Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

6th European Breast Cancer Conference

Berlin, Germany / April 15-19, 2008

According to Dr. Martine Piccart-Gebhart, Jules Bordet Institute, Free University of Brussels, Belgium, “It is our responsibility to make sure that each primary breast tumour is evaluated for either HER2 protein overexpression or HER2 gene amplification. This has been generated by striking results which have emerged from four large, multicentre, open-label, phase III randomized trials with an enrolment of more than 13,000 women with HER2-positive early breast cancer.”

Improved Survival

The studies referred to by Dr. Piccart-Gebhart are HERA (Herceptin Adjuvant trial), NASABP B-31 (National Surgical Adjuvant Breast and Bowel Project B-31), NCCTG N9831 (North Central Cancer Treatment Group N9831) and BCIRG 006 (Breast Cancer International Research Group 006).

These trials demonstrated that in women with early HER2-positive breast cancer, the recombinant humanized monoclonal antibody (MAb) against HER2, trastuzumab, in combination with or following standard chemotherapy, can reduce the risk of cancer recurrence by 33% to 52% and reduce the risk of death by 34% to 41%. Pivotal trials in women with metastatic HER2-positive breast cancer have shown that in combination with taxane chemotherapy, it can increase overall survival (OS) by 37% to 40%.

“It is not a surprise that treatment guidelines like those of the St. Gallen group emphasize the crucial need to prescribe one year of adjuvant trastuzumab to these women with HER2-positive breast cancer in addition to adjuvant chemotherapy, and adjuvant endocrine therapy if the tumour also expresses hormone receptors [HR],” HERA lead investigator Dr. Piccart-Gebhart observed.

The HERA trial randomized more than 5000 patients with HER2-positive, node-positive or high-risk node-negative breast cancer after standard neoadjuvant or adjuvant chemotherapy into three arms: either one or two years of trastuzumab, or observation. HERA was unique in allowing at least four cycles of a wide range of chemotherapy regimens, with or without radiotherapy, prior to trastuzumab. A third of the patients had node-negative disease and one-half had HR-positive disease.

Reporting results from a one-year median follow-up of HERA, Dr. Piccart-Gebhart noted that trastuzumab significantly prolonged disease-free survival (DFS) compared to the observation arm with a 46% reduced risk of relapse, which corresponds to an absolute DFS benefit of 8.4% at two years and these benefits were observed across all subgroups. It also prolonged OS, reducing the risk of death by one-third.

Benefits Outweigh Risks

“There is always a price to pay for such huge benefits, but it is a relatively small one in the case of trastuzumab,” Dr. Piccart-Gebhart remarked. “The risk of severe congestive heart failure [CHF] ranged from 0.4% to 3.8% in the four large studies,” she observed. “The incidence of NYHA class III/IV CHF was also low, 0.5% with trastuzumab and 0% with observation. One patient in the observation arm suffered cardiac death.”

Dr. Piccart-Gebhart described a range of options for prescribing chemotherapy for women with HER2-positive breast cancer. She proposed two key factors for individual treatment decision-making: an estimate of cardiac risk based on risk factors for cardiac toxicity identified in clinical trials, such as patient age and low left ventricular ejection fraction (LVEF) at the start of treatment; and the risk of early relapse, which is particularly high for women with positive nodes and those with HR-negative disease. “Based on those two factors, you could decide to select, for example, the non-anthracycline-containing platinum/taxane regimen for women who have both a high risk of early relapse and of cardiotoxicity,” she suggested. “On the other hand, you could decide to go for the sequential HERA regimen designed for women who have a somewhat lower risk of early relapse.”

Dr. Piccart-Gebhart noted that although an increased risk of cardiac dysfunction has been observed with trastuzumab, this is in general reversible and manageable. “Concerns regarding trastuzumab-related cardiac dysfunction should not overshadow the significant benefits associated with [it],” she told delegates.

NOAH: Seeking Pathologic Complete Response

The NOAH (Neoadjuvant Herceptin) trial evaluated neoadjuvant trastuzumab with chemotherapy in HER2-positive locally advanced breast cancer. The trial randomized 228 patients to receive three cycles of doxorubicin and paclitaxel, four cycles of paclitaxel and three cycles of CMF with or without concomitant trastuzumab (8 mg/kg loading dose, then 6 mg/kg q3w for one year) before surgery. Ninety-nine patients with HER2-negative breast cancer received the same chemotherapy regimen. Previously, Gianni et al. (ASCO 2007, abstract 532) reported that in HER 2-positive patients, the addition of trastuzumab significantly increased the pathologic complete response (pCR) from 23% to 43% (P=0.002) (Figure 1).

Figure 1. NOAH: pCR Results

In an update on NOAH, Dr. Wolfgang Eiermann, Red Cross Women’s Clinic, Munich, Germany, reported on an assessment by multivariate analysis of the likelihood that patient characteristics predicted for pCR. Results showed that the addition of trastuzumab and negative progesterone receptor (PgR) status were the only variables predicting for pCR in the HER2-positive population. In patients not given trastuzumab, HER2 status did not influence treatment results, but PgR status significantly predicted for pCR. “These data highlight the relevance of cross talk between hormone and HER2 receptors in modulating response to trastuzumab,” he concluded.

Optimizing Outcomes of Neoadjuvant Treatment

The first analysis of efficacy and safety in the German GeparQuattro study presented by Dr. Michael Untch, HELIOS Klinikum, Berlin, Germany, reported that trastuzumab combined with standard chemotherapy before and after surgery completely eradicated tumours in 45.5% of women with HER2-positive early breast cancer. This is an impressive finding, he noted, because the proportion of women achieving total tumour eradication with standard chemotherapy alone is less than 30%.

The largest trial to date of neoadjuvant therapy in HER2-positive patients, GeparQuattro enrolled 1510 breast cancer patients, 453 of whom had tumours overexpressing the HER2 receptor. They received four cycles of epirubicin/cyclophosphamide and were then randomized to either four cycles of docetaxel (standard arm) or four cycles of docetaxel/capecitabine (combination arm) or four cycles of docetaxel followed by four cycles of capecitabine (sequential arm). In addition, patients with HER2-positive tumours were given trastuzumab 6 mg/kg every three weeks concomitantly with all neoadjuvant chemotherapy before surgery and for up to one year following surgery.

At 15 months, researchers found no evidence of any cancer remaining in the breasts of 41.3% of women with HER2-positive tumours who had received both chemotherapy and trastuzumab, whereas the pCR rate was only 19.5% in women who had not received the MAb (P<0.001). There was no significant difference in the rates of breast-conserving surgery either with or without trastuzumab, at 61.8% or 63.1%, respectively.

Dr. Untch said toxicity in the neoadjuvant chemotherapy/trastuzumab population was no greater than with neoadjuvant chemotherapy alone. “In 97% of HER2-positive and 96% of HER2-negative patients, LVEF was greater than 55% and no patient developed a LVEF below 45%. There were no CHFs and no cardiac-related deaths.” No cardiac safety concerns were even observed in patients receiving concomitant or sequential anthracyclines.

He told delegates, “It was very reassuring to see that the GeparQuattro study confirmed the significant benefits with trastuzumab observed in other trials such as the NOAH study, indicating that it can be successfully combined with different chemotherapies in different patient groups.”