Fig. 1: MAPK activating mutations are enriched in metastatic HER2-amplified breast cancers and predict poor response to HER2-targeted therapy.

(a) Pattern and frequency of MAPK pathway activating mutations (OncoKb annotated) in 733 ERBB2-amplified breast tumors, stratified based on tumor type. (b) Frequency of MAPK alterations from (a) in metastatic and primary tumor samples, p < 0.05 by two-sided Fisher exact test. (c) Kaplan-Meier curve displaying progression-free survival of patients receiving first-line anti-HER2 therapy. Analysis was restricted to patients for whom genomic profiling was performed on a tumor specimen prior to starting first-line therapy, n = 145. Tumors with functional alterations in MAPK signaling members are shown in green, and tumors without MAPK alterations are shown in blue. P < 0.05, two-sided log-rank test. (d) The emergence of an NF1- loss of function alteration after exposure to anti-HER2 targeted therapy. This is a case of a 38-year-old female patient with de novo metastatic HER2-positive invasive ductal carcinoma of the left breast, who received first-line treatment with docetaxel, trastuzumab, and pertuzumab (THP), followed by maintenance with trastuzumab and pertuzumab (HP). She experienced a partial response (PR) after 6 months of therapy, which was maintained on HP for 31.5 months (959 days) when she experienced an isolated progression on the left axillary lymph nodes. Fused PET/CT scan axial images of PET Scan on HP and at the time of progression have been shown. Samples of the primary breast tumor and samples of progressing axillary lymph nodes, collected before and after exposure to anti-HER2 therapy, have been sequenced. (e) An NF1intragenic inversion (c.1527 + 970:NF1_chr17:g.57371683inv) was detected on left axillary lymph node biopsy but not in the pre-treatment tumor. This rearrangement extends 27 megabases, bisecting NF1 and resulting in inversion of exons 14-58 of NF1; this is predicted to result in loss of function due to involvement and complete inversion of the RAS GTPase domain. Abbreviations: IDC: invasive ductal carcinoma; ER: estrogen receptor: PR: progesterone receptor; POD: progression of disease; PR: partial response; PET: positron emission tomography; CT: computed tomography.