Adjuvant Trastuzumab Duration: When Is Enough, Enough?


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Andrew D. Seidman, MD

The duration of adjuvant systemic chemotherapy for breast cancer has been a subject of investigation, scrutiny, and meta-analysis.1,2 With the appreciation that prolonged regimens of cytotoxic chemotherapy of, for example, 1 to 2 years in duration were not superior in reducing breast cancer recurrence or death over those of 4 to 6 months in duration,3,4 such extended treatment programs have largely become a historical footnote. This important observation spares patients undue toxicity, and the health-care system is spared unnecessary costs.

With respect to adjuvant antiestrogen therapy, the opposite relationship has been revealed, with longer duration of therapy demonstrating improved outcomes.5-7 Such results, coupled with an appreciation of the indolent nature of some estrogen receptor–positive (eg, luminal A) breast cancers, lead to reasonable speculation that extended adjuvant endocrine therapy for durations even beyond a decade may one day be proven to be advantageous for some patients.

Trastuzumab Gold Standard

A recent report from Goldhirsch and colleagues,8 summarized in this issue of The ASCO Post, shows a lack of benefit for 2 years of trastuzumab (Herceptin) over 1 year, suggesting that for this agent—unlike the adjuvant chemotherapy and hormonal therapy duration story—perhaps we have hit the nail on the head from the outset. Indeed, the somewhat arbitrarily chosen 1 year duration of adjuvant trastuzumab may in fact be optimal.

In this quite large open-label randomized trial, with over 1,500 patients per arm randomly assigned to 1 vs 2 years of trastuzumab (vs none), no advantage in relapse-free survival or overall survival was noted for doubling the adjuvant trastuzumab exposure from 1 to 2 years, while an increase in some nonfatal adverse events occurred with longer treatment duration. Thus, for the moment, taken together with the PHARE trial result demonstrating that 6 months of trastuzumab was not noninferior to 12 months, 1 year of trastuzumab should remain the gold standard. The results of other trials of shorter duration vs 1 year of exposure are awaited.

Higher-Risk Patients

A provocative predefined subgroup analysis by hormone receptor status showed that a short-term reduction in breast cancer–related events occurred among patients with estrogen receptor–negative disease receiving trastuzumab for 2 years as compared to 1. This was not observed for patients with estrogen receptor–positive disease, most of whom received adjuvant antiestrogen therapy. While intriguing, this observation should not be practice-changing, as the authors note.

Could a higher-risk patient, for example one with ≥ 10 positive axillary lymph nodes and hormone receptor–negative, HER2-positive breast cancer possibly benefit from a more extended exposure to adjuvant trastuzumab? These results cannot adequately answer that question. Notably, about a quarter of patients enrolled in HERA had four or more involved axillary nodes.

It is quite possible that in the future, dual or multiple inhibition of HER2 will be demonstrated to prolong overall survival for HER2-positive early-stage breast cancer over trastuzumab alone, as has been demonstrated in the metastatic setting.9 While it is reasonable to speculate that the optimal duration of combined anti-HER2 agents in the adjuvant setting could be different (eg, possibly shorter) than the 1-year duration of trastuzumab anti-HER2 monotherapy that currently is the benchmark, such hypotheses will require prospective evaluation.

Closing Thoughts

Apart from the analysis of trastuzumab duration, this report is most gratifying for its demonstration of the durable and robust impact of adjuvant trastuzumab on long-term disease-free and overall survival. With a median follow-up of 8 years, overall survival is significantly prolonged (hazard ratio = 0.76, P = .0005), a result consistent with updated results of the National Surgical Adjuvant Breast and Bowel Project and Intergroup trials. Given the exciting results with newer anti-HER2 agents in more advanced-stage disease,9,10 there is much reason for optimism that further progress will be made for patients with HER2-positive early breast cancer in coming years. ■

Dr. Seidman is Attending Physician, Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, Professor of Medicine, Weill Cornell Medical College, New York.

Disclosure: Dr. Seidman has received consultant and speaker honoraria from Genentech/Roche.

References

1. Early Breast Cancer Trialists’ Collaborative Group: Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomized trials. Lancet 365:1687-1717, 2005.

2. Early Breast Cancer Trialists’ Collaborative Group: Comparisons between different polychemotherapy regimens for early breast cancer: Meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet 379:432-444, 2012.

3. Early Breast Cancer Trialists’ Collaborative Group: Multi-agent chemotherapy for early breast cancer. Cochrane Database Syst Rev 4:CD000487, 2008.

4. Early Breast Cancer Trialists’ Collaborative Group: Polychemotherapy for early breast cancer: An overview of the randomised trials. Lancet 352:930-942, 1998.

5. Goss PE, Ingle JN, Martino S, et al: Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: Updated findings from NCIC CTG AM.17. J Natl Cancer Inst 97:1262-1271, 2005.

6. Davies C, Pan H, Godwin J, et al: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor positive breast cancer: ATLAS, a randomized trial. Lancet 381:805-816, 2013.

7. Strasser-Weippl K, Badovinac-Crnjevic T, Fan L, et al: Extended adjuvant endocrine therapy in hormone-receptor positive breast cancer. Breast 22:S171-S175, 2013.

8. Goldhirsch A, Gelber R, Piccart-Gebhart MJ, et al: 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): An open-label, randomized controlled trial. Lancet 382:1021-1028, 2013.

9. Baselga J, Cortes J, Kim SB, et al: Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 366:109-119, 2012.

10. Verma S, Miles D, Gianni L, et al: Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 367:1783-1791, 2012. Erratum in N Engl J Med 368:2442, 2013.


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