Posted October 2, 2020

Mothaffar F. Rimawi, MD, and Rachel Schiff, PhD, Baylor College of Medicine

For approximately 20% of breast cancer patients, the HER2 oncogene is genetically amplified or otherwise overexpressed at the protein level, driving an aggressive subtype of disease known as HER2+ breast cancer. The antibody-based therapeutic trastuzumab, which inhibits HER2 activity and helps elicit immune response against the tumor, dramatically improves clinical outcomes for patients with HER2+ breast cancer when used in combination with chemotherapy. However, chemotherapy drugs often produce toxic side effects due to their non-specific nature, leading to efforts to reduce or eliminate their use. Several recent Phase II and III clinical trials in patients with HER2+ breast cancer, including TBCRC006, SOLTI-PAMELA, and TBCRC023, demonstrate that trastuzumab neoadjuvant therapy, when used in combination with lapatinib (a small molecule dual inhibitor of the epidermal growth factor receptor [EGFR] and HER2), without additional chemotherapy, results in pathologic complete response (pCR) more than 25% of the time. Pathologic complete response is associated with favorable long-term patient outcomes. These findings, however, suggest that a majority of patients with clinically defined HER2+ tumors likely harbor additional molecular irregularities that allow for resistance to anti-HER2 therapy and prevent pCR. Supported by a Fiscal Year 2016 Breast Cancer Research Program Breakthrough Award – Funding Level 3 – Clinical Trial – Partnering Principal Investigator (PI) Option, Dr. Rimawi and Dr. Schiff are seeking to determine why only a fraction of HER2+ breast cancer patients respond to HER2-targeted therapy and whether there are rational biomarkers that can be defined to help reduce exposure to toxic chemotherapy without sacrificing patient outcomes. 

As described in a recent publication in Annals of Oncology, Dr. Rimawi’s and Dr. Schiff’s research team evaluated initial breast tumors from patients enrolled in the TBCRC006 clinical trial for biomarkers that correlated with clinical response after 12 weeks of trastuzumab and lapatinib therapy. For patients who may benefit from adding trastuzumab to chemotherapy, the group initially determined that current clinical guidelines for defining HER2 positivity did not predict which patients would benefit from de-escalation to anti-HER2 therapy alone. A threshold higher than current clinical guidelines was required to yield pCR with this approach. However, even in the group of patients with higher HER2 levels, the majority (71%) did not experience pCR, suggesting that other factors contribute to treatment resistance. Mutations in the phosphoinositol-3-kinase (PI3K) gene or other irregularities in the pathway have been shown to activate the PI3K pathway downstream of HER2, and could therefore lead to a lack of response to HER2 inhibition. Examining HER2-overexpressing tumors that did not respond to therapy, the research team observed that 65% of patients harbored PI3K pathway irregularities, and pCR was seen in only 4% of patients if the PI3K pathway was deregulated. These data implicate irregularities in the PI3K pathway as a contributor to anti-HER2 therapy resistance. 

In another recent publication in the Journal of the National Cancer Institute, Drs. Rimawi and Schiff, in close collaboration with Dr. Prat (the PI of the SOLTI-PAMELA trial), identified an additional biomarker stratifying HER2+ tumor response to anti-HER2 therapies. HER2+ disease is comprised of four major subtypes (luminal A, luminal B, HER2-enriched [HER2-E], and basal-like), where the HER2-E subtype has markedly elevated levels of the HER2-encoding gene ERBB2 (Erb-B2 receptor tyrosine kinase 2), which drives increased EGFR pathway activation relative to the other subtypes. This suggests that patients with HER2-E subtype are likely to be more responsive to dual HER2 and EGFR blockade therapy. Examining patient tumors from the TBCRC006 and TBCRC023 trials, Drs. Rimawi and Schiff found that treatment of 27% of patients with HER2-E subtype resulted in pCR. When these tumors, or the tumors from the SOLTI-PAMELA trial, were evaluated for ERBB2 mRNA, those patients whose tumors were found to have higher baseline expression levels experienced pCR at a greater rate than those whose tumors had lower baseline ERBB2 expression. Examining tumors from all three trials combined, the research team found that tumors initially classified as the HER2-E subtype and having elevated ERBB2 mRNA levels showed the highest pCR rate when compared to HER2-E/low ERBB2, non-HER2-/high ERBB2, and non-HER2-E/low ERBB2. These findings were validated and found to be consistent in both the PER-ELISA and EGF104900 trial cohorts of advanced disease. This indicates that a HER2-E subtype with high levels of ERBB2 is another potential predictive biomarker of clinical response to dual HER2 and EGFR blockade therapy.  

The results of Dr. Rimawi’s and Dr. Schiff’s studies are important for refining the clinical definition of HER2 positivity, such that baseline levels of HER2 that exceed the current HER2 positivity threshold used for clinical screening to identify patients eligible to receive trastuzumab along with chemotherapy are necessary for a breast tumor to be truly responsive to anti-HER2 therapy alone. They have also discovered two important biomarkers that begin to stratify HER2+ disease and may better predict patient response to HER2 blockade alone. Taken together, adoption of altered HER2 screening thresholds and analysis of baseline tumor PI3K pathway activity and/or ERBB2 mRNA levels could help identify patients who will respond to anti-HER2 therapy alone, allowing for a de-escalation of patient exposure to chemotherapy during treatment. Moreover, these tools may identify patients who would benefit from the addition of chemotherapy, even in the context of HER2+ breast cancer. 

Publications: 

Prat A, Pascual T, De Angelis C, et al. 2020. HER2-enriched subtype and ERBB2 expression in HER2-positive breast cancer treated with dual HER2 blockade. Journal of the National Cancer Institute 112(1):36-44. 

Veeraraghavan J, De Angelis C, Mao R, et al. 2019. A combinatorial biomarker predicts pathologic complete response to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2+ breast cancer. Annals of Oncology 30(6):927-933. 

Link: 

Public and Technical Abstracts:  A New Paradigm for De-Escalation of Treatment in HER2-Positive Breast Cancer: Revolutionizing Care with More Effective and Less Toxic Therapy

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