|Year : 2016 | Volume
| Issue : 2 | Page : 87-92
Management of HER2-positive breast cancer: A review
S Viswanath, Abhishek Pathak
Department of Medical Oncology, Army Hospital (R&R), Delhi Cantt, New Delhi, India
|Date of Web Publication||5-Jul-2016|
Army Hospital (R&R), Delhi Cantt, New Delhi - 110 010
Source of Support: None, Conflict of Interest: None
HER2-positive breast cancers constitute 25-30% of breast cancers in women. These cancers have a different natural history, clinical course, and prognosis. After the discovery of HER2 amplification, various molecules have been developed to manipulate the activity of this biomarker. In this review, an attempt has been made to understand the possible ways of managing HER2-positive breast cancers in women in an era where we have a number of monoclonal antibodies and small molecule inhibitor to manipulate the activity of HER2.
Keywords: Breast cancer, HER2, monoclonal antibodies
|How to cite this article:|
Viswanath S, Pathak A. Management of HER2-positive breast cancer: A review. J NTR Univ Health Sci 2016;5:87-92
| Introduction|| |
Carcinoma of the breast and ovary constitutes 30% of cancers in females and are responsible for 25% of cancer deaths in women. Among breast cancers, 25-30% are HER2-positive (amplified) and these breast cancers have a different disease course and prognosis. 
HER2 has a similar structure to that of HER1 and neu was added as it was derived from rodent glioblastoma cell line (neu for neural-derived).  This was initially called c-erb-2. The discovery of c-erb-2 was published in the Proceedings of the National Academy of Sciences in October 1985.  Overexpression of c-erb-2 oncoprotein in human breast carcinoma was shown by Venter et al. in 1987. 
It is well-established that c-erb-2, now called as HER2, is both a prognostic and a predictive biomarker of breast cancer. With advances in drug development, a number of monoclonal antibodies and small molecule inhibitors have been developed against HER2.
| Methods for Identification of Her2 Overexpression|| |
The commonly used methods to assess HER2 over expression are: 
- Fluorescence in situ hybridization (FISH)
- Immunohistochemistry (IHC)
FISH detects the gene amplification by measuring the number of copies of HER2 genes in the tumor cells.  IHC measures the number of receptors on the cell surface and therefore, detects overexpression. 
Other tests which are increasingly used are:
- Chromogenic in situ hybridization (CISH) 
- Reverse-transcriptase polymerase chain reaction (RT-PCR) 
Anti HER2 therapy in neoadjuvant setting
Neoadjuvant chemotherapy (NACT) has become a standard of care in the management of locally advanced breast cancer (LABC). A subset of stage II (T3 N0), stage III, diseases, and inflammatory breast cancer.  About 7% of the breast cancer patients present as LABC. 
After the availability of monoclonal antibodies to HER2 and their successful use in metastatic and adjuvant settings, it was but natural to use them in a neoadjuvant setting in LABC, which are HER2-positive. The monoclonal antibody, which was initially studied was trastuzumab. Buzdar et al. showed in their study that addition of trastuzumab with NACT showed a significant improvement in pathological complete response (pCR), i.e., 66.7% as compared to 25% without trastuzumab  The NOAH trail published in Lancet in 2010 also showed that there was a significant improvement in the event-free survival with the addition of trastuzumab both in the neoadjuvant setting and continued to the adjuvant setting.  The GeparQuttro study showed that combining trastuzumab with anthracycline-based chemotherapy was feasible and using this combination, showed a significantly higher pCR but this did not convert into higher breast conservation surgeries.  The TECHNO trail, which also studied neoadjuvant use of trastuzumab also showed a significantly improved pCR in the trastuzumab-containing arm. The study also showed that patients who achieved pCR had improved survival.  The limitation of the study was that it was not randomized [Table 1].
Although all the abovementioned studies showed improved pCR, there was no significant improvement in the conversion rates to breast conservation and hence, neoadjuvant trastuzumab with chemotherapy was not followed by all in the oncology fraternity.
Combined antiHER2 therapy in neoadjuvant setting
With the advent of small molecule inhibitor (lapatinib) against HER2 and monoclonal antibodies with affinity to different epitopes of HER2, studies were conducted combining trastuzumab with these agents.
Combining lapatinib with trastuzumab
Lapatinib was approved for use by the FDA in 2010 in metastatic HER2-positive breast cancer, progressing on trastuzumab. Subsequently, studies were conducted to find out the efficacy of lapatinib in the neoadjuvant setting combined with trastuzumab. The Neo ALTTO study was a randomized phase III trial with three arms. In this study, the arm containing dual blockade showed a significantly higher pCR rate.  The lapatinib arm was associated with higher rate of grade 3 diarrhea.
The GeparQuinta study showed a higher pCR rate in the trastuzumab arm as compared to lapatinib arm.  The CHER-LOB study also showed that combining lapatinib with trastuzumab in the neoadjuvant setting in HER2-positive breast cancer showed higher pCR rates and that this combination could be used without the risk of cardiac failure. 
Although all above studies have shown improved pCR with combined blockade, it did not find favor in the oncology community due to gastrointestinal toxicity.
Combining pertuzumab and trastuzumab in neoadjuvant setting
In the tumor xenograft models, combination of pertuzumab and trastuzumab showed enhanced anti-tumor activity than compared to pertuzumab or trastuzumab alone.  The results of the xenograft trail were transferable to humans, first in the metastatic setting. Thereafter, the combination was studied in the neoadjuvant setting.
A phase III neoadjuvant study of pertuzumab and Herceptin in an early regime evaluation (Neosphere) study showed a significantly higher pCR rate for dual HER2 blockade (45.8%) when compared with single HER2 blockade (29%).  Subsequently, the TRYPHAENA study also showed the increased effectiveness of dual HER2 blockade with chemotherapy in the neoadjuvant setting and there was no significant cardiac toxicity. 
After going through the myriad of studies in the neoadjuvant setting in HER2-positive breast cancer and also the approvals by various regulatory authorities, the dual HER2 blockade with pertuzumab and trastuzumab, along with chemotherapy appears to be an option [Table 2].
|Table 2: Combining Lapatinib with Trastuzumab in The Neoadjuvant Setting|
Click here to view
Considering the primary resistance and the emergence of secondary resistance to HER2 blockade and also the economic impact, new biomarkers are being evaluated, viz, expression of p95HER2,  expression of plasma cell mutagens and 8q22 amplicon,  and expression of p4EBP1 (an activator of mTOR pathway). 
Anti-HER2 therapy in adjuvant setting
Slamon et al. showed that adding a monoclonal antibody against HER2 showed clinical benefit in first-line metastatic breast cancer.  After observing the clinical benefits of using monoclonal antibody against HER2 in the metastatic setting, investigators were encouraged to use it in the adjuvant setting. The early studies were published in the New England Journal of Medicine (NEJM) in the year 2005; in fact, it had two papers published in the same issue. One-year observation of the HERA trail was published, which showed a significantly improved disease-free survival among women with HER2-positive breast cancer who received adjuvant trastuzumab.  Another trial by Romond, et al. showed trastuzumab combined with paclitaxel after doxorubicin and cyclophosphamide improves outcomes among women with surgically removed HER2-positive breast cancer.  In fact in this study, the NSABP-13 and NCCTG trial N9831 were analyzed. The abovementioned papers, which analyzed three studies concluded that adjuvant trastuzumab improved the outcomes. A 4-year follow-up of patients who received 1 year of adjuvant trastuzumab enrolled in HERA study was done. Treatment with adjuvant trastuzumab for 1 year after chemotherapy is associated with significant clinical benefit at 4-year median follow-up.  In the year 2013, the comparison between 1 year and 2 years arm of adjuvant trastuzumab of the HERA trial was published and 2 years of adjuvant trastuzumab is not more effective than 1 year of treatment for patients with HER2-positive early breast cancer. One year of treatment provides a significant disease-free and overall survival (OS) benefit compared with observation and remains the standard of care.  The BCIRG-006 study showed that nonanthracycline-containing chemotherapy regimens combined with trastuzumab in the adjuvant setting also improved the disease-free and OS.  The risk benefit ratio was in favor of nonanthracycline-containing regimens.
With all these trails adjuvant trastuzumab for 1 year has become a standard of care for HER2-positive patients. The decision to use anthracycline based regimen or nonanthracycline-based regimen depends on tumor-related risk factors and the cardiac risk factors.
Anti-HER2 therapy in metastatic setting
There are three monoclonal antibodies, i.e., trastuzumab, pertuzumab and trastuzumab emtansine, (T-DM1) and a small molecule tyrosine kinase inhibitor, lapatinib, which are available to block HER2 in the metastatic setting.
Cobleigh, et al. in 1999, through a multinational study, showed that trastuzumab could be used safely and showed durable objective response.  As already mentioned, Slamon et al. showed an improved disease-free survival by adding trantuzumab to therapy in the metastatic setting in the year 2001.  This trial can be mentioned as a landmark in the management of metastatic HER2-positive breast cancer. This trial showed that, as compared with the best available standard chemotherapy, concurrent treatment with trastuzumab and first-line chemotherapy was associated with a significantly longer time to disease progression, a higher rate of response, a longer duration of response, and improved OS. After this, chemotherapy with trastuzumab became the preferred standard of care in the HER2-positive metastatic breast cancers. Trastuzumab in combination with docetaxol , and vinorelbine  were also found to be effective.
It was shown in preclinical studies that dual HER2 blockade was more effective. ,, The Clinical Evaluation of the pertuzumab and trastuzumab (CLEOPATRA) trial was a large phase III randomized trial in which 808 patients with HER2+ MBC were randomized to trastuzumab plus docetaxel (TH) with or without pertuzumab in the first-line setting. The pertuzumab group showed significant improvement in Progression free survival [18.5 months vs 12.4 months, 95% confidence interval (CI): 0.51-0.75, P < 0.001) and OS rates. , With this study outcome, dual HER2 blockade has become the preferred regimen in first-line treatment of metastatic HER2-positive breast cancer patients.
The MARIANNE trial is evaluating the role of first-line T-DM1 in HER2+MBC.  The results are awaited.
Anti-HER2 therapy in metastatic setting progressing while on trastuzumab
Gayer, et al. showed that lapatinib plus capecitabine is superior to capecitabine alone in women with HER2-positive advanced breast cancer that has progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab.  This was further confirmed in a phase III study published in 2008 by Cameron et al. where there was an attempt to find a biomarker to identify a subgroup, that would not be benefitted, but this could not be identified. 
In women who have received multiple lines of chemotherapy and also progressed on trastuzumab, one of the options is to use of dual blockade of HER2 without adding chemotherapy. The EGF 104900 study showed that combining lapatinib and trantuzumab showed a significant improvement in medial OS.  Lapatinib became one of the options for treating patients who were progressing on trastuzumab therapy either with capecitabine or trastuzumab.
Trastuzumab emtansine (T-DM1) is conjugated monoclonal antibody against HER2. This has showed promising results in the management of metastatic HER2-positive breast cancer. EMILIA group had shown that T-DM1 significantly prolonged progression-free and OS with less toxicity than lapatinib plus capecitabine in patients with HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane.  This study led to the approval T-DM1 in 2013.
The summary of the role of HER2 blockade in the management of HER2-positive breast cancers in women can be done by classifying the role in three different settings and the possible regimens are:
- Trastuzumab plus chemotherapy
- Pertuzumab plus trastuzumab plus chemotherapy
- Adjuvant chemotherapy plus adjuvant trastuzumab for 1 year
- If trastuzumab has been started in the neoadjuvant setting, along with chemotherapy, then chemotherapy is to be continued in the adjuvant setting with trastuzumab for the total duration of 1 year in both the neoadjuvant and adjuvant settings combined.
- Trastuzumab continued till progression
- If patient has progressed within 6 months of completing adjuvant trastuzumab, then the preferred choices are pertuzumab plus trastuzumab plus docetaxol or lapatinib plus capecitabine.
- Pertuzumab plus trastuzumab plus docetaxol is an option for first-line metastatic.
- If the patient progresses after first-line, then trastuzumab emtansine (T-DM1) is an option.
- If the patient progresses while on first-line regimen, changing the chemotherapy component, along with trastuzumab is also an option.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, et al
. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancers. Science 1989;244:707-12.
Coussens L, Yang-Feng TL, Liao YC, Chen E, Gray A, McGrath J, et al
. Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science 1985;230:1132-9.
Semba K, Kamata N, Toyoshima K, Yamamota T. A v-erbB-related protoocogene, c-erbB-2, is distinct from the c-erbB-1/epidermal growth factor-receptor gene and is amplified in a human salivary gland adenocarcinoma. Proc Natl Acad Sci U S A 1985;82:6497-501.
Venter DJ, Tuzi NL, Kumar S, Gullick WJ. Overexpression of the c-erbB-2 oncoprotein in human breast carcinomas: Immunohistological assessment correlates with gene amplification. Lancet 1987;2:69-72.
Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, et al
.; American Society of Clinical Oncology; College of American Pathologists. 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;25:118-45.
Ménard S, Tagliabue E, Campiglio M, Pupa SM. Role of HER2 gene overexpression in breast carcinoma. J Cell Physiol 2000;182:150-62.
Todoroviæ-Rakoviæ N, Jovanoviæ D, Neskoviæ-Konstantinoviæ Z, Nikoliæ-Vukosavljeviæ D. Prognostic value of HER2 gene amplification detected by chromogenic in situ
hybridization (CISH) in metastatic breast cancer. Exp Mol Pathol 2007;82:262-8.
Vinatzer U, Dampier B, Streubel B, Pancher M, Seewald MJ, Stratowa C, et al
. Expression of HER2 and the coamplified genes GRB7 and MLN64 in human breast cancer: Quantitative real-time reverse transcription-PCR as a diagnostic alternative to immunohistochemistry and fluorescence in situ
hybridization. Clin Cancer Res 2005;11:8348-57.
Singletary SE, Allred C, Ashley P, Bassett LW, Berry D, Bland KI, et al
. Revision of the American Joint Committee on Cancer staging system for breast cancer. J Clin Oncol 2002;20:3628-36.
National Cancer Institute, DCCPS, Surveillance Research Program Cancer Statistics Branch (2001) SEER Program Public Use Data Tapes. 1973-1998.
Buzdar AU, Ibrahim NK, Francis D, Booser DJ, Thomas ES, Theriault RL, et al
. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: Results of a randomized trail in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol 2005;23:3676-85.
Gianni L, Eiermann W, Semiglazov V, Manikhas A, Lluch A, Tjulandin S, et al
. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): A randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet 2010;375:377-84.
Untch M, Rezai M, Loibl S, Fasching PA, Huober J, Tesch H, et al
. Neoadjuvant treatment with trastuzumab in HER2-positive breast cancer: Results from the GeparQuattro study. J Clin Oncol 2010;28:2024-31.
Untch M, Fasching PA, Konency GE, Hasmüller S, Lebeau A, Kreienberg R, et al
. Pathologic complete response after neoadjuvant chemotherapy plus trastuzumab predicts favorable survival in human epidermal growth factor receptor 2-overexpressing breast cancer: Results from the TECHNO trial of the AGO and GBG study groups. J Clin Oncol 2011;29:3351-7.
Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, et al
. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALLTO): A randomised, open-label, multicentre, phase 3 trial. Lancet 2012;379:633-40.
Untch M, Loibl S, Bischoff J, Eidtmann H, Kaufmann M, Blohmer JU, et al
.; German Breast Group (GBG); Arbeitsgemeinschaft Gynäkologische Onkologie-Breast (AGO-B) Study Group. Lapatinab versus trastuzumab in combination with neoadjuvant antracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): A randomised phase 3 trial. Lancet Oncol 2012;13:135-44.
Guarneri V, Frassoldati A, Bottini A, Cagossi K, Bisagni G, Sarti S, et al
. Preoperative chemotherapy plus trastuzumab, lapatinib, or both in human epidermal growth factor receptor 2-positive operable breast cancer: Results of the randomised phase II CHER-LOB study. J Clin Oncol 2012;30:1989-95.
Scheuer W, Friess T, Burtscher H, Bossenmaier B, Endl J, Hasmann M. Strongly enhanced antitumor activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumor models. Cancer Res 2009;69:9330-6.
Gianni L, Prenkowski 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;13:25-32.
Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Hegg R, 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;24:2278-84.
Scaltriti M, Rojo F, Ocaña A, Anido J, Guzman M, Cortes J, et al
. Expression of p95HER2, a truncated form of the HER2 receptor, and response to anti-HER2 therapies in breast cancer. J Natl Cancer Inst 2007;99:628-38.
Bianchini G, Prat A, Pickl M, Belousov A, Koehler A, Semiglazov V, et al
. Response to neoadjuvant trastuzumab and chemotherapy in ER+ and ER-HER2-positive breast cancers: Gene expression analysis. J Clin Oncol 2011;29:abstract 529.
Huober J, Loibl S, Untch M. New molecular biomarker for resistance to trastuzumab-based in primary HER2 positive breast cancer - A translational investigation from the neoadjuvant GeparQuattro study. Cancer Res 2010;70:abstract PD02-06.
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;344:783-92.
Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, et al
.; Herceptin Adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353:1659-72.
Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, et al
. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353:1673-84.
Gianni L, Dafni U, Gelber RD, Azambuja E, Muehlbauer S, Goldhirsch A, et al
.; Herceptin Adjuvant (HERA) Trial Study Team. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: A 4-year follow-up of a randomised controlled trial. Lancet Oncol 2011;12:236-44.
Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, de Azambuja E, Procter M, Suter TM, et al
.; Herceptin Adjuvant (HERA) Trial Study Team. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): An open-label, randomised controlled trial. Lancet 2013;382:1021-8.
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;365:1273-83.
Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, et al
. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 1999;17:2639-48.
Esteva FJ, Valero V, Booser D, Guerra LT, Murray JL, Pusztai L, et al
. Phase II study of weekly docetaxel and trastuzumab for patients with HER-2-overexpressing metastatic breast cancer. J Clin Oncol 2002;20:1800-8.
Marty M, Cognetti F, Maraninchi D, Snyder R, Mauriac L, Tubiana-Hulin M, et al
. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: The M77001 study group. J Clin Oncol 2005;23:4265-74.
Burstein HJ, Keshaviah A, Baron AD, Hart RD, Lambert-Falls R, Marcom PK, et al
. Trastuzumab plus vinorelbine or taxane chemotherapy for HER2-overexpressing metastatic breast cancer: The trastuzumab and vinorelbine or taxane study. Cancer 2007;110:965-72.
Nahta R, Hung MC, Esteva FJ. The HER-2-targeting antibodies trastuzumab and pertuzumab synergistically inhibit the survival of breast cancer cells. Cancer Res 2004;64:2343-6.
Lee-Hoeflich ST, Crocker L, Yao E, Pham T, Munroe X, Hoeflich KP, et al
. A central role for HER3 in HER2-amplified breast cancer: Implications for targeted therapy. Cancer Res 2008;68:5878-87.
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;366:109-19.
Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, et al
.; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 2015;372:724-34.
Ellis PA, Barrios CH, Eiermann W, Toi M, Im YH, Conte PF, 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. J Clin Oncol 2015;33:abstr 507.
Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, et al
. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006;355:2733-43.
Cameron D, Casey M, Press M, Lindquist D, Pienkowski T, Romieu CG, et al
. A phase III randomised comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: Updated efficacy and biomarker analyses. Breast Cancer Res Treat 2008;112:533-43.
Blackwell KL, Burstein HJ, Storniolo AM, Rugo HS, Sledge G, Aktan G, et al
. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: Final results from the EGF104900 study. J Clin Oncol 2012;30:2585-92.
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;367:1783-91.
[Table 1], [Table 2]