ASCO 2013 Report — Breast Cancer
ASCO 2013 Report — Breast Cancer
- William J. Gradishar, MDAU1223
A review of the latest treatment regimens
- William J. Gradishar, MDAU1223
At this year's annual meeting of the American Society of Clinical Oncology (ASCO 2013), held May 31 through June 5 in Chicago, specialists discussed the latest findings in cancer research. The editors of Journal Watch Oncology and Hematology were in attendance to report highlights of the conference. Here, Editor-in-Chief William Gradishar, MD, reviews presentations on new breast cancer treatments.
Longer-Duration Tamoxifen Therapy Is Beneficial
The standard duration of adjuvant tamoxifen therapy for patients with estrogen receptor (ER)–positive breast cancer has been 5 years since follow-up of the NSABP B-14 trial (J Natl Cancer Inst 2001; 93:684) showed that longer durations of the ER inhibitor tamoxifen were associated with statistically inferior disease-free survival (DFS) and a trend toward inferior overall survival. Although aromatase inhibitors (AIs) have gained widespread use in postmenopausal patients, tamoxifen continues to be used in sequence with AIs or in those who cannot tolerate AIs, and it remains the adjuvant endocrine therapy of choice for premenopausal women.
In contrast to the NSABP B-14 study findings, a pooled analysis of 17,477 breast cancer patients in the recently published ATLAS trial (JW Oncol Hematol Dec 11 2012) and the aTTom trial by Gray and colleagues (Abstract 5) demonstrates that longer-duration tamoxifen therapy confers benefit.
Patients who received 10 versus 5 years of tamoxifen achieved a 9% reduction in the risk for death (P=0.008) and a 15% reduction in recurrences (P=0.003). No increase in non–breast cancer deaths was observed with longer-duration therapy. Of note, the benefit was not evident for 10 years, reflecting the known carryover effect of tamoxifen. Although an increase in thrombotic events and endometrial carcinoma occurred with longer-duration therapy, the improvements in breast cancer endpoints translated into a net benefit.
Premenopausal women with an elevated risk for recurrence would be considered for longer-duration tamoxifen therapy, but the decision must include consideration of the toxicity of ongoing treatment, effects on fertility and family planning, and the reality of diminishing compliance. Postmenopausal women unable to tolerate AIs would also be candidates for longer durations of tamoxifen.
Adjuvant Paclitaxel: Weekly or Every 2 Weeks?
One common adjuvant chemotherapy regimen is the dose-dense schedule of the anthracycline doxorubicin (A) plus cyclophosphamide (C) followed by the taxane paclitaxel (T; AC every 2 weeks for 4 cycles, followed by T every 2 weeks for 4 cycles). Alternatively, the taxane component could be administered weekly for 12 weeks. Which approach is chosen is frequently based on physician preference, convenience, and tolerability.
Now, findings from the SWOG 0221 trial by Budd and colleagues (Abstract CRA1008) suggest that a weekly schedule may be preferred. In the trial, 3200 patients who completed adjuvant AC therapy were randomized to receive T either every 2 weeks (175 mg/m2 for 6 cycles) or weekly (80 mg/m2 for 12 cycles).
At follow-up of 4.4 years, the two groups achieved equivalent disease-free survival. The weekly versus 2-week regimen was associated with less musculoskeletal toxicity (3% vs. 11%), fewer allergic reactions (6% vs. 14%), and less neuropathy (10% vs. 17%); grade 3 or 4 hematologic toxicity was more common with the weekly regimen (17% vs. 6%; P<0.001).
As noted in the discussion, determining whether a meaningful difference between the regimens exists will require additional analysis that includes integration of disease subtypes, regimens, and outcomes. For now, any of the current anthracycline/taxane regimens listed by the National Comprehensive Cancer Network would be reasonable choices for adjuvant chemotherapy in breast cancer.
Everolimus Improves Progression-Free Survival
Inhibition of the mammalian target of rapamycin (mTOR) is important for overcoming endocrine resistance in ER-positive breast cancer, and positive results from the BOLERO-2 trial (N Engl J Med 2012 Feb 9; 366:520) led to the approval of the mTOR inhibitor everolimus in combination with exemestane for patients who develop progressive disease after treatment with a nonsteroidal aromatase inhibitor. The importance of the mTOR signaling pathway is not restricted to endocrine-sensitive breast cancer. Preclinical data suggest that targeting human epidermal growth factor receptor-2 (HER2) and mTOR may overcome trastuzumab resistance.
Now, O'Regan and colleagues have conducted the multicenter, phase III, randomized, controlled, double-blind BOLERO-3 trial (Abstract 505) to evaluate the combination of the mTOR inhibitor everolimus, the chemotherapy agent vinorelbine, and the HER2 inhibitor trastuzumab versus vinorelbine and trastuzumab in 569 patients with HER2-positive advanced breast cancer; 84% of patients received trastuzumab in the metastatic disease setting and developed disease progression, whereas 16% developed disease progression while receiving adjuvant trastuzumab or within 12 months of receiving it. Patients could have received up to three treatment regimens for metastatic disease; 27% of patients received prior lapatinib.
The inclusion of everolimus conferred a significant improvement in progression-free survival (7.0 vs. 5.8 months; P=0.0067) but no improvement in rates of overall survival (at current follow-up), objective response, or clinical benefit. The addition of everolimus to chemotherapy (5 mg daily) was associated with toxicities similar to that seen when everolimus was combined with the AI exemestane: stomatitis, fatigue, rash, hyperglycemia, and rare pneumonitis.
The combination of everolimus, vinorelbine, and trastuzumab may provide yet another option for patients with HER2-positive metastatic breast cancer. But, if approved, it will likely be positioned after both first-line trastuzumab, pertuzumab, and a taxane and second-line trastuzumab emtansine (T-DM1; JW Oncol Hematol Feb 26 2013). Other treatment considerations in this space include lapatinib and capecitabine, alternative trastuzumab/chemotherapy combinations, and the combination of trastuzumab and lapatinib.
Editor Disclosures at Time of Publication
Disclosures for William J. Gradishar, MD at time of publication Consultant / Advisory board Biologics, Inc.; Celgene; Myriad; Novartis Grant / research support Breast Cancer Research Fund Editorial boards Clinical Breast Cancer; Journal of Clinical Oncology; Oncology