ASCO Clinical Practice Guideline: Chemotherapy and Targeted Therapy in Advanced HER2-Negative or HER2 Status–Unknown Breast Cancer

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Ann H. Partridge, MD, and colleagues

New ASCO Clinical Practice Guideline in Breast Cancer

No single agent has demonstrated superiority in advanced breast cancer. Among those appropriate for first-line chemotherapy, evidence of efficacy is strongest for taxanes and anthracyclines.

—Ann H. Partridge, MD, and colleagues

The American Society of Clinical Oncology has released a new clinical practice guideline on chemotherapy and targeted therapy for women with advanced HER2-negative or HER2 status–unknown breast cancer. The guideline is published in the Journal of Clinical Oncology.1

In formulating the consensus guideline, an expert panel undertook a systematic review of randomized evidence from 1993 through the present to address pressing questions in the field. Data from 79 studies form the evidentiary basis of the guideline, including 20 systematic reviews or meta-analyses, 30 studies of first-line treatment options, and 29 studies of second-line or subsequent treatment.

The expert panel was co-chaired by Ann H. Partridge, MD, of Dana-Farber Cancer Institute, Boston, and Ian E. Smith, MD, of Royal Marsden Hospital, London.

A summary of guideline questions and recommendations follows.

Treatment Indications

What are the indications for chemotherapy vs endocrine therapy in estrogen receptor–positive first-relapse metastatic breast cancer?

Endocrine therapy should be standard first-line treatment in hormone receptor [HR]-positive advanced/metastatic disease, except for immediately life-threatening disease or if there is concern over endocrine resistance. The main benefit is less toxicity and better quality of life (potential benefit = high); the potential harm is that metastatic disease could progress rapidly and prove fatal in the absence of response, but risk of this is low. Quality of evidence = intermediate; strength of recommendation = strong. (Qualifying statement: The basis for the recommendation is the relative likelihood of response to chemotherapy vs endocrine therapy and not the rapidity of response, for which there are no good data.)

Optimal First-Line Regimen

Is there an optimal first-line chemotherapy or targeted therapy regimen?

Sequential single-agent chemotherapy rather than combination therapy should be offered, but combination regimens may be considered for immediately life-threatening disease. The benefit is less toxicity and better quality of life (potential benefit = high). The potential harm is for rapidly progressing, life-threatening disease to escape control in the absence of response (potential harm = high), but risk of this is low. Quality of evidence = high; strength of recommendation = strong.

With regard to targeted agents, the role of bevacizumab (Avastin) is controversial. Bevacizumab should be considered with single-agent chemotherapy only when there is immediately life-threatening disease or severe symptoms, given improved response rates observed with the combination. It is recognized that there is no currently approved indication for bevacizumab in the United States because the weight of evidence indicates no significant survival benefit. Other targeted agents should not be used in addition to or instead of chemotherapy outside of a clinical trial.

The benefit associated with targeted agents is improved disease control (potential benefit = moderate). The potential harms are unique toxicity, increased costs, and barriers to access (potential harm = high). Quality of evidence = high; strength of recommendation = moderate. (Qualifying statement: Bevacizumab added to single-agent chemotherapy improves response and progression-free survival but not overall survival.)

No single agent has demonstrated superiority in advanced breast cancer. Among those appropriate for first-line chemotherapy, evidence of efficacy is strongest for taxanes and anthracyclines. Other options include capecitabine, gemcitabine, platinum-based compounds, vinorelbine, and ixabepilone (Ixempra). Treatment selection should be based on previous therapy, differential toxicity, comorbid conditions, and patient preferences. Drugs for which clinical resistance has already been shown should not be reused.

The benefit of single-agent therapy is a patient-tailored approach with potential improvements in disease control and quality of life (potential benefit = high). The harm is the potential use of a less active agent (potential harm = low). Quality of evidence supporting activity of a number of single agents = high, but there is insufficient evidence to support superiority of any single agent; strength of the recommendation = strong.

Chemotherapy should be continued until progression of disease, 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 HR-positive disease) may be considered in some patients.

The benefits of continuing chemotherapy until disease progression are more time before progression and modestly improved survival (potential benefit = high). The harm is more-prolonged toxicity (potential harm = moderate). Quality of evidence = high; strength of recommendation = strong. (Qualifying statement: Achieving balance in continuing treatment to maintain disease control and coping with progressive toxicity is difficult and is influenced by many factors, including drug used—eg, long-term use of capecitabine is relatively easy, whereas use of docetaxel is limited by cumulative toxicity; the strategy requires a continuing dialogue between doctor and patient.)

Tailored Therapy

Should first-line treatment vary by hormone receptor status, tumor subtypes, or clinical characteristics?

Chemotherapy regimens currently should not be specifically tailored to different breast cancer subtypes (eg, triple-negative, lobular), due to absence of evidence proving differential efficacies. In addition, in vitro chemoresistance assays should not be used to select treatment.

The benefits of this nontailored approach are not omitting potentially efficacious treatment and cost-saving on in vitro assays (potential benefit = high). Strength of recommendation = moderate. (Qualifying statement: This recommendation will need to be modified if ongoing or future research suggests benefits of tailoring.)

Subsequent Therapy

Is there an optimal second- or later-line chemotherapy or targeted therapy regimen?

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. No clear evidence exists for the superiority of any regimen. Active agents include those active in first-line treatment.

The benefit of drug therapy after the first-line setting is further chance of disease control and symptomatic improvement (potential benefit = high). The harm is toxicity (potential harm = high). Strength of recommendation = strong. (Qualifying statement: The most convincing data are for eribulin [Halaven] based on survival superiority against best standard treatment in a recent large randomized controlled trial, but there is a lack of good comparative data among the various agents.)

Stopping Drug Therapy

At what point should anticancer therapy be discontinued?

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

Benefits of palliative care include a patient-centered approach emphasizing quality of life (potential benefit = high). The main harm is fear of abandonment and giving up hope, which can be addressed by effective communication and appropriate end-of-life planning (potential harm = moderate). Quality of evidence = intermediate; strength of recommendation = strong. (Qualifying statement: Response to second and subsequent lines of chemotherapy is strongly influenced by response to earlier treatment; patients with no response to up to two initial lines of treatment are less likely to respond to a third or subsequent line.)

Clinicians should encourage all eligible patients to enroll onto clinical trials, including 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. The benefits are that more patients will be directed to clinical studies providing treatment benefits and that the medical community will benefit from more research to improve treatments. The potential harm is that patients will receive inferior treatment. There is no strong evidence to suggest this approach might impair outcome. Strength of recommendation = strong. ■

Disclosure: For full disclosures of the guideline panel members, visit


1. Partridge AH, Rumble RB, Carey LA, et al: Chemotherapy and targeted therapy for women with human epidermal growth factor receptor 2–negative (or unknown) advanced breast cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. September 2, 2014 (early release online).


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