NCCN: Continuing Education
Accreditation Statement
This activity has been designed to meet the educational needs of physicians, nurses, and pharmacists involved in the management of patients with cancer. There is no fee for this article. The National Comprehensive Cancer Network (NCCN) is accredited by the ACCME to provide continuing medical education for physicians. NCCN designates this journal-based CE activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
NCCN is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center‘s Commission on Accreditation.
NCCN designates this educational activity for a maximum of 1.0 contact hour. Accreditation as a provider refers to recognition of educational activities only; accredited status does not imply endorsement by NCCN or ANCC of any commercial products discussed/displayed in conjunction with the educational activity. Kristina M. Gregory, RN, MSN, OCN, is our nurse planner for this educational activity.
National Comprehensive Cancer Network is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. NCCN designates this continuing education activity for 1.0 contact hour(s) (0.1 CEUs) of continuing education credit in states that recognize ACPE accredited providers. This is a knowledge-based activity. UAN: 0836-0000-15-011-H01-P
All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the learning objectives and author disclosures; 2) study the education content; 3) take the posttest with a 66% minimum passing score and complete the evaluation at http://education.nccn.org/node/77396; and 4) view/print certificate.
Release date: December 21, 2015; Expiration date: December 21, 2016.
Learning Objectives:
Upon completion of this activity, participants will be able to:
Integrate into professional practice the updates to the NCCN Guidelines for Breast Cancer
Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Breast Cancer
NCCN Guidelines Insights: Breast Cancer, Version 1.2016
Version 1.2016 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 12; 10.6004/jnccn.2015.0176
NCCN Categories of Evidence and Consensus
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Overview
Breast cancer is the most common malignancy in women in the United States and is second only to lung cancer as a cause of cancer death. The American Cancer Society estimates that 234,190 Americans will be diagnosed with breast cancer and 40,730 will die of the disease in the United States in 2015.1 The therapeutic options for patients with noninvasive or invasive breast cancer are complex and varied. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer include up-to-date guidelines for the clinical management of patients with carcinoma in situ, invasive breast cancer, Paget's disease, Phyllodes tumor, inflammatory breast cancer, and breast cancer during pregnancy. These guidelines are developed by a multidisciplinary panel of representatives from NCCN Member Institutions with breast cancer–focused expertise in the fields of medical oncology, surgical oncology, radiation oncology, pathology, reconstructive surgery, and patient advocacy.
NCCN Guidelines Insights: Breast Cancer, Version 1.2016
Version 1.2016 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 12; 10.6004/jnccn.2015.0176
These NCCN Guidelines Insights highlight the important updates/changes specific to the update of systemic therapies in the 2016 version of the NCCN Guidelines for Breast Cancer. These include an outline of the principles of preoperative systemic therapy; new adjuvant endocrine therapy options for premenopausal women and for women with hormone receptor–positive, recurrent, or stage IV disease; and updated recommendations for adotrastuzumab emtansine (T-DM1) for patients with HER2-positive metastatic breast cancer.
Principles of Preoperative Systemic Therapy
The NCCN Breast Cancer Panel has outlined the rationale, appropriate patient selection, and response assessment for preoperative systemic therapy in a new section titled “Principles of Preoperative Systemic Chemotherapy” (see BINV-L, pages 1477–1478).
Rationale for Preoperative Chemotherapy
Randomized clinical trials have found no significant differences in long-term outcomes when systemic chemotherapy is given before or after surgery.2,3 Historically, a primary advantage of administering preoperative systemic therapy has been to improve surgical outcomes. Preoperative systemic therapy can render inoperable tumors resectable and also allow the downstaging of patients with operable breast cancer who desire breast conservation.4 Results from large clinical trials and retrospective reviews indicate that breast-conservation rates are improved with preoperative systemic therapy.3,5 Clinicians need to carefully consider the extent of disease in the breast and the likelihood of adequate tumor response before recommending preoperative systemic therapy in order to improve the likelihood of successful breast conservation.
In addition, use of preoperative systemic therapy may provide important prognostic information based
NCCN Guidelines Insights: Breast Cancer, Version 1.2016
Version 1.2016 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 12; 10.6004/jnccn.2015.0176
Other benefits of preoperative systemic therapy are that it allows time for appropriate genetic testing and for planning breast reconstruction in patients proceeding with mastectomy. For those with significant residual disease after standard preoperative systemic therapy, it may provide an opportunity to identify patients who are candidates for clinical trials of novel agents in the adjuvant setting. To date, the tailoring of therapy based on poor response to standard preoperative chemotherapy has not yet shown improved outcomes. Preoperative systemic therapy also serves as an excellent research platform to test novel therapies and predictive biomarkers by providing tumor specimens and blood samples before and during systemic treatment.
Selection of Patients for Preoperative Therapy
Not all patients are appropriate candidates for preoperative systemic therapy. According to the NCCN Breast Cancer Panel, among patients with inoperable breast tumors, preoperative systemic therapy is indicated in those with locally advanced or inoperable breast cancer, including those with inflammatory breast cancer, those with N2 and N3 regional lymph node nodal disease, and those with T4 tumors. In patients with operable breast cancer who are clear candidates for adjuvant chemotherapy, preoperative systemic therapy may be administered if a patient desires breast-conserving surgery but surgery
NCCN Guidelines Insights: Breast Cancer, Version 1.2016
Version 1.2016 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 12; 10.6004/jnccn.2015.0176
The NCCN Breast Cancer Panel cautions that preoperative systemic therapy is not appropriate for certain patients. Preoperative systemic therapy should not be offered for patients with extensive in situ disease for whom the extent of invasive disease cannot be defined; in patients in whom the extent of the tumor is poorly delineated; or in those whose tumors are not palpable or clinically assessable. The decision to use preoperative therapy should be made in the context of a coordinated and collaborative multidisciplinary team.
Preoperative Systemic Therapy Options
Chemotherapy: A number of chemotherapy regimens have activity in the preoperative setting. According to the panel, the regimens recommended in the adjuvant setting may be considered in the preoperative setting. In both settings, the underlying goal remains the same: eradication or control of undiscovered distant metastases.
Endocrine Therapy: Neoadjuvant endocrine therapy alone may be offered to those with strongly hormone receptor–positive tumors.9–15 According to
NCCN Guidelines Insights: Breast Cancer, Version 1.2016
Version 1.2016 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 12; 10.6004/jnccn.2015.0176
HER2-Targeted Therapy: For patients with HER2-positive breast cancer who are candidates for preoperative systemic therapy, chemotherapy and trastuzumab-based therapy is recommended.16 Chemotherapy and dual anti-HER2 blockade associated with trastuzumab plus pertuzumab has shown significant improvements in the pCR rate when compared with chemotherapy and one anti-HER2 agent in the preoperative setting.17–19 In the Neosphere trial, the addition of pertuzumab to trastuzumab and docetaxel preoperatively led to a statistically significant increase in pCR in the breast (16.8% increase; 95% CI, 3.5–30.1; P=.0141).19 In the TRYPHAENA trial, preoperative therapy with pertuzumab and trastuzumab given along with anthracycline-containing or anthracycline-free standard chemotherapy regimens to patients with operable, locally advanced, or inflammatory HER2-positive breast cancer showed pCR rates in all treatment arms ranging from 57% to 66%.20 The mean change in left ventricular ejection fraction was similar in all treatment arms.20 The NCCN Breast Cancer Panel supports the FDA-approved indication that a pertuzumab-containing regimen may be administered preoperatively to patients with greater than or equal to T2 or greater than or equal to N1 HER2-positive, early-stage breast cancer.
Response Assessment During Preoperative Chemotherapy: The panel recommends that tumor response should be routinely assessed by clinical examination during the delivery of preoperative systemic therapy. Patients with operable breast cancer experiencing progression of disease while undergoing
NCCN Guidelines Insights: Breast Cancer, Version 1.2016
Version 1.2016 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 12; 10.6004/jnccn.2015.0176
New Adjuvant Endocrine Therapy Options for Premenopausal Women
Recent data from the randomized TEXT and SOFT trials evaluating adjuvant endocrine therapy show that the AI exemestane plus ovarian suppression significantly reduces recurrences compared with tamoxifen plus ovarian suppression.
In the TEXT and SOFT randomized trials, premenopausal women with hormone receptor–positive early-stage breast cancer were assigned to receive exemestane plus ovarian suppression or tamoxifen plus ovarian suppression for 5 years.21 Suppression of ovarian estrogen production was achieved with the use of the gonadotropin-releasing hormone agonist triptorelin, oophorectomy, or ovarian irradiation. The DFS was 92.8% in the exemestane plus ovarian suppression group, compared with 88.8% in the tamoxifen plus ovarian suppression group (hazard ratio [HR] for recurrence, 0.66; 95% CI, 0.55–0.80; P<.001).21 The OS did not differ significantly between the 2 groups (HR for death in the exemestane plus ovarian suppression group, 1.14; 95% CI, 0.86–1.51; P=.37).21
In the SOFT trial,22 premenopausal women with hormone receptor–positive breast cancer were randomized to tamoxifen alone, tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression for 5 years. In the primary analysis, tamoxifen plus ovarian suppression was not superior to tamoxifen alone for DFS. After 67 months of median follow-up, the DFS rate at 5 years was 86.6% in the tamoxifen/ovarian suppression group and 84.7% in the tamoxifen alone group (HR, 0.83; 95% CI, 0.66–1.04; P=.10).22 In a subgroup analysis, women at high risk of recurrence who received prior chemotherapy had improved outcomes with ovarian suppression. Their chance of remaining disease-free at 5 years was 78% with tamoxifen alone, 82.5% with tamoxifen and ovarian suppression, and 85.7% with exemestane and ovarian suppression.22 In the subgroup of women with no prior chemotherapy, no meaningful benefit was seen from ovarian suppression, because women who received tamoxifen alone had a 95% chance of remaining disease-free for 5 years.22 The overall survival data from these trials are still pending because the overall follow-up is relatively short in the context of endocrine-sensitive disease.
NCCN Recommendations
Based on the results of the SOFT and TEXT trials, the NCCN Breast Cancer Panel has included ovarian suppression plus an AI for 5 years as an adjuvant endocrine therapy option for premenopausal women with hormone receptor–positive breast cancer who are at higher risk of recurrence (young age, high-grade tumor, lymph node involvement) (see BINV-J, page 1479).
New Endocrine Therapy Options for Metastatic Breast Cancer
Palbociclib, a highly selective inhibitor of CDK 4/6 kinase activity, has a role in treating women with estrogen receptor (ER)–positive metastatic breast cancer in combination with endocrine therapy. A phase II, open-label, randomized, multicenter trial evaluated the safety and efficacy of palbociclib in combination with letrozole versus letrozole alone as first-line treatment for patients with advanced ER-positive, HER2-negative breast cancer.23 The reported median progression-free survival (PFS) was double with the combination regimen compared with letrozole alone (20.2 months for the palbociclib plus letrozole group and 10.2 months for the letrozole alone group; HR, 0.488; 95% CI, 0.319–0.748).23 Grade 3/4 adverse reactions reported at a higher incidence in the palbociclib plus letrozole versus letrozole alone group included neutropenia (54% vs 1%) and leukopenia (19% vs 0%). Based on this study, the FDA approved palbociclib in combination with letrozole for the treatment of postmenopausal women with ER-positive, HER2-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease.
The phase III trial (PALOMA-3) compared the combination of palbociclib and fulvestrant versus fulvestrant alone in premenopausal or postmenopausal patients with hormone receptor–positive, HER2-negative advanced breast cancer whose disease progressed on previous endocrine therapy. Premenopausal or perimenopausal patients also received goserelin. The median PFS was 9.2 months for the combination compared with 3.8 months for fulvestrant alone (HR, 0.42; P<.000001), with similar discontinuation rates because of adverse effects (2.6% and 1.7%, respectively).24 Grade 3/4 adverse events of palbociclib and fulvestrant were mainly confined to neutropenia, with the same low incidence (0.6%) of febrile neutropenia in both arms. Overall survival data from this trial are immature.24
NCCN Recommendations
The NCCN Breast Cancer Panel has included the combination of palbociclib with letrozole as a first-line endocrine therapy option for postmenopausal patients with hormone receptor–positive, HER2-negative metastatic breast cancer. In addition, the recently updated version of these guidelines includes palbociclib with fulvestrant as a category 1 option for women with hormone receptor–positive (postmenopausal or premenopausal women receiving ovarian suppression with an luteinizing hormone–releasing hormone agonist), HER2-negative metastatic breast cancer whose disease has progressed on endocrine therapy (see BINV-N, page 1480).
New Option for First-Line HER2-Targeted Therapy in Select Patients With Metastatic Breast Cancer
HER2 is a proto-oncogene located on chromosome 17 and is amplified in 15% to 20% of breast carcinomas.25 Before the approval of trastuzumab, amplification of HER2 was considered a poor prognostic factor in patients with metastatic breast cancer. With the introduction of trastuzumab, the outcomes of patients with HER2-postive metastatic breast cancer dramatically improved.26 Newer drugs targeting the HER2 pathway, including pertuzumab and adotrastuzumab emtansine (T-DM1), have been developed and added to the current standard of care.27
In a phase III trial (MARIANNE), 1095 patients with locally advanced or metastatic breast cancer were randomized to first-line treatment with T-DM1 with or without pertuzumab or to treatment with trastuzumab plus a taxane. The primary end points were safety and PFS assessed by independent review. The PFS for T-DM1 with pertuzumab was found to be noninferior to trastuzumab and a taxane (15.2 and 13.7 months, respectively; HR, 0.87; 97.5% CI, 0.69–1.08; P=.14).28 The PFS for T-DM1 alone was noninferior to trastuzumab plus a taxane (14.1 and 13.7, respectively; HR, 0.91; 97.5% CI, 0.73–1.13; P=.31).28 The incidence of grades 3 through 5 adverse events was 54.1%, 45.4%, and 46.2% in the trastuzumab plus a taxane arm, T-DM1 arm, and T-DM1 plus pertuzumab arm, respectively. Health-related quality of life was maintained for a longer duration, with a median of 7.7 months for T-DM1 (HR, 0.70; 95% CI, 0.57–0.86) and a median of 9 months for T-DM1 plus pertuzumab (HR, 0.68; 95% CI, 0.55–0.84) compared with a median of 3.9 months for trastuzumab and a taxane.28
NCCN Recommendations
Based on the MARIANNE trial data demonstrating T-DM1 and T-DM1 with pertuzumab being noninferior, with better quality of life compared with trastuzumab plus taxane, and possibly better-tolerated for some patients,28 the NCCN panel included T-DM1 as one of the first-line options for the treatment of patients with HER2-positive metastatic breast cancer (see BINV-O and BINV-22, pages 1481 and 1482, respectively). Pertuzumab, trastuzumab, and a taxane, however, remains the preferred frontline regimen for HER2-positive metastatic disease based on data demonstrating improved OS compared with trastuzumab and a taxane. TDM-1 as first-line therapy should be considered only in patients not suitable for the preferred treatment.
Conclusions
The NCCN Guidelines are in continuous evolution. They are updated annually, and sometimes more often when new high-quality clinical data become available in the interim. The recommendations in the NCCN Guidelines for Breast Cancer, with few exceptions, are based on the evidence from clinical trials. Expert medical clinical judgment is required to apply these guidelines in the context of an individual patient to provide optimal care. Ultimately, the physician and the patient have the responsibility to jointly explore and select the most appropriate option from among the available alternatives. When possible, consistent with NCCN philosophy, the panel strongly encourages patient/physician participation in prospective clinical trials. The full version of the 2016 NCCN Guidelines for Breast Cancer is available online (NCCN.org).
References
- 2.↑
Mauri D, Pavlidis N, Ioannidis JP. Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis. J Natl Cancer Inst 2005;97:188–194.
- 3.↑
Rastogi P, Anderson SJ, Bear HD et al.. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol 2008;26:778–785.
- 4.↑
Gralow JR, Burstein HJ, Wood W et al.. Preoperative therapy in invasive breast cancer: pathologic assessment and systemic therapy issues in operable disease. J Clin Oncol 2008;26:814–819.
- 5.↑
Killelea BK, Yang VQ, Mougalian S et al.. Neoadjuvant chemotherapy for breast cancer increases the rate of breast conservation: results from the National Cancer Database. J Am Coll Surg 2015;220:1063–1069.
- 6.↑
Liedtke C, Mazouni C, Hess KR et al.. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol 2008;26:1275–1281.
- 7.
Cortazar P, Zhang L, Untch M et al.. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 2014;384:164–172.
- 8.↑
von Minckwitz G, Untch M, Blohmer JU et al.. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol 2012;30:1796–1804.
- 9.↑
Cataliotti L, Buzdar AU, Noguchi S et al.. Comparison of anastrozole versus tamoxifen as preoperative therapy in postmenopausal women with hormone receptor-positive breast cancer: the Pre-Operative “Arimidex” Compared to Tamoxifen (PROACT) trial. Cancer 2006;106:2095–2103.
- 10.
Smith IE, Dowsett M, Ebbs SR et al.. Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: the Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) multicenter double-blind randomized trial. J Clin Oncol 2005;23:5108–5116.
- 11.
Eiermann W, Paepke S, Appfelstaedt J et al.. Preoperative treatment of postmenopausal breast cancer patients with letrozole: a randomized double-blind multicenter study. Ann Oncol 2001;12:1527–1532.
- 12.
Ellis MJ, Ma C. Letrozole in the neoadjuvant setting: the P024 trial. Breast Cancer Res Treat 2007;105(Suppl 1):33–43.
- 13.
Ellis MJ, Suman VJ, Hoog J et al.. Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype--ACOSOG Z1031. J Clin Oncol 2011;29:2342–2349.
- 14.
Masuda N, Sagara Y, Kinoshita T et al.. Neoadjuvant anastrozole versus tamoxifen in patients receiving goserelin for premenopausal breast cancer (STAGE): a double-blind, randomised phase 3 trial. Lancet Oncol 2012;13:345–352.
- 15.↑
Torrisi R, Bagnardi V, Rotmensz N et al.. Letrozole plus GnRH analogue as preoperative and adjuvant therapy in premenopausal women with ER positive locally advanced breast cancer. Breast Cancer Res Treat 2011;126:431–441.
- 16.↑
Petrelli F, Borgonovo K, Cabiddu M et al.. Neoadjuvant chemotherapy and concomitant trastuzumab in breast cancer: a pooled analysis of two randomized trials. Anticancer Drugs 2011;22:128–135.
- 17.↑
Piccart-Gebhart M, Holmes AP, de Azambuja E et al.. The association between event-free survival and pathological complete response to neoadjuvant lapatinib, trastuzumab or their combination in HER2-positive breast cancer. Survival follow-up analysis of the NeoALTTO study (BIG 1-06) [abstract]. Cancer Res 2013;73:Abstract S1–01.
- 18.
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 2012;13:25–32.
- 19.↑
Gianni L, Pienkowski T, Im YH et al.. Five-year analysis of the phase II NeoSphere trial evaluating four cycles of neoadjuvant docetaxel (D) and/or trastuzumab (T) and/or pertuzumab (P) [abstract]. J Clin Oncol 2015;33:Abstract 505.
- 20.↑
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 2013;24:2278–2284.
- 21.↑
Pagani O, Regan MM, Walley BA et al.. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med 2014;371:107–118.
- 22.↑
Francis PA, Regan MM, Fleming GF et al.. Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med 2015;372:436–446.
- 23.↑
Finn RS, Crown JP, Lang I et al.. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol 2015;16:25–35.
- 24.↑
Turner NC, Ro J, Andre F et al.. Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med 2015;373:209–219.
- 25.↑
Wolff AC, Hammond MEH, Schwartz JN et al.. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 2007;25:118–145.
- 26.↑
Dawood S, Broglio K, Buzdar AU et al.. Prognosis of women with metastatic breast cancer by HER2 status and trastuzumab treatment: an institutional-based review. J Clin Oncol 2010;28:92–98.
- 27.↑
Baselga J, Cortes J, Kim SB et al.. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 2012;366:109–119.
- 28.↑
Ellis PA, Barrios CH, Eiermann W et al.. Phase III, randomized study of trastuzumab emtansine (T-DM1) {+/-} pertuzumab (P) vs trastuzumab + taxane (HT) for first-line treatment of HER2-positive MBC: primary results from the MARIANNE study [abstract]. J Clin Oncol 2015;33:Abstract 507.
