Precision medicine continues to improve for breast cancer, and new discoveries are likely to influence treatment decisions for early-stage and metastatic HER2-positive breast cancer.

At the “HER2+ Breast Cancer” education session, held on December 6 at the 2016 San Antonio Breast Cancer Symposium (SABCS) in Texas, the latest advances of the understanding of HER2-positive breast cancer, including its underlying biology, the nuances of managing early-stage disease, and long-term treatment considerations for metastatic disease, were discussed.1

HER2-positive Pathophysiology

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During the last 15 years, researchers have identified 4 major molecular subtypes of breast cancer: luminal A, luminal B, HER2-enriched, and basal-like. A study by The Cancer Genome Atlas (TCGA) Project confirmed that the 4 intrinsic subtypes encompass most of the heterogeneity found in breast cancer.2 Aleix Prat, MD, PhD, of the August Pi i Sunyer Biomedical Research Institute and Vall d´Hebron Institute of Oncology in Barcelona, Spain presented “Recent Insights into the Biology of HER2+ Breast Cancer” at the education session, which included a discussion of the intrinsic subtypes.

The luminal A and B subtypes express proliferation or cell cycle-associated genes and genes involved in hormone-regulated pathways, with luminal B expressing these genes to a higher extent than luminal A subtypes, but lower levels of the progesterone receptor and FOXA1. HER2-enriched breast cancers highly express their namesake, HER2, and genes associated with it. In contrast, basal-like subtypes express high levels of proliferation-associated genes, as well as keratin-related genes.

About 45% of HER2-positive breast cancers are classified as HER2-enriched, with 27%, 18%, and 11% classified as luminal B, luminal A, and basal-like, respectively. 

But the current treatment paradigm bases therapy selection on pathologic surrogates that categorize breast cancer as hormone receptor-positive, HER2-positive, or triple-negative. HER2-directed therapy (such as trastuzumab), for example, is associated with improved outcomes among patients with HER2-positive disease.

“The clinical significance of intrinsic subtypes within HER2+ breast cancer is currently under investigation,” Dr Prat told Cancer Therapy Advisor. “The limited evidence so far suggests that HER2+ tumors of the HER2-enriched subtype benefit the most from anti-HER2 therapies, though further evidence is needed.” HER2-enriched disease is associated with improved pathologic complete response (pCR) and event-free survival compared with non-HER2-enriched disease.

A study conducted by Dr Prat and colleagues demonstrated differences in pCR after treatment with HER2-directed therapy with or without chemotherapy based on intrinsic subtype.3 According to Dr Prat, “the probability of a HER2+ tumor to disappear at surgery following treatment with dual HER2 blockade is 40% compared to 10% if the tumor is non-HER2-enriched.”

An important aspect of this finding is the potential to identify a subgroup of patients for whom treatment de-escalation by treating without chemotherapy may be appropriate. “Further studies are needed to demonstrate this hypothesis, since we are aware that we are overtreating many patients with HER2+ disease,” he noted.

Researchers are continuing to fine-tune the clinical use of intrinsic subtype, particularly to optimize treatment selection. Dr Prat told Cancer Therapy Advisor that “the big challenge in the upcoming years is to demonstrate that the identification of a particular biological feature, or a combination of features, can help us make better treatment decisions. To accomplish this, integrative analysis of multidimensional genomic and clinical data will likely be needed.”

Treatment for Early-stage HER2-positive Disease

Treatment de-escalation was also discussed by Sara Tolaney, MD, MPH, of the Dana-Farber Cancer Institute in Boston, Massachusetts, during her presentation, “Optimizing HER2-directed Treatment in Early Stage Disease,” at the education session.

The introduction of HER2-directed therapy dramatically altered the outcomes of patients with HER2-positive breast cancer—from a median overall survival of 14 months to 29 months, and an increase in 5-year survival from 2% to 31%, per a registry study from Sweden.4 The current treatment of early stage disease is anthracycline-containing chemotherapy and trastuzumab in the adjuvant setting. In the neoadjuvant setting, many oncologists are adding pertuzumab. But these regimens are associated with toxicity, such as the potential for the rare complication of cardiotoxicity.

Dr Tolaney told Cancer Therapy Advisor that “we have data suggesting that giving just a taxane with trastuzumab without an anthracycline produces very low rates of recurrence in patients with stage I, HER2-positive disease. This suggests that there are some patients for whom we can de-escalate treatment, while providing highly efficacious therapy with less toxicity.”

Other questions remain about optimizing HER2-directed therapy, such as the duration of treatment. The standard of care remains 1 year of HER2 blockade, after the PHARE and HERA trials failed to demonstrate improvement in outcomes with 6 or 24 months of treatment, respectively.5,6

But the role of maintenance therapy after the 1 year of trastuzumab with another agent is still being investigated. The ExteNET trial demonstrated that a year of the tyrosine kinase inhibitor (TKI), neratinib, following a completed year of trastuzumab resulted in significantly improved 2-year invasive disease-free survival.7 Dr Tolaney noted, however, that these data are from very early follow-up and the additional year of therapy resulted in increased toxicities. “I think that all of us are awaiting longer-term follow-up from those data,” she told Cancer Therapy Advisor.

Dr Tolaney also discussed several trials that have the potential to be practice-changing for early-stage disease. The phase 3 trials KATHERINE (NCT01772472) and KAITLIN (NCT01966471) are evaluating ado-trastuzumab emtansine (T-DM1). KATHERINE is a head-to-head trial of T-DM1 versus trastuzumab, whereas KAITLIN is comparing T-DM1 plus pertuzumab with taxane-based chemotherapy plus trastuzumab and pertuzumab. According to Dr Tolaney: “both of these trials have looked at the question of whether adding T-DM1 to the adjuvant setting would be useful, and that could potential change practice if any of those trials are positive.”

Another trial is evaluating the role of pertuzumab in the adjuvant setting, because it is currently approved only for the preoperative setting for early stage disease. “If the APHINITY trial (NCT01358877) is positive—and many of us are anticipating those results probably next year—then it is likely that it would be approved as an adjuvant added to standard therapy, and that would certainly be practice-changing,” Dr Tolany said.

Long-term Treatment of Metastatic Disease

“Widening the Scenario for Long-term Treatment of Metastatic HER2+ Breast Cancer,” was presented by Luca Gianni, MD, of the San Raffaele Hospital-Scientific Institute in Milano, Italy.

Since the approval of trastuzumab, 3 additional HER2-directed agents were approved for the treatment of metastatic disease, including pertuzumab, T-DM1, and lapatinib, a TKI. Despite these advances, the response rate to first-line treatment is between 50% to 80%—and 20% to 40% in the second-line setting—and they are not considered curative.

A new approach to metastatic disease is targeting the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway, which is an integral player in HER2 signaling, and may represent a mechanism for resistance to HER2-directed therapies. The mTOR inhibitor, everolimus, was studied in the BOLERO-1 and -3 trials with mixed results. In BOLERO-1, there was no improvement in progression-free survival (PFS) with the addition of everolimus to paclitaxel and trastuzumab in the first-line setting. In BOLERO-3, there was a modest but significant improvement in PFS with the addition of everolimus to vinorelbine and trastuzumab among patients whose disease was trastuzumab-resistant. An important limitation of using everolimus, however, is its toxicity.8

An alpha-specific PI3K inhibitor, alpelisib, is under investigation as an adjuvant to T-DM1 in a phase 1 trial (NCT02038010) for second-line treatment of metastatic disease, with early results demonstrating high response rates.

Another approach to improving response rates is improving HER2 TKIs to address acquired resistance. Afatinib, for example, is a highly selective HER1, HER2, and HER4 inhibitor that forms irreversible, covalent bonds. A phase 2 trial demonstrated high response rates, but with higher toxicity characteristic of TKIs: rash and diarrhea.  A phase 3 trial was discontinued early due to toxicity and shorter OS, leaving the future of this agent in question.

Another TKI, neratinib, shows promise in terms of response rates, but nearly all patients experience treatment-related diarrhea. A phase 3 trial (NCT01808573) is ongoing in which neratinib plus capecitabine is compared with lapatinib plus capecitabine.

In contrast, the TKI ONT-380 is reversible and selective for HER2, but does not substantially inhibit HER1 activity, which may result in more mild toxicity. This agent also shows activity in the central nervous system, which may hold promise for treating brain metastases.

Other approaches include immune-modulating agents such as ertumaxomab, a bispecific antibody that targets both HER2 and CD3, and checkpoint inhibitors targeting PD-1 or PD-L1. An antibody-drug conjugate, MM-302, targets HER2 and acts as a homing-device that delivers a nanoparticle containing doxorubicin to HER2-positive breast cancer cells. These agents are in ongoing trials, and may provide additional options for patients with metastatic HER2-positive disease.



  1. Prat A, Tolaney S, Gianni L. HER2+ breast cancer. 39th San Antonio Breast Cancer Symposium; December 2016; San Antonio, TX.
  2. Prat A, Pineda E, Adamo B, et al. Clinical implications of the intrinsic subtypes of breast cancer. Breast. 2015;24:S26-35.
  3. Prat A, Bianchini G, Thomas M, et al. Research-based PAM50 subtype predictor identifies higher responses and improved survival outcomes in HER2-positive breast cancer in the NOAH study. Clin Cancer Res. 2014;20:511-21.
  4. Sundquist M, Brudin L, Tejler G. Improved survival in metastatic breast cancer 1985-2016. Breast. 2016;31:46-50.
  5. Pivot X, Romieu G, Debled M, et al. 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial. Lancet Oncol. 2013;14:741-8.
  6. Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, et al. 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.
  7. Chan A, Delaloge S, Holmes FA, et al. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016;17:367-77.
  8. Santa-Maria CA, Nye L, Mutonga MB, et al. Management of metastatic HER2-positive breast cancer: where are we and where do we go from here? Oncology (Williston Park). 2016;30:148-55.