Chemotherapy and Targeted Therapy for Women with HER2-negative (or unknown) Advanced Breast Cancer

Endocrine therapy, rather than chemotherapy, should be offered as the standard first-line treatment for patients with hormone receptor-positive advanced/metastatic breast cancer, except for immediately life threatening disease or if there is concern regarding endocrine resistance.

Sequential single-agent chemotherapy rather than combination therapy should be offered, although combination regimens may be considered for immediately life-threatening disease for which time may allow only one potential chance for therapy.

With regard to targeted agents, the role of bevacizumab is controversial, and this therapy should be considered (where available) with single-agent chemotherapy only when there is immediately life-threatening disease or severe symptoms, in view of improved response rates. It is recognized that there is not currently an approved indication for bevacizumab in the United States because the weight of evidence shows no significant survival benefit. Other targeted agents should not be used either in addition to, or as a replacement for, chemotherapy in this setting outside of a trial.

No single agent has demonstrated superiority in the treatment of patients with advanced breast cancer, and there are several active agents appropriate for first-line chemotherapy. The evidence for efficacy is strongest for taxanes and anthracyclines. Other options include capecitabine, gemcitabine, platinum-based compounds, vinorelbine, and ixabepilone. Treatment selection should be based on previous therapy, differential toxicity, comorbid conditions, and patient preferences. Specifically, drugs for which clinical resistance has already been shown should not be reused. The evidence quality supporting the activity of a number of single agents is high, but there is insufficient evidence to support superiority of any single agent.

Chemotherapy should be continued until progression of disease as tolerated because it modestly improves overall survival and substantially improves progression-free survival, but this has to be balanced against toxicity and quality of life. Short breaks, flexibility in scheduling, or a switch to endocrine therapy (in patients with hormone receptor-positive disease) may be offered to selected patients.

Chemotherapy regimens should not be specifically tailored to different breast cancer subtypes (e.g. triple negative, lobular) at the present time due to the absence of evidence proving differential efficacies. In addition, in vitro chemoresistance assays should not be used to select treatment.

Second- and later-line therapy may be of clinical benefit and should be offered as determined by previous treatments, toxicity, coexisting medical conditions, and patient choice. As with first-line treatment, no clear evidence exists for the superiority of one specific drug or regimen. Active agents include those active in first-line treatment. The quality of the evidence ranges from high to low as reported in multiple randomized trials.

Palliative care should be offered throughout the continuum of care. As there are diminishing returns with later lines of chemotherapy, clinicians should also offer best supportive care without further chemotherapy as an option.

As there is no cure yet for patients with advanced breast cancer, clinicians should encourage all eligible patients to enroll onto clinical trials. This should include the option of phase II and even targeted phase I trials before all standard lines of therapy have been used, in the absence of immediately life-threatening disease. There is no strong evidence to suggest this approach might impair outcome.