Chemotherapy for Triple-Negative Breast Cancer: Is More Better?

Triple-negative breast cancer (TNBC) remains defined by what it is not: the breast cancer that lacks a biomarker for rational use of a targeted therapy. Yet chemotherapy, that nonspecific and often toxic anticancer weapon, can be effective against TNBC and remains the sole proven systemic approach for prevention of recurrence and improvement of survival in patients with TNBC. The Oxford Overview meta-analysis has shown unequivocally that combination chemotherapy that includes the alkylator cyclophosphamide augmented by anthracycline and taxane agents is valuable for TNBC. Omission of either the anthracycline or the taxane yields inferior outcomes in TNBC. The question is: Would additional chemotherapy be beneficial? This question has been asked in many ways, and, so far, the answer about the addition of more of the same chemotherapy has been no. Randomized trials established that dose-escalation of doxorubicin or cyclophosphamide does not improve outcomes. Additional cycles of the same regimen (eg, 12 months of cyclophosphamide plus methotrexate plus fluorouracil instead of 6 months, or six cycles of doxorubicin plus cyclophosphamide instead of four) do not meaningfully change results. Thus, combination alkylator and anthracycline chemotherapy followed by sequential taxane treatment deployed on dose-dense schedules remains the gold standard (neo)adjuvant treatment of TNBC. Several recent studies have examined novel chemotherapy approaches for breast cancer treatment, including triple-negative tumors. These trials have explored the use of low-dose, metronomic chemotherapy as a maintenance program, the incorporation of the antimetabolite capecitabine as an adjuvant treatment, and the addition of platinum analogs to neoadjuvant treatment. Collectively, they raise intriguing questions about new chemotherapy approaches for TNBC. In the article that accompanies this editorial, investigators at the European Institute of Oncology explored whether a maintenance program of low-dose cyclosphosphamide and methotrexate would reduce recurrence in high-risk, early-stage breast cancer. Given the favorable impact of adjuvant endocrine therapy in estrogen receptor–positive breast cancer, they focused primarily on hormone receptor–negative disease in the trial, IBCSG (International Breast Cancer Study Group) 22-00. Patients received standard surgery and radiation therapy as appropriate, and all patients received standard adjuvant chemotherapy. Eligible patients were then randomly assigned to receive no additional treatment or to receive 1 year of low-dose metronomic therapy with oral cyclophosphamide (C) 50 mg per day paired with methotrexate (M) 2.5 mg twice a day (ie, CM) on days 1 and 2 of every week. The rationale for the CM regimen came from several observations: It was reasonably well tolerated, it was convenient and inexpensive, and the metronomic schedule might provide additional antineoplastic or antiangiogenic benefits. Final results showed that metronomic CM did not reduce the recurrence of breast cancer; however, there was a trend toward lower recurrence among women with TNBC who received CM, especially among those with higher-risk, node-positive tumors. Patients were accrued to this trial from 2001 through 2012, an era when significant change occurred in the management of hormone receptor–negative breast cancer. Women with human epidermal growth factor receptor 2–positive cancers began to receive treatment with trastuzumab. Meanwhile, anthracyclines and taxanes became standard treatments. Because only 26% of the patients in IBCSG 22-00 received alkylator/anthracycline/taxane–based chemotherapy, it remains unclear how metronomic CM would affect outcomes in patients with TNBCwho were treated with contemporary adjuvant regimens. On the basis of results from IBCSG 22-00, adjuvant metronomic CM cannot be recommended as a therapeutic maneuver for high-risk, early-stage breast cancer. There has long been interest in other antimetabolite treatments as potential adjuvant therapies for breast cancer. Fluorouracil remains an ingredient in multiple classic adjuvant chemotherapy regimens, such as cyclophosphamide, methotrexate, and fluorouracil; cyclophosphamide, epirubicin, and flourouracil (or flourouracil, epirubicin, and then cyclophosphamide); cyclophosphamide, doxorubicin, flourouracil; and related combinations, although the benefit of the added fluorouracil is unclear. The oral fluoropyrimidine derivative capecitabine has been studied as part of adjuvant chemotherapy, with mixed results. None of the trials—National Surgical Adjuvant Breast and Bowel Project Trial B-40 (NSABP-40), the US Oncology group trial 01062, or the Finland Capecitabine Trial (FinXX)—that added capecitabine to standard anthracyclineand taxane-based chemotherapy demonstrated an overall clinical benefit. However, in the US Oncology and FinXX studies, there are suggestions of reduced recurrence among women with TNBC. The Chinese Breast Cancer Study Group (CBCSG) 10 study was