CG Consult of the week 01.11.2023

Case History:

A 72-year-old female previously diagnosed with breast cancer was presented with lung and extensive bone secondaries. Histopathology test confirmed invasive ductal carcinoma; ER negative, PR negative, Her2neu2- positive. She was started on palliative chemotherapy with trastuzumab + pertuzumab + docetaxel and completed 12 cycles. PET CT showed a good response, and she was continued on maintenance dual antibody therapy until disease was progressed with new bone lesions. The treatment was switched to trastuzumab emtansine therapy with partial response to date. Genomic profiling was performed on a biopsy from the primary tumor site to aid clinical decision making going forward.

Genomic Profiling Results:

  • ERBB2 S310F
  • PIK3CA H1047R
  • LYN amplification
  • CCND3 amplification
  • TP53 R248Q

Questions from the oncologist:

  • Compared to ERBB2 gene amplification, little is known about the efficacy of HER2-tageted therapy in patients with HER2-mutated metastatic breast cancer. Given that there is no evidence of HER2 protein expression or gene amplification, would the patient benefit from HER2-targeted therapies?
  • Is a PIK3CA inhibitor an option in this patient?
  • Are there any novel therapeutic combinations we should be aware of?


First, advise the oncologist that patient support and advocacy groups exist for European breast cancer patients at and for triple-negative breast cancer patients at

This case highlights two interesting topics: 1) antibody-drug conjugates (ADCs) as cancer chemotherapy in HER-activated tumors and 2) concomitant ERBB2 and PIK3CA aberrations from both biological and clinical perspectives.

First, in addition to gene amplification, HER2 signaling can also be activated by specific mutations, most of which are located either in its extracellular domain, such as seen in this case, or in the kinase domain. Receptor activation through gene mutation facilitates internalization of the receptor, which ADCs exploit. A recent study confirmed the clinical activity of anti-HER2 ADCs in lung cancers with HER2-activating mutations, regardless of the quantity of protein expression (1). Given that T-DXd delivers its cytotoxic payload via a unique bystander effect, regardless of the level of HER2 expression (2, 3), T-DXd is worth considering in a case like this. Notably, the results of the Phase III DESTINY-Breast04 trial of T-DXd reported substantial survival benefit among patients with low expression of HER2 (4).

Second, combinatorial strategies may overcome resistance to HER2-targeted therapies. Translational studies have highlighted mutations in PIK3CA as a major driver of resistance to HER2-targeted agents. Concomitant PIK3CA and ERBB2 aberrations invite consideration of targeted agents against these variants, but PI3K blockade in HER2-activated breast cancer cells appears to stimulate increased HER3 expression (5). Even in the absence of PIK3CA mutations, the formation of HER2:HER3 heterodimers triggers the activation of downstream pathways in HER2-driven tumors (6). Suppressing the expression of HER3 or blocking its interaction with HER2 may overcome this resistance mechanism to PI3K inhibition (7). Combination therapy inhibiting HER2, HER3, and PI3K is highly effective in patient-derived xenograft models of breast cancer, and may represent a therapeutic rationale in a case like this.

Learnings From This Case: 

  • ADC-based therapies represent new treatment options for patients with ERBB2-mutant cancers..
  • Amplified and/or mutant ERBB2 may respond to T-DXd
  • Concurrent HER2 and HER3 blockade in HER2-activated tumors may address resistance to PI3K inhibition



Disclaimer: all CGCotW cases are based on a true story. No resemblance to persons alive or deceased is intended or should be inferred. ©️ CGC Genomics Consults AG

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