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Breast Cancer and HER2 Overview of HER2 Breast Cancer

  • Author: Maurie Markman, MD, MS; Chief Editor: Karl S Roth, MD  more...
 
Updated: Aug 24, 2015
 

Practice Essentials

ERBB2 is a transmembrane tyrosine kinase receptor and a member of the ErbB protein family (ie, the epidermal growth factor receptor [EGFR] family). ERBB2 is most commonly known as HER2 and sometimes also as NEU. For this article, it will be referred to as HER2. HER2 gene product is overexpressed in 18-20% of invasive breast cancers.[1]

The American Society of Clinical Oncology and the College of American Pathologists issued the following updated recommendations for HER2 testing in breast cancer[2] :

  • HER2 status should be determined in all patients with invasive breast cancer on the basis of 1 or more test results.
  • HER2-positive status is indicated by evidence of protein overexpression or gene amplification.
  • When results are equivocal, reflex testing should be performed with an alternative assay, and repeat testing should be considered if results are discordant with other findings.
  • Laboratories should be able to show high concordance with a validated HER2 test on a large and representative set of specimens, and testing must be performed in an accredited laboratory.
  • Providers should recommend HER2-targeted therapies if the patient's HER2 test result is positive and such treatment is clinically appropriate. Most experts do not recommend HER2-targeted therapy if the HER2 test result is negative and there is no histopathologic discordance with HER2 testing. Delay the decision to recommend HER2-targeted therapy if the HER2 test result is equivocal. Reflex testing should be done on the same specimen.

These recommendations have also been adapted and studied in other countries, such as England, France, and Italy.[3, 4, 5]

Testing for HER2

Testing for HER2 may be done by means of either immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH).

The scoring method for HER2 expression on IHC is based on the cell membrane staining pattern and is as follows:

  • 3+: Positive HER2 expression - Uniform intense membrane staining of more than 30% of invasive tumor cells.
  • 2+: Equivocal for HER2 protein expression - Complete membrane staining that is either nonuniform or weak in intensity but has circumferential distribution in at least 10% of cells.
  • 0 or 1+: Negative for HER2 protein expression.
  • HER2 test results must be reported as indeterminate if technical issues prevent one or both tests from being interpreted accurately.

FISH has been used to establish HER2 status when IHC yields equivocal results, but it is now also being used alone for this purpose in an increasing number of centers. The interpretation for HER2 FISH testing (HER2-to-CEP17 ratio and gene copy number) is as follows:

  • Positive HER2 amplification: FISH ratio higher than 2.2 or HER2 gene copy greater than 6.0.
  • Equivocal HER2 amplification: FISH ratio of 1.8-2.2 or HER2 gene copy of 4.0-6.0.
  • Negative HER2 amplification: FISH ratio lower than 1.8 or HER2 gene copy less than 4.0.

Treatment of HER2-positive breast cancer

HER2 agents used in adjuvant therapy for HER2-positive breast cancer include the following:

  • Trastuzumab
  • Lapatinib, particularly in combination with capecitabine
  • Pertuzumab

Agents used in the treatment of HER2-positive metastatic breast cancer include the following:

  • Trastuzumab (in conjunction with other chemotherapy)
  • Trastuzumab emtansine
  • Lapatinib
  • Pertuzumab

Novel HER2 agents under evaluation include the following:

  • Ado-trastuzumab
  • Neratinib
  • Amrubicin
  • Dasatinib
  • HER2 chimeric receptor and TGF-beta dominant negative receptor expressing EBV-specific lymphocytes
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Overview of HER2 Breast Cancer

ERBB2 is a transmembrane tyrosine kinase receptor and a member of the ErbB protein family, more commonly known as the epidermal growth factor receptor (EGFR) family. ERBB2 is most commonly known as HER2 and sometimes as also NEU. For this article, it will be referred to as HER2. Activation of this class of cellular receptors is known to result in increased activity of a variety of molecular pathways associated with tumor growth and progression. HER2 gene product is overexpressed in 18-20% of invasive breast cancers, which has both prognostic and predictive implications.

Before the routine use of trastuzumab (Herceptin, a monoclonal antibody) in adjuvant therapy, HER2 overexpression was associated with a more aggressive tumor phenotype and worse prognosis (higher rate of recurrence and mortality), independent of other clinical features (eg, age, stage, tumor grade), especially in patients who did not receive adjuvant chemotherapy.

Additionally, HER2 status has been shown to be predictive for response to certain chemotherapeutic agents (ie, doxorubicin [Adriamycin]; and HER2-targeted therapies trastuzumab, pertuzumab, and lapatinib [Tykerb, a small-molecule oral tyrosine kinase inhibitor directed specifically to the HER2 receptor]).

Retrospectively analyzed results from clinical trials have shown that HER2-positive patients benefit from anthracycline-based regimens secondary to the co-amplification of topoisomerase II with HER2. Preliminary data also suggest that HER2 may predict response to and benefit from paclitaxel in the adjuvant setting.

Go to Breast Cancer for complete information on this topic.

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Testing for HER2

Although several methods for HER2 testing have been developed, approximately 20% of current HER2 testing may be inaccurate. Therefore, the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) have recommended guidelines in HER2 testing to ensure accuracy.

Breast cancer specimens should initially undergo HER2 testing by a validated immunohistochemistry (IHC) assay (ie, HercepTest, Dako, Glostrup, Denmark) for HER2 protein expression.[6] The scoring method for HER2 expression is based on the cell membrane staining pattern and is as follows:

  • 3+: Positive HER2 expression - Uniform intense membrane staining of more than 30% of invasive tumor cells.
  • 2+: Equivocal for HER2 protein expression - Complete membrane staining that is either nonuniform or weak in intensity but has circumferential distribution in at least 10% of cells.
  • 0 or 1+: Negative for HER2 protein expression.

Breast cancer specimens with equivocal IHC should undergo validation using a HER2 gene amplification method, such as fluorescence in situ hybridization (FISH). More centers are relying on FISH alone for determining HER2 status.

In general, FISH testing is thought to be more reliable than IHC, but it is more expensive. Equivocal IHC results can be seen in 15% of invasive breast cancers, whereas equivocal HER2 FISH results are seen in less than 3% of invasive breast cancer specimens and those that had previously been considered HER2 positive. Discordant results (IHC 3+/FISH negative or IHC less than 3+/FISH positive) have been observed in approximately 4% of specimens. Currently, no data support excluding this group from treatment with trastuzumab.

Newer methodologies for establishing HER2 status, including reverse transcriptase–polymerase chain reaction (RT-PCR) and chromogenic in situ hybridization (CISH), have not yet been validated. The interpretation for HER2 FISH testing (HER2/CEP17 ratio and gene copy number) is given below:

  • Positive HER2 amplification: FISH ratio is greater than 2.2 or HER2 gene copy is greater than 6.0.
  • Equivocal HER2 amplification: FISH ratio of 1.8-2.2 or HER2 gene copy of 4.0-6.0.
  • Negative HER2 amplification: FISH ratio is less than 1.8 or HER2 gene copy of less than 4.0.
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Adjuvant Therapy for HER2-Positive Breast Cancer

Overexpression of HER2 occurs in approximately 20% of breast cancers and was correlated with a more aggressive phenotype and worse prognosis before the development of HER2-targeted therapies. The advent of trastuzumab, a monoclonal antibody (mAb) targeting the extracellular domain of the receptor, has changed the treatment paradigm for HER2-positive breast cancer. Trastuzumab has a powerful synergism with a variety of chemotherapeutics, yet lacks the side effects (with the notable exception of cardiotoxicity, which means it generally should not be given with anthracyclines).

Results are available from studies (HERA, FinHer, NSABP B-31, BCIRG006, N9831) that have demonstrated that the inclusion of trastuzumab produces roughly a 50% improvement in disease-free survival and 33% improvement in overall survival, regardless of the chemotherapy regimen or sequence of trastuzumab delivery. These trials randomized 11,650 women with early-stage HER2-positive breast cancer to trastuzumab versus non-trastuzumab-based adjuvant chemotherapy, and based on their results, trastuzumab was approved by the US Food and Drug Administration (FDA) for the treatment of HER2-positive disease in the adjuvant setting.

Another study from the BCIRG006 further established that adjuvant trastuzumab for 1 year improved disease-free and overall survival among women with early-stage HER2-positive breast cancer at 5 years, and found that a nonanthracycline regimen plus trastuzumab had a more favorable risk-benefit ratio than anthracycline-based regimens due to similar efficacy, fewer acute toxic effects, and lower risks of cardiotoxicity and leukemia.[7]

Whether the combination of 2 anti-HER2-targeted therapies with chemotherapy will prove beneficial in early-stage disease is currently being tested in the ongoing phase III ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Options) trial, as well as the similar Neo ALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization) trial.

A study that evaluated the efficacy of lapatinib in HER2-negative and HER2-uncharacterized metastatic breast cancer concluded that although patients with HER2-negative or HER2-untested metastatic breast cancer did not experience benefit from the addition of lapatinib to paclitaxel, first-line therapy with paclitaxel-lapatinib significantly improved clinical outcomes in patients who were HER2-positive.[8]

Baselga et al reported that adding pertuzumab to traditional therapy with trastuzumab and docetaxel improved disease-free survival time in patients with HER2- positive metatstatic breast cancer.[9] Pertuzumab gained approvals for neoadjuvant treatment in combination with trastuzumab and docetaxel for patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer.[10]

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Treatment of HER2-Positive Metastatic Breast Cancer

In the metastatic setting, a pivotal phase III trial compared first-line chemotherapy (doxorubicin/epirubicin and cyclophosphamide or paclitaxel) plus trastuzumab versus chemotherapy alone in HER2-positive patients. Trastuzumab plus chemotherapy was associated with a significant improvement in time to disease progression (7.4 mo vs 4.6 mo), objective response rate (50% vs 32%), and 1-year survival (25.1 mo vs 20.3 mo) compared with chemotherapy alone.[11]

Additionally, there is evidence suggesting that up-front use of trastuzumab with chemotherapy, in women with advanced HER2-positive breast cancer, prolongs life as compared with sequential administration, with trastuzumab reserved for the time of disease progression on an initial chemotherapy regimen. Based on these results, the FDA approved trastuzumab for first-line therapy in HER2-positive metastatic breast cancer. However, the question of optimal duration of trastuzumab therapy remains unresolved.

Clinical evidence to support continued trastuzumab treatment after initial progression has emerged. Retrospective studies have described a response to trastuzumab in multiple lines of therapy, and patients treated with more than 2 trastuzumab-containing regimens appear to have advantageous overall survival and TTP outcomes.

Results from a prospective, randomized study of 112 patients with HER2-positive metastatic breast cancer initially progressing on a trastuzumab-based therapy (GBG-26/BIG 3-05 study) showed that trastuzumab/capecitabine resulted in a longer progression-free survival (8.2 mo vs 5.6 mo) and overall survival (25.5 mo vs 20.4 mo) as compared with the capecitabine-only arm.[12] Objective response rates were also significantly improved in the combination arm (48.1%) versus capecitabine alone (27%). Larger trials are currently ongoing to assess the activity of trastuzumab in multiple lines of treatment.

Another agent used in the treatment of HER2-positive metastatic breast cancer is lapatinib, a tyrosine kinase inhibitor (TKI). Lapatinib was approved in 2007 for the treatment of metastatic breast cancer in HER2-positive patients after progression on trastuzumab. This small molecule is known to block multiple epidermal growth factor receptors (EGFRs), EGFR (HER-1) and HER2, and is generally well tolerated, with the main toxicities being diarrhea, skin rash, fatigue, and nausea.

An analysis of cardiac toxicity found that 1.6% of patients exposed to lapatinib experienced a decline in left ventricular ejection fraction (LVEF), with 0.2% being symptomatic, lower than the comparable incidence observed with trastuzumab.[13] Preclinical data have indicated synergistic activity between lapatinib and trastuzumab, leading to a randomized study of this combination.

A phase III trial involving 296 heavily pretreated, trastuzumab-refractory metastatic breast cancer patients randomized to treatment with lapatinib alone or lapatinib with trastuzumab reported combination therapy significantly improved progression-free survival (8.4 wks vs 12 wks) compared with lapatinib alone.[14]

There was a nonsignificant trend toward improved median overall survival. Diarrhea and rash were the most common side effects. An asymptomatic decline in LVEF was seen in 5% of patients in the combination arm, compared with 2% in the lapatinib-alone arm.

In onestudy, 991 patients with HER2-positive advanced breast cancer previously treated with trastuzumab and taxane were randomized to treatment with the antibody-drug conjugate trastuzumab emtansine or lapatinib plus capecitabine. Trastuzumab emtansine was shown to significantly prolong progression-free (9.6 months vs. 6.4 months) and overall survival (30.9 months vs. 25.1 months) compared with lapatinib plus capecitabine, and was associated with a better toxicity profile.[15]

Baselga et al reported that adding pertuzumab to traditional therapy with trastuzumab and docetaxel improved disease-free survival time in patients with HER2- positive metatstatic breast cancer.[9] For more information, see Novel HER2 Receptor Agents.

See Breast Cancer Treatment Protocols for summarized information.

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Novel HER2 Receptor Agents

Only 1 in 3 HER2-positive metastatic breast cancer patients respond to single-agent trastuzumab, and most, if not all, eventually develop resistance. To overcome resistance, trastuzumab has been modified using a covalent linker to attach DM1, a derivative of the microtubule destabilizer maytansine. Ado-trastuzumab (Kadcyla) was approved as a single agent for treatment of HER2-positive, metastatic breast cancer in patients who have already undergone unsuccessful treatment with trastuzumab and a taxane, either separately or in combination.

By exploiting trastuzumab to target the cytotoxic activity of DM1 to HER2-overexpressing cells, ado-trastuzumab offers a novel mechanism for overcoming trastuzumab resistance. A phase I trial of every-3-week ado-trastuzumab demonstrated a clinical benefit rate of 53% in metastatic breast cancer patients that had progressed on previous trastuzumab. Additionally, preliminary results from a phase II trial reported an objective response rate of 43%.[16] Approval was based on results from EMILIA, an international phase III study comparing ado-trastuzumab to lapatinib plus capecitabine (n=991). The study showed a significantly prolonged progression-free and overall survival with less toxicity than lapatinib plus capecitabine.[17]

Pertuzumab (Perjeta), a humanized monoclonal antibody that blocks the activation of the HER2 receptor by hindering dimerization, was approved by the FDA in combination with trastuzumab and docetaxel. This novel therapy is targeted at HER2- positive metastatic breast cancer patients previously not treated with hormone therapy or chemotherapy. Its future use in earlier stages is currently being investigated.

FDA-approval of pertuzumab was based on results from the Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) trial. Pertuzumab elicits action at a different ligand binding site from trastuzumab to prevent HER2 dimerization. The combination of both HER2 receptor antibodies (pertuzumab plus trastuzumab) is superior to either agent alone. The trial compared first-line trastuzumab plus docetaxel (plus placebo) to trastuzumab plus docetaxel plus pertuzumab in HER2-postive metastatic breast cancer. Results from the study showed an average increase in progression-free survival of 6.1 months in patients receiving pertuzumab in addition to trastuzumab and docetaxel with minimal to no increase in cardiac toxic effects.[9]

The FDA approved pertuzumab for neoadjuvant treatment in combination with trastuzumab and docetaxel for patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive). Approval was based on a randomized trial that compared a number of regimens with and without pertuzumab in women with HER2-positive breast cancer. In the trial, 39.3% of patients treated with pertuzumab, trastuzumab, and docetaxel (n = 107) achieved a pathologic complete response (pCR), compared with 21.5% of patients treated with trastuzumab and docetaxel (n = 107) at the time of surgery.[10]

Neratinib (HKI-272) is an oral irreversible tyrosine kinase inhibitor (TKI) of HER2 and EGFR. Preliminary phase I data from 23 HER2-positive or EGFR-positive advanced breast cancer patients demonstrated antitumor activity in 7 patients. A phase II open label study in LABC showed a 16-week progression-free survival rate of 75% in 36 trastuzumab-naive patients and 51% in previously treated disease.

Several ongoing phase I/II trials are investigating this TKI combination with trastuzumab, paclitaxel, or vinorelbine in patients with trastuzumab-refractory breast cancer. Other EGFR TKIs, such as gefitinib and erlotinib, have been studied in combination with trastuzumab and endocrine therapy with disappointing results.

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Contributor Information and Disclosures
Author

Maurie Markman, MD, MS President, Medicine and Science, Cancer Treatment Centers of America

Maurie Markman, MD, MS is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Medical Association, American Society of Hematology, Clinical Immunology Society, Ohio State Medical Association, Society of Gynecologic Oncology, SWOG, Texas Medical Association, American Society of Clinical Oncology, American Federation for Clinical Research, Harris County Medical Society, Society for Immunotherapy of Cancer, International Gynecologic Cancer Society, Society for Integrative Oncology, Academy of Medicine of Cleveland & Northern Ohio, Gynecologic Oncology Group, International Society for Regional Cancer Therapy, New York State Society for Internal Medicine, Public Responsibility in Medicine and Research

Disclosure: Received consulting fee from Genentech for consulting; Received consulting fee from Cellgene for consulting; Received consulting fee from Novartis for consulting; Received consulting fee from Sanofi-Adventis for consulting; Received consulting fee from Glaxo-Smith-Kline for consulting; Received consulting fee from Amgen for consulting.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Eric T Rush, MD, FAAP, FACMG Clinical Geneticist, Munroe-Meyer Institute for Genetics and Rehabilitation; Assistant Professor of Pediatrics and Internal Medicine, University of Nebraska Medical Center

Eric T Rush, MD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American College of Physicians, Nebraska Medical Association

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Alexion Pharmaceuticals<br/>Honoraria for: Alexion Pharmaceuticals and Biomarin Pharmaceuticals.

Chief Editor

Karl S Roth, MD Retired Professor and Chair, Department of Pediatrics, Creighton University School of Medicine

Karl S Roth, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American College of Nutrition, American Pediatric Society, American Society for Nutrition, American Society of Nephrology, Association of American Medical Colleges, Medical Society of Virginia, New York Academy of Sciences, Sigma Xi, Society for Pediatric Research, Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

References
  1. Moasser MM, Krop IE. The Evolving Landscape of HER2 Targeting in Breast Cancer. JAMA Oncol. 2015 Jul 23. [Medline].

  2. Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, et al. Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Update. J Clin Oncol. 2013 Oct 7. [Medline].

  3. Rakha EA, Pinder SE, Bartlett JM, Ibrahim M, Starczynski J, Carder PJ, et al. Updated UK Recommendations for HER2 assessment in breast cancer. J Clin Pathol. 2015 Feb. 68 (2):93-9. [Medline].

  4. Penault-Llorca F, Vincent-Salomon A, Mathieu MC, et al. [2014 update of the GEFPICS' recommendations for HER2 status determination in breast cancers in France]. Ann Pathol. 2014 Oct. 34 (5):352-65. [Medline].

  5. Bianchi S, Caini S, Paglierani M, Saieva C, Vezzosi V, Baroni G, et al. Accuracy and Reproducibility of HER2 Status in Breast Cancer Using Immunohistochemistry: A Quality Control Study in Tuscany Evaluating the Impact of Updated 2013 ASCO/CAP Recommendations. Pathol Oncol Res. 2015 Apr. 21 (2):477-85. [Medline].

  6. [Guideline] Wolff AC, Hammond ME, 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. Jan 1 2007. 25(1):118-45.

  7. Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011 Oct 6. 365(14):1273-83. [Medline].

  8. Di Leo A, Gomez HL, Aziz Z, Zvirbule Z, Bines J, Arbushites MC, et al. Phase III, double-blind, randomized study comparing lapatinib plus paclitaxel with placebo plus paclitaxel as first-line treatment for metastatic breast cancer. J Clin Oncol. 2008 Dec 1. 26(34):5544-52. [Medline]. [Full Text].

  9. Baselga J, Cortés J, Kim SB, Im SA, Hegg R, Im YH, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012 Jan 12. 366(2):109-19. [Medline].

  10. Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, 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 Jan. 13(1):25-32. [Medline].

  11. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001 Mar 15. 344(11):783-92. [Medline]. [Full Text].

  12. Von Minckwitz G, Zielinski C, Maarteense E, et al. Capecitabine vs. capecitabine + trastuzumab in patients with HER2-positive metastatic breast cancer progressing during trastuzumab treatment: The TBP phase III study (GBG 26/BIG 3-05) Journal of Clinical Oncology, 2008 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 26, No 15S (May 20 Supplement), 2008:1025.

  13. Perez EA, Koehler M, Byrne J, Preston AJ, Rappold E, Ewer MS. Cardiac safety of lapatinib: pooled analysis of 3689 patients enrolled in clinical trials. Mayo Clin Proc. 2008 Jun. 83(6):679-86. [Medline].

  14. Blackwell KL, Burstein HJ, Storniolo AM, Rugo H, Sledge G, Koehler M, et al. Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol. 2010 Mar 1. 28(7):1124-30. [Medline].

  15. Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, et al. Trastuzumab Emtansine for HER2-Positive Advanced Breast Cancer. N Engl J Med. 2012 Oct 1. [Medline].

  16. Vukelja S, Rugo H, Vogel C, et al. A phase II study of trastuzumab-DM1, a first-in-class HER2 antibody-drug conjugate, in patients with HER2+ metastatic breast cancer. Cancer Res. 2009. 69(suppl 2):71s:Abstract 33.

  17. Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012 Nov 8. 367(19):1783-91. [Medline].

 
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