ASCO Guideline Addresses Controversial Areas in Adjuvant Therapy for Breast Cancer



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Anthracycline/taxane regimens remain a standard of care for high-risk disease, and [docetaxel/cyclophosphamide] can be considered in low-risk patients or in those with significant cardiac risk factors.
— Sara M. Tolaney, MD, MPH

ASCO has published an adaptation of the 2015 Cancer Care Ontario (CCO) clinical practice guideline on adjuvant chemotherapy for early-stage breast cancer.1 There were several areas of controversy that the guideline attempts to address.

Should Anthracyclines Be Standard of Care?

The guideline supports the use of anthracycline- and taxane-based therapy for higher-risk disease. It also suggests that, for HER2-negative disease, when an anthracycline is not preferred, docetaxel/cyclophosphamide (TC) for four cycles or cyclophosphamide/methotrexate/fluorouracil (CMF) for six cycles is an alternative to doxorubicin/cyclophosphamide (AC).

For HER2-positive disease, the guideline recommends trastuzumab (Herceptin) plus chemotherapy in patients with node-positive disease or tumors > 1 cm. Either docetaxel/carboplatin/trastuzumab or AC followed by taxane/trastuzumab is a reasonable approach for higher-risk HER2-positive disease, based on data from the Breast Cancer International Research Group (BCIRG) 006 study.2

At the time this guideline was published, data had not been available from the ABC (Anthracyclines in Early Breast Cancer) adjuvant trials.3 These studies were analyzed together and compared anthracycline/taxane regimens with six cycles of TC. They demonstrated that TC was not as effective as the anthracycline/taxane regimens, with a hazard ratio of 1.23 favoring the use of anthracyclines. The benefit was greatest within hormone receptor–negative and node-positive patients. Given these data, anthracycline/taxane regimens remain a standard of care for high-risk disease, and TC can be considered in low-risk patients or in those with significant cardiac risk factors.

Should Patients With T1abN0 HER2-Positive Tumors Receive Therapy?

For patients with node-negative tumors that are < 1 cm, the guideline states that trastuzumab plus chemotherapy can be considered. Since there are limited data available for this population from the pivotal adjuvant trials, the ASCO panel believes the decision for therapy in this group should be individualized. Data from two phase II studies for this population suggest that recurrences are rare in patients treated with chemotherapy and trastuzumab. The APT trial looked at treatment with paclitaxel and trastuzumab for 12 weeks, followed by 9 months of trastuzumab monotherapy; the investigators found that the 4-year disease-free survival was 98.7%.4 Another trial looked at treatment with docetaxel/cyclophosphamide/trastuzumab and demonstrated that for patients with node-negative tumors, the 2-year disease-free survival was 98.1%.5 Given the excellent results seen in these trials, many physicians are treating patients with HER2-positive tumors < 1 cm (particularly those with T1b tumors), despite the lack of data from randomized clinical trials, as we know from historical data in untreated patients that the risk of recurrence for this population may be as high as 10% to 20%.6,7

Should Pertuzumab Be Used in the Adjuvant Setting?

The guideline notes that pertuzumab (Perjeta) received accelerated approval by the U.S. Food and Drug Administration (FDA) in 2013 for use in the preoperative setting, based on the results of two clinical trials showing improvement in pathologic complete response with the addition of pertuzumab.8,9

At this time, the guidelines do not recommend the routine use of platinum therapy in patients receiving preoperative or adjuvant chemotherapy for triple-negative breast cancer.
— Sara M. Tolaney, MD, MPH

Data are not yet available from the already enrolled adjuvant trial, which randomized patients to receive chemotherapy with or without pertuzumab (APHINITY). If these data demonstrate improved outcomes with pertuzumab, the FDA will likely grant pertuzumab full approval. Currently, the National Comprehensive Cancer Network Guidelines® support the use of pertuzumab in the adjuvant setting. This differs from the ASCO guideline adaptation, which neither recommends nor dissuades from the use of pertuzumab.

Should Patients With Triple-Negative Breast Cancer Receive Carboplatin?

Although preoperative trials have demonstrated that adding platinum therapy to an anthracycline-and-taxane backbone improves pathologic complete response, these studies were not powered to evaluate survival outcomes and also noted higher rates of treatment discontinuation and myelosuppression.10,11 At this time, the guideline does not recommend the routine use of platinum therapy in patients receiving preoperative or adjuvant chemotherapy for triple-negative breast cancer and rather recommend awaiting results of the ongoing trial that is evaluating this question (NRG-BR003). ■ 

Disclosure: Dr. Tolaney has received research funding from Genentech, Exelixis, Lilly, Novartis, Merck, and Pfizer.

References

1. Denduluri N, Somerfield MR, Eisen A, et al: Selection of optimal adjuvant chemotherapy regimens for human epidermal growth factor receptor 2 (HER2)-negative and adjuvant targeted therapy for HER2-positive breast cancers: An American Society of Clinical Oncology guideline adaptation of the Cancer Care Ontario clinical practice guideline. J Clin Oncol 34:2416-2427, 2016.

2. Slamon DJ, Eiermann W, Robert NJ, et al: Ten year follow-up of BCIRG-006 comparing doxorubicin plus cyclophosphamide followed by docetaxel with doxorubicin plus cyclophosphamide followed by docetaxel and trastuzumab with docetaxel, carboplatin and trastuzumab in HER2+ early breast cancer. 2015 San Antonio Breast Cancer Symposium. Abstract S5-04. Presented December 11, 2015.

3. Blum JL, Flynn PJ, Yothers G, et al: Interim joint analysis of the ABC (anthracyclines in early breast cancer) phase III trials (USOR 06-090, NSABP B-46I/USOR 07132, NSABP B-49 [NRG Oncology]) comparing docetaxel + cyclophosphamide v anthracycline/taxane-based chemotherapy regimens in women with high-risk, HER2-negative breast cancer. 2016 ASCO Annual Meeting. Abstract 1000. Presented June 4, 2016.

4. Tolaney SM, Barry WT, Dang CT, et al: Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med 372:134-141, 2015.

5. Jones SE, Collea R, Paul D, et al: Adjuvant docetaxel and cyclophosphamide plus trastuzumab in patients with HER2-amplified early stage breast cancer: A single-group, open-label, phase 2 study. Lancet Oncol 14:1121-1128, 2013.

6. Vaz Duarte Luis IM, Ottesen RA, Hughes ME, et al: Time trends in the use of adjuvant chemotherapy and outcomes in women with T1N0 breast cancer in the National Comprehensive Cancer Network (NCCN). 2013 ASCO Annual Meeting. Abstract 1006.

7. Gonzalez-Angulo AM, Litton JK, Broglio KR, et al: High risk of recurrence for patients with breast cancer who have human epidermal growth factor receptor 2-positive, node-negative tumors 1 cm or smaller. J Clin Oncol 27:5700-5706, 2009.

8. Schneeweiss A, Chia S, Hickish T, et al: Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: A randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol 24:2278-2284, 2013.

9. Gianni L, Pienkowski T, Im YH, et al: Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): A randomised multicentre, open-label, phase 2 trial. Lancet Oncol 13:25-32, 2012.

10. Sikov WM, Berry DA, Perou CM, et al: Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). J Clin Oncol 33:13-21, 2015.

11. von Minckwitz G, Schneeweiss A, Loibl S, et al: Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): A randomised phase 2 trial. Lancet Oncol 15:747-756, 2014.


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ASCO Adapts CCO Guideline on Selection of Optimal Adjuvant Therapies for HER2-Negative and HER2-Positive Breast Cancers


No phase III evidence exists for the addition of trastuzumab to some chemotherapy regimens, such as docetaxel/cyclophosphamide. However, those regimens might be in use and are reasonable options, particularly for mitigating cardiotoxicity in certain patients.
— Neelima...


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