Long Term Adjuvant Therapy is Improving Outcomes in Breast Cancer and is a Key Theme at SABCS 2012
| Dec 7, 2012
Co-authored by Josh Garcia, Associate Consultant
At SABCS, 2012 seemed to be the year for long-term follow-up data for a number of adjuvant therapies in resectable breast cancer treatment. In the HER2-positive setting, the final analysis was presented from the NASBP-31/NCCTG N9831 studies, the seminal studies that introduced adjuvant Herceptin® (trastuzumab, Genentech/Roche) as the standard of care. In addition, the duration of adjuvant Herceptin was solidified with the data from the HERA and PHARE studies, reprised from the European Society of Medical Oncology (ESMO) 2012 Conference, but there were a few pieces of new information. Beyond HER2, the analysis of 10 years versus five years of adjuvant tamoxifen in estrogen receptor (ER) positive patients from the ATLAS study was also a highlight of the conference.
Long-term results from the NASBP-31/NCCTG N9831 studies showed that the benefit of adjuvant Herceptin was durable with benefits in both disease-free survival (DFS) and overall survival (OS) persisting now beyond 10 years (Romond, Abstract S5-5). At 10 years out from randomization, adding Herceptin to adjuvant therapy showed an 11.5% improvement in DFS (73.7% versus 62.2%; HR=0.60, p<0.0001) and an 8.8% improvement in OS (75.2% versus 84.0%; HR= 0.63, p<0.0001). In this trial, one year of adjuvant Herceptin was somewhat arbitrarily chosen as the study regimen, leaving questions as to whether shorter or longer durations of Herceptin could be beneficial; questions answered in the HERA and PHARE studies (Abstracts S5-5 and S5-3).
A very brief summary of the findings (as the data was essentially the same as was presented at ESMO 2012) is that one year of adjuvant Herceptin will remain the standard of care. The HERA study showed that two years of Herceptin offered no additional benefit beyond what is achieved with one year of Herceptin, and the PHARE non-inferiority results showed that six months of therapy was inconclusive but potentially inferior to one year of Herceptin. A key point highlighted by both presentations was the need for significant long-term follow-up for any major practice-changing adjuvant therapy trial. In the HERA study, results at the four-year follow-up suggested that two years of Herceptin may have been beneficial in hormone receptor (HR) negative patients, but the newer eight-year follow-up data showed that the benefit was transient and there was a risk in over-treating patients and subjecting them to unnecessary cardiac toxicity.
Finally, the 10 years versus five years of adjuvant tamoxifen in ER-positive patients in the ATLAS study created a lively discussion at the symposium (Davies, Abstract S1-2). The data showed that 10 years of treatment was superior to five years, with the interesting caveat that the benefit does not show up until after the 10 years of therapy. The hazard ratio (HR) for the 10-year cohort versus the five-year in years five through nine was 0.97, no difference. But in the years after 10 (this was a 15-year follow-up) the HR improves to 0.71 (p=0.0016). It is currently unclear why the majority of the benefit is showing up after patients go off therapy, but this phenomenon is also observed in the five-year arm compared to placebo where the survival benefit continued to increase beyond the five years of therapy. Regarding toxicity concerns, 10 years of tamoxifen increased endometrial cancer mortality rates from 0.2% with five years of therapy to 0.4%. However, it was generally agreed that the benefit in breast cancer morality outweighed the risk of endometrial cancer mortality.
After the presentation was when the real debate began. It was immediately pointed out in the question and answer session that these results do not appear to be as favorable as the results of the NCIC CTG MA.17 study (Jin, J Clin Oncol 30:718-721, 2011), which looked at switching to five years of the aromatase inhibitor, Femara (letrozole, Novartis) after an initial five years on tamoxifen. Acknowledging that cross-trial comparisons are always a risky exercise, it was pointed out that tamoxifen showed no survival benefit in years five through nine of therapy, but the Femara trial showed a beneficial HR of 0.61 over that same period. This is a debate that will be hashed out in the clinic in the coming months and years, but aromatase inhibitors appear to be in a relatively strong position.
The common theme for all of these studies is that adjuvant therapy is improving outcomes in breast cancer and that can always be considered a positive result. Also, those patients who may be ineligible for aromatase inhibitors, will be able to benefit from the new 10-year tamoxifen standard of care. It is clear that long-term follow-up is the key for getting the most out of these adjuvant therapy studies.