1 year of trastuzumab (n = 1,694).

The Herceptin Adjuvant (HERA) (BIG-01-01 [NCT00045032]) trial examined the efficacy of trastuzumab as adjuvant treatment for HER2-positive breast cancer if used after completion of the primary treatment. For most patients, primary treatment consisted of an anthracycline-containing chemotherapy regimen given preoperatively or postoperatively, with or without locoregional radiation therapy. Trastuzumab was given every 3 weeks starting within 7 weeks of the completion of primary treatment.[128][Level of evidence A1] Patients were randomly assigned to one of three study arms:Of the patients in the group comparing 1 year of trastuzumab versus observation, the median age was 49 years, about 33% had node-negative disease, and nearly 50% had hormone receptor–negative disease.[129]The following results were observed for patients assigned to 1 year of trastuzumab versus patients assigned to observation:The following results were observed for patients assigned to 1 year of trastuzumab versus patients assigned to 2 years of trastuzumab:Symptomatic cardiac events occurred in 1% of the patients who received trastuzumab and in 0.1% of the observation group.

2 years of trastuzumab (n = 1,694).

The Herceptin Adjuvant (HERA) (BIG-01-01 [NCT00045032]) trial examined the efficacy of trastuzumab as adjuvant treatment for HER2-positive breast cancer if used after completion of the primary treatment. For most patients, primary treatment consisted of an anthracycline-containing chemotherapy regimen given preoperatively or postoperatively, with or without locoregional radiation therapy. Trastuzumab was given every 3 weeks starting within 7 weeks of the completion of primary treatment.[128][Level of evidence A1] Patients were randomly assigned to one of three study arms:Of the patients in the group comparing 1 year of trastuzumab versus observation, the median age was 49 years, about 33% had node-negative disease, and nearly 50% had hormone receptor–negative disease.[129]The following results were observed for patients assigned to 1 year of trastuzumab versus patients assigned to observation:The following results were observed for patients assigned to 1 year of trastuzumab versus patients assigned to 2 years of trastuzumab:Symptomatic cardiac events occurred in 1% of the patients who received trastuzumab and in 0.1% of the observation group.

After a median follow-up of 11 years,[129] 1 year of trastuzumab improved DFS (10-year DFS rate, 72% vs. 66%; HR, 0.76; 95% CI, 0.68–0.86; P < .0001), despite a crossover of 52% of the patients on observation.

The Herceptin Adjuvant (HERA) (BIG-01-01 [NCT00045032]) trial examined the efficacy of trastuzumab as adjuvant treatment for HER2-positive breast cancer if used after completion of the primary treatment. For most patients, primary treatment consisted of an anthracycline-containing chemotherapy regimen given preoperatively or postoperatively, with or without locoregional radiation therapy. Trastuzumab was given every 3 weeks starting within 7 weeks of the completion of primary treatment.[128][Level of evidence A1] Patients were randomly assigned to one of three study arms:Of the patients in the group comparing 1 year of trastuzumab versus observation, the median age was 49 years, about 33% had node-negative disease, and nearly 50% had hormone receptor–negative disease.[129]The following results were observed for patients assigned to 1 year of trastuzumab versus patients assigned to observation:The following results were observed for patients assigned to 1 year of trastuzumab versus patients assigned to 2 years of trastuzumab:Symptomatic cardiac events occurred in 1% of the patients who received trastuzumab and in 0.1% of the observation group.

One year of trastuzumab also improved OS (12-year OS rate, 79% vs. 73%; HR, 0.74; 95% CI, 0.64–0.86; P < .0001).[129][Level of evidence A1]

The Herceptin Adjuvant (HERA) (BIG-01-01 [NCT00045032]) trial examined the efficacy of trastuzumab as adjuvant treatment for HER2-positive breast cancer if used after completion of the primary treatment. For most patients, primary treatment consisted of an anthracycline-containing chemotherapy regimen given preoperatively or postoperatively, with or without locoregional radiation therapy. Trastuzumab was given every 3 weeks starting within 7 weeks of the completion of primary treatment.[128][Level of evidence A1] Patients were randomly assigned to one of three study arms:Of the patients in the group comparing 1 year of trastuzumab versus observation, the median age was 49 years, about 33% had node-negative disease, and nearly 50% had hormone receptor–negative disease.[129]The following results were observed for patients assigned to 1 year of trastuzumab versus patients assigned to observation:The following results were observed for patients assigned to 1 year of trastuzumab versus patients assigned to 2 years of trastuzumab:Symptomatic cardiac events occurred in 1% of the patients who received trastuzumab and in 0.1% of the observation group.

After a median follow-up of 11 years, there was no DFS benefit to an additional year of trastuzumab (HR, 1.02; 95% CI, 0.89–1.17).

In the combined analysis of the NSABP-B-31 (NCT00004067) and intergroup NCCTG-N9831 (NCT00005970) trials, trastuzumab was given weekly, concurrently, or immediately after the paclitaxel component of the AC with paclitaxel regimen.[130,131][Level of evidence A1]

In the combined analysis of the NSABP-B-31 (NCT00004067) and intergroup NCCTG-N9831 (NCT00005970) trials, trastuzumab was given weekly, concurrently, or immediately after the paclitaxel component of the AC with paclitaxel regimen.[130,131][Level of evidence A1]

The HERA results were confirmed in a joint analysis of the two studies, with a combined enrollment of 3,676 patients. A highly statistically significant improvement in DFS (3-year DFS rate, 87% vs. 75%; HR, 0.48; P < .001) was observed, as was a significant improvement in OS (3-year OS rate, 94.3% in the trastuzumab group vs. 91.7% in the control group; 4-year OS rate, 91.4% in the trastuzumab group vs. 86.6% in the control group; HR, 0.67; P = .015).[130]

In the combined analysis of the NSABP-B-31 (NCT00004067) and intergroup NCCTG-N9831 (NCT00005970) trials, trastuzumab was given weekly, concurrently, or immediately after the paclitaxel component of the AC with paclitaxel regimen.[130,131][Level of evidence A1]

Patients treated with trastuzumab experienced a longer DFS, with a 52% lower risk of a DFS event (HR, 0.48; 95% CI, 0.39–0.59; P < .001), corresponding to an absolute difference in DFS of 11.8% at 3 years and 18% at 4 years. The risk of distant recurrence in patients treated with trastuzumab was 53% lower (HR, 0.47; 95% CI, 0.37–0.61; P < .001), and the risk of death was 33% lower (HR, 0.67; 95% CI, 0.48–0.93; P = .015).[130]

In the combined analysis of the NSABP-B-31 (NCT00004067) and intergroup NCCTG-N9831 (NCT00005970) trials, trastuzumab was given weekly, concurrently, or immediately after the paclitaxel component of the AC with paclitaxel regimen.[130,131][Level of evidence A1]

In an updated analysis with a median follow-up of 8.4 years, the addition of trastuzumab to chemotherapy led to a 37% relative improvement in OS (HR, 0.63; 95% CI, 0.54–0.73; P < .001) and an increase in the 10-year OS rate from 75.2% to 84%.[132]

In the BCIRG-006 trial (NCT00021255), 3,222 women with early-stage HER2-overexpressing breast cancer were randomly assigned to receive AC followed by docetaxel (AC-T), AC followed by docetaxel plus trastuzumab (AC-T plus trastuzumab), or docetaxel, carboplatin, plus trastuzumab (TCH, a non–anthracycline-containing regimen).[133][Level of evidence A1]

In the BCIRG-006 trial (NCT00021255), 3,222 women with early-stage HER2-overexpressing breast cancer were randomly assigned to receive AC followed by docetaxel (AC-T), AC followed by docetaxel plus trastuzumab (AC-T plus trastuzumab), or docetaxel, carboplatin, plus trastuzumab (TCH, a non–anthracycline-containing regimen).[133][Level of evidence A1]

A significant DFS and OS benefit was seen in both groups treated with trastuzumab compared with the control group that did not receive trastuzumab.

In the BCIRG-006 trial (NCT00021255), 3,222 women with early-stage HER2-overexpressing breast cancer were randomly assigned to receive AC followed by docetaxel (AC-T), AC followed by docetaxel plus trastuzumab (AC-T plus trastuzumab), or docetaxel, carboplatin, plus trastuzumab (TCH, a non–anthracycline-containing regimen).[133][Level of evidence A1]

For patients receiving AC-T plus trastuzumab, the 5-year DFS rate was 84% (HR for the comparison with AC-T, 0.64; P < .001), and the OS rate was 92% (HR, 0.63; P < .001). For patients receiving TCH, the 5-year DFS rate was 81% (HR, 0.75; P = .04), and the OS rate was 91% (HR, 0.77; P = .04). The control group had a 5-year DFS rate of 75% and an OS rate of 87%.

In the BCIRG-006 trial (NCT00021255), 3,222 women with early-stage HER2-overexpressing breast cancer were randomly assigned to receive AC followed by docetaxel (AC-T), AC followed by docetaxel plus trastuzumab (AC-T plus trastuzumab), or docetaxel, carboplatin, plus trastuzumab (TCH, a non–anthracycline-containing regimen).[133][Level of evidence A1]

The authors stated that there was no significant difference in DFS or OS between the two trastuzumab-containing regimens. However, the study was not powered to detect equivalence between the two trastuzumab-containing regimens.

In the BCIRG-006 trial (NCT00021255), 3,222 women with early-stage HER2-overexpressing breast cancer were randomly assigned to receive AC followed by docetaxel (AC-T), AC followed by docetaxel plus trastuzumab (AC-T plus trastuzumab), or docetaxel, carboplatin, plus trastuzumab (TCH, a non–anthracycline-containing regimen).[133][Level of evidence A1]

The rates of congestive heart failure and cardiac dysfunction were significantly higher in the group receiving AC-T plus trastuzumab than in the TCH group (P < .001).

In the BCIRG-006 trial (NCT00021255), 3,222 women with early-stage HER2-overexpressing breast cancer were randomly assigned to receive AC followed by docetaxel (AC-T), AC followed by docetaxel plus trastuzumab (AC-T plus trastuzumab), or docetaxel, carboplatin, plus trastuzumab (TCH, a non–anthracycline-containing regimen).[133][Level of evidence A1]

These trial findings raise the question of whether anthracyclines are needed for the adjuvant treatment of HER2-overexpressing breast cancer. The group receiving AC-trastuzumab showed a small but not statistically significant benefit over TCH.

In the BCIRG-006 trial (NCT00021255), 3,222 women with early-stage HER2-overexpressing breast cancer were randomly assigned to receive AC followed by docetaxel (AC-T), AC followed by docetaxel plus trastuzumab (AC-T plus trastuzumab), or docetaxel, carboplatin, plus trastuzumab (TCH, a non–anthracycline-containing regimen).[133][Level of evidence A1]

This trial supports the use of TCH as an alternative adjuvant regimen for women with early-stage HER2-overexpressing breast cancer, particularly in those with concerns about cardiac toxic effects.

The Finland Herceptin (FINHER) study assessed the impact of a much shorter course of trastuzumab. In this trial, 232 women younger than 67 years with node-positive or high-risk (>2 cm tumor size) node-negative HER2-overexpressing breast cancer were given nine weekly infusions of trastuzumab concurrently with docetaxel or vinorelbine followed by FEC.[134][Level of evidence A1]

The Finland Herceptin (FINHER) study assessed the impact of a much shorter course of trastuzumab. In this trial, 232 women younger than 67 years with node-positive or high-risk (>2 cm tumor size) node-negative HER2-overexpressing breast cancer were given nine weekly infusions of trastuzumab concurrently with docetaxel or vinorelbine followed by FEC.[134][Level of evidence A1]

At a 3-year median follow-up, the risk of recurrence and/or death was significantly reduced in patients receiving trastuzumab (3-year DFS rate, 89% vs. 78%; HR, 0.41; P = .01; 95% CI, 0.21–0.83).

The Finland Herceptin (FINHER) study assessed the impact of a much shorter course of trastuzumab. In this trial, 232 women younger than 67 years with node-positive or high-risk (>2 cm tumor size) node-negative HER2-overexpressing breast cancer were given nine weekly infusions of trastuzumab concurrently with docetaxel or vinorelbine followed by FEC.[134][Level of evidence A1]

The difference in OS (HR, 0.41) was not statistically significant (P = .07; 95% CI, 0.16–1.08).

Several studies have compared 6 months of trastuzumab administration to 12 months.[135-137]

Several studies have compared 6 months of trastuzumab administration to 12 months.[135-137]

In an interim analysis of the PHARE trial (NCT00381901), the 2-year DFS rate was 93.8% (95% CI, 92.6%–94.9%) in the 12-month group and 91.1% (89.7%–92.4%) in the 6-month group (HR, 1.28; 95% CI, 1.05–1.56; noninferiority, P = .29).[135][Level of evidence A1]

Several studies have compared 6 months of trastuzumab administration to 12 months.[135-137] › In an interim analysis of the PHARE trial (NCT00381901), the 2-year DFS rate was 93.8% (95% CI, 92.6%–94.9%) in the 12-month group and 91.1% (89.7%–92.4%) in the 6-month group (HR, 1.28; 95% CI, 1.05–1.56; noninferiority, P = .29).[135][Level of evidence A1]

In the final analysis, after 704 events were observed, the adjusted HR was 1.08 (95% CI, 0.93–1.25), and the prespecified noninferiority HR of 1.15 was not excluded.

Several studies have compared 6 months of trastuzumab administration to 12 months.[135-137]

Similar results were noted in a much smaller study of 481 patients led by the Hellenic Oncology Research Group.[136][Level of evidence A1]

Several studies have compared 6 months of trastuzumab administration to 12 months.[135-137]

In contrast, the PERSEPHONE trial (NCT00712140), which enrolled 4,088 patients who experienced 512 DFS events at the time of analysis, excluded its prespecified noninferiority margin (HR, 1.07; 90% CI, 0.93−1.24; noninferiority, P = .011).[137][Level of evidence A1]

The SOLD trial (NCT00593697) compared 9 weeks of trastuzumab with 1 year of trastuzumab in 2,174 women with HER2-positive breast cancer.[138]

The SOLD trial (NCT00593697) compared 9 weeks of trastuzumab with 1 year of trastuzumab in 2,174 women with HER2-positive breast cancer.[138]

Noninferiority of the 9-week treatment could not be demonstrated for DFS (HR, 1.39; 2-sided 90% CI, 1.12−1.72).[138][Level of evidence B1]

A meta-analysis that included these trials concluded that, with respect to OS, 1 year of trastuzumab was superior to a shorter duration of therapy; however, there was no significant benefit of 1 year of therapy in patients with low-risk disease.[139][Level of evidence A1]