High-Risk, HER2-Positive Breast Cancer: Neoadjuvant and Adjuvant Treatment Options

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Although most patients with breast cancer are considered to have an overall excellent prognosis, 600,000 people still die annually of the disease around the world. Even in HER2-positive breast cancer, a subtype that has seen a transformation of outcomes in the past 2 decades, there’s still room for improvement.

During the ASCO20 Virtual Education Program, Roisin M. Connolly, MB, BCh, MD, of the University College Cork and Cork University Hospital, Ireland, discussed the need for better treatment decisions based on available data, validated predictive biomarkers, and patient preference in high-risk, HER2-positive breast cancer.1

“Each and every patient deserves equal access to cost-effective therapies, clinical trials, and optimal survivorship care in the following years.”
— Roisin M. Connolly, MB, BCh, MD

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“In the coming years, we will be able to better tailor the treatment plan to the individual patient,” said Dr. Connolly. “A robust biomarker at diagnosis or early in the treatment course will allow us to make an informed decision based on available data and the preferences of that individual patient. The future is bright for HER2-positive breast cancer,” she added.

As Dr. Connolly explained, approximately 15% to 20% of breast cancers are HER2-positive, a subtype traditionally associated with a poor prognosis in the absence of HER2-directed therapy and with a propensity for central nervous system (CNS) metastases. The development of HER2-directed therapies, however, has led to advances in the treatment of HER2-positive disease, first in the adjuvant setting (2000s) and then in the neoadjuvant setting (2010s).

Current regimens result in disease-free survival at 3 years of approximately 95%. For patients with more than four positive lymph nodes, disease-free survival is between 85% and 90%. The critical question moving forward, according to Dr. Connolly, is whether to focus exclusively on trials that escalate therapy or consider a two-pronged approach.

“Ideally, we can escalate treatment for patients who truly need it, such as those with residual disease after neoadjuvant therapy, and consider ways to use less aggressive regimens in select patient populations,” Dr. Connolly said.

Standard Biomarkers Still Essential

According to Dr. Connolly, identifying patients at baseline or early in the treatment course who may benefit less from aggressive, multiagent therapy is an area of active investigation that requires careful clinical trial design and robust biomarker development and validation. Physicians must also be cautious, she added, as so few biomarkers ultimately succeed in changing practice. The most important biomarkers in breast cancer remain the estrogen, progesterone, and HER2 receptors, and understanding of these biomarkers continues to evolve.

Pathologic complete response rates and long-term outcomes have both been shown to differ based on estrogen-receptor status, for example.2 HER2 heterogeneity by baseline fluorescent in situ hybridization, which was found in approximately 10% of patients in one study, was also associated with poor pathologic complete response to trastuzumab emtansine (T-DM1) and pertuzumab, said Dr. Connolly. She noted the majority of tumors exhibiting heterogeneity were hormone receptor–positive and had low levels of HER2 protein expression.3

HER2-Enriched Testing

Despite the predictive value of standard biomarkers, the scientific community is moving beyond them in an effort to further dissect the heterogeneity of breast cancer. Genomic studies have established five breast cancer intrinsic subtypes (luminal A, luminal B, HER2–enriched, claudin–low, basal–like) and a normal breast group.4

The HER2-enriched subtype can be observed in all tumor types, not only those with HER2-positive breast cancer, by standard criteria, said Dr. Connolly. Within HER2-positive breast cancer, the frequency of the HER2-enriched subtype varies between hormone receptor–positive and hormone receptor–negative disease.

In addition, recent analyses led by Prat et al have suggested a higher chance of pathologic complete response after HER2-directed regimens in patients with both the HER2-enriched subtype and high HER2 messenger RNA.5 A separate analysis also found that the HER2-enriched subtype itself is significantly associated with pathologic complete response across 16 studies, 5 of which incorporated HER2-directed therapy alone without chemotherapy.6

Finally, a composite assay combining measures of HER2 addiction (tumors that are “addicted” to HER2 signaling) with PIK3CA mutation status also identified an association with pathologic complete response.7

“These results are extremely promising, but as with all biomarkers, they require prospective clinical validation in the coming years before they can be used to make treatment decisions,” Dr. Connolly said.

Other Tissue and Blood-Based Biomarkers

Many other promising tissue- and blood-based biomarkers are also under investigation. As Dr. Connolly reported, positive PIK3CA mutation status was associated with a lower chance of pathologic complete response in a meta-analysis of five neoadjuvant trials that incorporated various HER2-directed therapy backbones.8

Immune-related biomarkers are also of great interest, said Dr. Connolly. She noted that concentration of tumor-infiltrating lymphocytes has been associated with pathologic complete response and survival in six HER2-positive neoadjuvant trials.9 In addition, early data suggest that detection of circulating tumor DNA (ctDNA) after neoadjuvant therapy may predict early relapse.10

“Testing of ctDNA is a highly promising area of investigation,” commented Dr. Connolly. “This approach may be worth exploring for clinical trials of novel drugs aiming to prevent recurrence from breast cancer in high-risk populations.”

Image-Based Approaches

Research has also highlighted the potential role of changes in standardized uptake values in positron-emission tomography (PET) in predicting response to therapy. Results of the Neo-ALTTO PET substudy showed that pathologic complete response rates after trastuzumab- and lapatinib-based chemotherapy regimens were higher in those deemed 

responders to PET vs nonresponders.11 In this study, a decline in standardized uptake value of 15% from baseline to 2 and 6 weeks was defined as PET response. However, more recent data from the TBCRC026 trial suggest that a 40% decline in standardized uptake value max by 2 weeks most optimally predicted pathologic complete response.12

“Again, additional prospective validation is required for these imaging approaches before they can become standard of care,” Dr. Connolly said.

Clinical and Societal Challenges

Given that approximately 15% of patients treated with HER2-directed therapy continue to experience disease relapse, novel treatment approaches are urgently needed. According to Dr. Connolly, drugs recently approved for use in the metastatic setting, such as tucatinib and fam-trastuzumab deruxtecan-nxki (T-DXd), may help tackle this problem. However, providers must also address disparities in access to care.

“By tailoring care to the individual patient, physicians can help minimize toxicity and maximize quality of life, but on a more global perspective, equal access to multidisciplinary expert breast cancer care could save many lives,” said Dr. Connolly. She noted that access to standard estrogen receptor/progesterone receptor and HER2 testing is not widespread around the world. “Each and every patient deserves equal access to cost-effective therapies, clinical trials, and optimal survivorship care in the following years.” 

DISCLOSURE: Dr. Connolly has received research funding for clinical trials from Genentech/Roche, MacroGenics, Merck, Novartis, and Puma Biotechnology and has received travel, accommodations, and/or expenses from Genentech/Roche.


1. Connolly RM: Embrace the positive: Neoadjuvant and adjuvant options for high-risk, HER2-positive breast cancer. ASCO20 Virtual Education Program.

2. Chumsri S, Li Z, Serie DJ, et al: Incidence of late relapses in patients with HER2-positive breast cancer receiving adjuvant trastuzumab: Combined analysis of NCCTG N9831 (Alliance) and NRG Oncology/NSABP B-31. J Clin Oncol 37:3425-3435, 2019.

3. Metzger Filho O, Viale G, Trippa L, et al: HER2 heterogeneity as a predictor of response to neoadjuvant T-DM1 plus pertuzumab: Results from a prospective clinical trial. 2019 ASCO Annual Meeting. Abstract 502. Presented June 3, 2019.

4. Prat A, Perou CM: Deconstructing the molecular portraits of breast cancer. Mol Oncol 5:5-23, 2011.

5. Prat A, Pascual T, De Angelis C, et al: HER2-enriched subtype and ERBB2 expression in HER2-positive breast cancer treated with dual HER2 blockade. J Natl Cancer Inst 112:46-54, 2020.

6. Schettini F, Pascual T, Conte B, et al: HER2-enriched subtype and pathological complete response in HER2-positive breast cancer: A systematic review and meta-analysis. Cancer Treat Rev 84:101965, 2020.

7. Veeraraghavan J, Gutierrez C, De Angelis C, et al: A multiparameter classifier to predict response to lapatinib plus trastuzumab without chemotherapy in HER2+ breast cancer. ASCO20 Virtual Scientific Program. Abstract 1011.

8. Loibl S, Majewski I, Guarneri V, et al: PIK3CA mutations are associated with reduced pathological complete response rates in primary HER2-positive breast cancer: Pooled analysis of 967 patients from five prospective trials investigating lapatinib and trastuzumab. Ann Oncol 27:1519-1525, 2016.

9. Denkert C, von Minckwitz G, Darb-Esfahani S, et al: Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: A pooled analysis of 3771 patients treated with neoadjuvant therapy. Lancet Oncol 19:40-50, 2018.

10. Turner N, Kingston B, Kilburn L, et al: Results from the plasmaMATCH trial: A multiple parallel cohort, multi-centre clinical trial of circulating tumour DNA testing to direct targeted therapies in patients with advanced breast cancer (CRUK/15/010). 2019 San Antonio Breast Cancer Symposium. Abstract GS3-06. Presented December 12, 2019.

11. Gebhart G, Gámez C, Holmes E, et al: 18F-FDG PET/CT for early prediction of response to neoadjuvant lapatinib, trastuzumab, and their combination in HER2-positive breast cancer: Results from Neo-ALTTO. J Nucl Med 54:1862-1868, 2013.

12. Connolly RM, Leal JP, Solnes L, et al: TBCRC026: Phase II trial correlating standardized uptake value with pathologic complete response to pertuzumab and trastuzumab in breast cancer. J Clin Oncol 37:714-722, 2019.