The American Society of Clinical Oncology has issued a new clinical practice guideline on the use of chemotherapy and targeted therapy for women with human epidermal growth factor 2 (HER2)-negative (or unknown) locally advanced and/or metastatic breast cancer who are being considered for treatment with chemotherapy and/or targeted therapy. This is the first clinical practice guideline ASCO has published specifically for this subset of patients.
“The vast majority of patients with advanced breast cancer are HER2-negative,” Ann Partridge, MD, MPH, Co-Chair of the ASCO panel that developed the guideline and Director of the Adult Survivorship Program at the Susan F. Smith Center for Women's Cancers at Dana Farber Cancer Institute, said in a phone interview. “So this guideline is filling a gap—where historically doctors and patients have had to digest the evolving data on their own—the recommendations are now based on the evidence and supporting that evidence with expert consensus.”
The guideline's key recommendations emphasize using hormone therapy in hormone-sensitive disease; using single-agent, sequential chemotherapy when chemotherapy is needed; and incorporating palliative care more and earlier to improve outcomes and reduce suffering.
The first recommendation in the new guideline is that endocrine therapy should be offered as the standard first-line treatment for patients with hormone receptor-positive advanced/metastatic breast cancer (versus chemotherapy), except for immediately life-threatening disease or if there is concern regarding endocrine resistance.
The main benefit for endocrine therapy, the guideline notes, is less toxicity and better quality of life for the patient; with the potential harm being that metastatic disease could progress rapidly and prove fatal if there is no response—although the risk of that harm is low.
“In a patient with hormone-sensitive breast cancer, often the best approach in terms of both control of disease as well as symptom management is to try hormonal therapy first, because it's as likely, if not more likely, to be effective and can be tolerated for a long time,” Partridge explained. Patients may mistakenly be given chemotherapy, which may be thought to be more aggressive, “but that doesn't necessarily translate to better outcomes, and certainly can translate to more toxicity.”
The quality of the evidence for the recommendation is intermediate, the guideline notes; the strength of the recommendation is strong; and it is supported by evidence and expert consensus.
The second recommendation is that 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—the benefit being less toxicity and better quality of life. A potential harm, the guideline notes, is for rapidly progressing, life-threatening disease to escape control if response to a single agent is not achieved.
“Once a patient needs chemotherapy, the bottom line is that single-agent sequential therapy is generally preferred because it tends to be both as effective and less toxic than combination therapies, and most of the time you don't need a combination,” she said.
Evidence for this recommendation is high and includes a randomized controlled trial, and the strength of the recommendation is strong, the guideline notes.
Another key recommendation is that palliative care should be offered throughout the continuum of care; and clinicians should also offer best supportive care without further chemotherapy as an option as there are diminishing returns with later lines of chemotherapy.
This includes symptom management, as well as psychosocial and other side effects, Partridge said. “We're increasingly learning the importance of paying attention to all of those concerns along the entire cancer journey, and particularly with advanced cancer.”
The evidence for the recommendation is intermediate and supported by several randomized clinical trials in patients with advanced cancer; and the strength of the recommendation is strong, the guideline notes.
Additional recommendations in the guideline are:
- In regards to targeted agents, the role of bevacizumab is controversial; 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 (but recognizing that bevacizumab is not currently approved for use in the U.S. because evidence does not show a significant survival benefit); and 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 being 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;
- Chemotherapy should be continued until disease progression, as tolerated—chemotherapy has been shown to produce a modest increase in overall survival and to substantially increase progression-free survival, but the decision to continue chemotherapy should 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—at the present time, there is an absence of evidence proving differential efficacies; and 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; and 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); and
- As there is no cure yet for patients with advanced breast cancer, clinicians should encourage all eligible patients to enroll in clinical trials, which should include the option of Phase II and targeted Phase I trials before all standard lines of therapy have been used, in the absence of immediately life-threatening disease.
ASCO notes that the new guideline is based on 79 studies conducted from 1993 to May 2013. Articles were selected for inclusion based on: including women age 18 and older with HER2-negative (or unknown) advanced breast cancer, including a minimum of 25 patients per study arm, and having been published in MEDLINE or as an abstract at specific conference proceedings.
The studies selected included 20 systematic reviews and/or meta-analyses, 30 trials on first-line treatment, and 29 trials on second-line and subsequent treatment. The expert panel was multidisciplinary, including medical oncology, community oncology, patient representation, and guideline methodology.
The guideline is now available published online ahead of print in the Journal of Clinical Oncology (doi: 10.1200/JCO.2014.56.7479).