Adjuvant chemotherapy for node negative, high Recurrence ScoreTM breast cancer: in defense of de-escalation

Abstract

Recent clinical trials have demonstrated the ability to de-escalate therapy for early stage breast cancer regardless of whether the intervention is surgical, radiotherapeutic, or systemic. The expectation of improved outcomes with contemporary therapy coupled with a desire to minimize toxicity have motivated these efforts. Patients with early breast cancer no longer only wish to be cured and have their breast conserved but also avoid lymphedema, unnecessary radiotherapy, and many toxicities that have historically accompanied cytotoxic chemotherapy. Witness the rising use of scalp cooling devices to mitigate against alopecia, the use of icing of hands and feet to avoid nail toxicity, and strategies to minimize taxane-associated peripheral neuropathy. The initial demonstration that patients with HR+/HER2−, node negative high 21-gene Recurrence Score (RS) breast cancer benefit from adjuvant chemotherapy showed a 28% absolute reduction in distant recurrence when either cyclophosphamide, methotrexate, and fluorouracil (CMF) or MF were administered as an addition to tamoxifen. In the TAILORx trial, where medical oncologists were given the opportunity to choose the chemotherapy regimen for patients with T1-2N0, HR+/HER2− breast cancer, the selections for those with RS >25 were: docetaxel/cyclophosphamide (TC) 45%, anthracycline ± taxane: 26%, anthracycline+ taxane: 19%, other/not specified: 6%, and CMF: 4%. For patients with RS <25 randomized to chemotherapy (which did not improve outcomes), only 8% chose CMF. This begs a specific question: is the incremental toxicity associated with anthracycline and/or taxane administration in this population of patients with HR+/HER2−, node negative breast cancer, as compared to CMF, warranted? Logically, answering this would require a direct randomized trial of an anthracycline and/or taxane-containing regimen versus CMF in this population. Such a trial does not exist and is not likely to be conducted. The alternative approach is to identify randomized trials that address that question and use risk models to extrapolate to the specific population in question. Again, such studies exist for anthracycline regimens versus CMF but not for taxanes. Finally, and least satisfying, one must make indirect and cross-study comparisons to attempt to estimate relative benefits. (It is fair to stipulate the differences in toxicity since those are not histology or anatomy dependent, unlike benefits). Now, consider the patient with RS of 28 with an average-sized tumor and negative nodes. The estimated absolute reduction in 10-year risk of distant recurrence for CMF/MF over tamoxifen alone (5 years) is 5%. One might argue that anthracycline-based regimens would offer an incremental benefit over CMF, given the 4% reduction in recurrence and mortality observed across randomized trials of anthracycline versus CMF in 9527 patients the EBCTG meta-analysis. Notably, these patients had unknown HER2 status when randomized and largely received non-dosedense anthracycline schedules. It is possible that the specific population with a high RS derives no such benefit since they are all HER2 negative (by definition) and a subsequent analysis of these data for 3818 patients with known HER2-negative disease after testing of archived tissue showed no benefit in disease-free or overall survival for anthracycline-based adjuvant therapy over CMF. One trial (USORT 9735) has demonstrated that four cycles of TC is superior to four cycles of AC, both administered in q-3 weekly cycles. Of note, more than half of the patients enrolled had node-positive disease, and more than a quarter had HR-negative breast cancer. Curiously, in a trial (ECOG 2197) 3-fold larger than this study, the combination of doxorubicin and docetaxel (AT) was not superior to the identical AC regimen. Furthermore, the DFS favored AT over AC for ERpatients (HR 1.24, 95% CI: 0.95–1.62), and AC for ER+ patients (HR 0.79, 95% CI: 0.60–1.03). No trial has compared TC to CMF, yet randomized trials involving over 5,000 patients comparing AC × 4 q 3 weeks to CMF showed no advantage for the anthracycline-based regimen. Finally, in the “ABC” trials (USOR 06–090, NSABP B-46-I/USOR 07132, and NSABP B-49/NRG Oncology), patients with node negative, ER+ breast cancer had a HR for DFS that trended strongly in favor of TC (×6), rather than AC plus taxane (0.69; 95% CI 0.39–1.19), with all other groups favoring AC plus taxane. It is hard to draw a conclusion that “more than CMF” or “more than AC” is advantageous since none of these trials provide a top line result confirming a clear and convincing benefit. Might a taxane-containing regimen add enough benefit to AC × 4 in HR+/HER2− breast cancer patients to justify the sequential combination in patients with node negative, high RS disease? Among 1065 node-positive, HR+ patients with known RS enrolled in NSABP B-28, the likelihood ratio test for interaction between the use of paclitaxel or not did not show differential treatment effect across RS groups, arguing against escalation of chemotherapy as a function of RS, or a unique RS-paclitaxel benefit relationship. This argues that escalation of chemotherapy based on a specific RS value above 25 (e.g., 30 vs. 35 vs. 40) is not evidence-based. So why was TC the most popular regimen employed in TAILORx, despite the differential toxicity expected as compared to CMF? For some patients, the issues of alopecia and neuropathy may be as fundamental as whether an assay directs the use of any chemotherapy versus none at all. Why are medical oncologists convinced that escalation from the regimen that