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by Dr. C.H. Weaver M.D. updated 9/6/2021

Herceptin® (trastuzumab) was initially approved by the U.S. Food and Drug Administration (FDA) for use in the post-surgery treatment of early-stage breast cancer (ESBC) that is HER2-positive in 2006. The approval initially specified that Herceptin be given in combination with the chemotherapy drugs doxorubicin, cyclophosphamide, and paclitaxel and was based on the results of two clinical trials published in the New
England Journal of Medicine.

The FDA later expanded the indication of Herceptin to be used as monotherapy for the adjuvant treatment of HER2 - positive breast cancer based on follow-up results from HERA, in which a group of patients on Herceptin monotherapy following combination therapy had a 46% reduction in recurrences compared to those who were not on Herceptin.

Treatment of HER2 positive Early Stage Breast Cancer

Breast cancer is diagnosed in over 200,000 women annually in the US alone. Early breast cancer refers to cancer that has not spread outside the breast and regional lymph nodes. Standard treatment for early breast cancer typically includes the surgical removal of the cancer, followed by systemic treatment with chemotherapy, precision cancer medicines and/or hormonal therapy and radiation.

The addition of Herceptin to chemotherapy has demonstrated improved outcomes, including survival, in patients with HER2-positive metastatic breast cancer.

The first trial reported in the New England Journal of Medicine was an international, multi-center trial called the HERA trial. It included nearly 5,100 women with early-stage, HER2-positive breast cancer who had completed surgery with or without radiation therapy and chemotherapy. Patients then received either one year of treatment with Herceptin, two years of treatment with Herceptin, or no further treatment (observation).

Herceptin significantly improved outcomes at a median follow-up of one year:

  • Patients treated with Herceptin had a 46% reduced risk of death, a cancer recurrence, cancer in the other breast, or cancer other than breast cancer.
  • At two years, cancer-free survival was improved by 8.4% overall in the patients treated with Herceptin.
  • Severe side effects affecting the heart (cardiotoxicity) occurred in 0.5% of patients treated with Herceptin.

The second clinical trial reported in the New England Journal of Medicine was a combined analysis of two separate clinical trials; they include the National Surgical Adjuvant Breast and Bowel Project trial (B-31) and the North Central Cancer Treatment Group trial (N9831). Both trials included women with early breast cancer who received surgery with or without radiation therapy, followed by chemotherapy (including doxorubicin and cyclophosphamide), followed by Taxol. Approximately half of the women were treated with Herceptin while being treated with Taxol.

At three years follow-up, the addition of Herceptin significantly improved survival among these women:

  • Patients treated with Herceptin had an approximate 50% reduced risk of a cancer recurrence, a second cancer, or death.
  • Patients treated with Herceptin had a 33% reduced risk of death compared to those treated with chemotherapy only.
  • Rates of severe cardiotoxicity occurred in approximately 4% of patients treated with Herceptin in the B-31 trial and approximately 3% of patients treated with Herceptin on the N9831 trial.

According to a meta-analysis published in The Lancet Oncology in September 2021 Treating early-stage, HER2-positive breast cancer with adjuvant trastuzumab plus chemotherapy results in long-term benefits, including a reduced risk of recurrence and breast cancer-related mortality,

Doctors conducted a meta-analysis of 13,864 patients enrolled in 7 randomized, controlled trials designed to compare adjuvant trastuzumab plus chemotherapy with chemotherapy alone.

Compared with chemotherapy alone, trastuzumab plus chemotherapy resulted in a significant decrease in breast cancer and breast cancer-related mortality. The absolute 10-year recurrence risk was reduced by 9%, the 10-year risk of breast cancer mortality was reduced by 6.4%, and the all-cause mortality risk was reduced by 6.5% with the addition of trastuzumab. There was no significant difference in risk reduction for recurrence between estrogen receptor-positive or -negative tumors or other histopathologic features.

The analysis confirms that breast cancer recurrence and mortality can be reduced by a third by adding 1 year of trastuzumab treatment to adjuvant chemotherapy in patients with early-stage, HER2-positive breast cancer,” the study authors concluded.17

How long should Herceptin be administered?

The HERA study was a phase III clinical trial that randomly assigned HER2-positive early breast cancer patients to one of three treatment groups following adjuvant chemotherapy: observation, one year of Herceptin, or two years of Herceptin.

Overall survival and cancer-free survival were significantly better in the women randomly assigned to one year of Herceptin compared to the women in the observation group. Risk of death was 34% lower among women treated with one year of Herceptin. Herceptin protected against both distant metastases as well as local recurrence.8

Concern of side effects to the heart from Herceptin have led doctors to evaluate shorter courses of Herceptin treatment. The net result of these studies according to Dr. Harold Burstein M.D. a leading authority on the topic is that the optimal duration of Herceptin treatment remains one year for ESBC patients.

Mavroudis and colleagues conducted the HORG trial to examine 6 versus 12 months of Herceptin therapy in a cohort of 481 women with early, HER2-positive breast cancer.9

The analysis included 240 women in the 6-month group who were followed for 51 months and 241 women in the 12-month group who were followed for 47 months. Disease relapse rates were 11.7% in the 6-month group and 7.1% for the 12-month group. Overall survival was comparable between the two treatment arms, as was cardiac toxicity.8

All five trials that have examined the question of 6 vs. 12 months of Herceptin have similar results.4-8

Can Herceptin and Radiation Therapy be Safely Combined? 

A 2021 research publication offers conclusive evidence that, for patients with HER-2 positive breast cancer who are treated with both chemotherapy and modern radiation therapy, the radiation itself brings little or no additional risk of damage to the heart.

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Herceptin has the potential to damage the heart muscle, which can increase the risk for heart failure. As a result patients must be closely monitored for years following treatment. Researchers analyzed 3,321 HER-2 positive breast cancer patients from across Europe, UK, Australia and Canada who had been treated with Herceptin with or without radiation. Cardiac function for each patient had been closely monitored over a median follow-up period of 11 years. The team’s research revealed that, over a 10-year period following treatment, the incidence of having a cardiovascular event such as a heart attack was minimal (just 0.6 to 1.0 percent).18

Neoadjuvant Herceptin® plus Taxotere® in ESBC

The combination of Herceptin with a chemotherapy agent improves breast cancer outcomes compared to chemotherapy alone in ESBC. Neoadjuvant therapy may be used in patients with ESBC to optimize their chances of undergoing breast-conserving surgery (surgical removal of the cancer and surrounding healthy tissue) instead of a mastectomy (surgical removal of the complete breast).

Neoadjuvant therapy often shrinks the cancer enough so that surgical removal is feasible with breast-conserving therapy without compromising long-term outcomes. Since the addition of Herceptin to chemotherapy has demonstrated improved outcomes compared to chemotherapy alone in ESBC, researchers also evaluated Herceptin for use as neoadjuvant therapy.

A small French trial of Herceptin plus Taxotere administered as neoadjuvant therapy in patients with stages II-III breast cancer reported a partial or complete disappearance of cancer in 96% of patients allowing breast-conserving surgery in 77% of patients.13

A Phase III clinical trial among 228 women with HER2-positive, locally advanced breast cancer confirmed the benefit reporting that at three years 70.1% of women treated with neoadjuvant chemotherapy plus Herceptin were free of cancer recurrence or progression compared with 53.3% of women treated with neoadjuvant chemotherapy alone.14

Taxol/Herceptin Effective in Stage I HER2-Positive, Node-Negative Breast Cancer

The combination of Taxol® and Herceptin® followed by Herceptin alone showed benefit and was well tolerated by women with stage I HER2-positive, node-negative breast cancer.

The APT study included 406 women with HER2-positive, node-negative tumors that measured less than 3 cm. The study was a nonrandomized prospective trial to define the outcomes in a uniformly treated cohort. Patients received Taxol/Herceptin for 12 weeks followed by 9 months of Herceptin.

After a median follow-up of 3.6 years, disease-free survival was 98.7 percent and recurrence or death occurred in 2.5 percent of patients. There were no new contralateral primary breast cancers. Distant recurrences were observed in two patients. By hormone receptor status, disease-free survival rates were 98.5 percent in receptor-positive patients and 99.2 percent in receptor-negative patients.

Two patients developed symptomatic congestive heart failure. Few other adverse events were noted.

The limitations of the study were that it was a non-randomized, single-arm study and about 20 percent of patients had T1a tumors, which are already associated with a favorable prognosis. Still, the researchers concluded that this adjuvant regimen should be considered a standard strategy to prevent recurrence in stage I HER2-positive, node-negative breast cancer.15

Other HER2 Therapies Combined with Herceptin

Tykerb and Herceptin Combination Therapy Fails to Improve Outcomes for Early Stage HER2 Breast Cancer

The ALTTO trial, begun in 2007, enrolled 8381 women in 44 countries with HER2-positive early breast cancer. Patients were assigned to one of four treatment groups: Herceptin alone, Tykerb alone, Herceptin followed by Tykerb, or Herceptin plus Tykerb. Patients were treated with the regimens for 1 year. All patients were also receiving chemotherapy.

Researchers found that disease-free survival at 4 years did not improve when the concurrent combination therapy was compared to Herceptin alone. It was also true that the sequential administering of Herceptin and Tykerb versus Herceptin alone did not improve disease-free survival.16

Researchers also reported that patients with the dual therapy when compared to Herceptin alone had higher rates of side effects such as diarrhea, rash, and problems with the liver and biliary tract.

Subcutaneous Herceptin Now an Option

Dr. Jackisch M.D. and colleagues from Germany reported the results of an open-label, multi-center, international clinical trial to compare the effectiveness and safety of subcutaneous and IV Herceptin in patients with HER2-positive ESBC.

A total of 596 individuals were enrolled in the clinical trial between October 19, 2009, and December 1, 2010 and have now been followed for 6 years.

Patients were given 8 cycles of standard chemotherapy and either a fixed-dose of subcutaneous or IV Herceptin for 10 after surgery to complete 1 year of anti-HER2 therapy.

The overall survival and progression free survival were essentially identical for IV and subcutaneous Herceptin. Moreover, the rates of significant cardiac and other serious side effects were similar.

The study suggests that subcutaneous Herceptin is as an effective alternative route of administration for patients with HER2-positive ESBC.16


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