ERBB2 Amplification and HER2 Expression in Salivary Duct Carcinoma: Evaluation of Scoring Guidelines and Potential for Expanded Anti-HER2 Therapy.

Salivary duct carcinoma (SDC) is aggressive with limited therapeutic options. A subset of SDC display human epidermal growth factor receptor 2 (HER2) protein overexpression by immunohistochemistry, and some show ERBB2 gene amplification. Guidelines for HER2 scoring are not firmly established. Recent advances in breast carcinoma have established a role for anti-HER2 therapies in lesions with low HER2 expression lacking ERBB2 amplification. Delineating HER2 staining patterns in SDC is critical for evaluating anti-HER2 treatments. In total, 53 cases of SDC resected at our institution between 2004 and 2020 were identified. Androgen receptor (AR) and HER2 immunohistochemistry and ERBB2 fluorescence in situ hybridization were performed in all cases. AR expression was scored for percentage positive cells and categorized as positive (>10% of cells), low positive (1%-10%), or negative (<1%). HER2 staining levels and patterns were recorded, scored using 2018 ASCO/CAP guidelines, and categorized into HER2-positive (3+ or 2+ with ERBB2 amplification), HER2-low (1+ or 2+ without ERBB2 amplification), HER2-very low (faint staining in <10% of cells), or HER2-absent types. Clinical parameters and vital status were recorded. Median age was 70 years, with a male predominance. ERBB2-amplified tumors (11/53; 20.8%) presented at lower pT stages (pTis/pT1/pT2; P = .005, Fisher exact test) and more frequently had perineural invasion (P = .007, Fisher exact test) compared with ERBB2 nonamplified tumors; no other pathologic features differed significantly by gene amplification status. In addition, 2+ HER2 staining by 2018 ASCO/CAP criteria was most common (26/53; 49%); only 4 cases (8%) were HER2-absent status; 3+ HER2 staining was found in 9 tumors, and all were ERBB2 amplified. Six patients with HER2-expressing tumors received trastuzumab therapy, including 2 with ERBB2-amplified tumors. Overall survival and recurrence-free survival did not differ significantly based on ERBB2 status. This work suggests that 2018 ASCO/CAP guidelines for HER2 evaluation in breast carcinoma could be applied to SDC. Our findings also show broad overexpression of HER2 in SDC raising the possibility that more patients may benefit from anti-HER2-directed therapies.

Urothelial cancer harbours EGFR and HER2 amplifications and exon 20 insertions.

OBJECTIVE: To review the genomic landscape of advanced urothelial carcinoma (UC) to assess the frequencies of EGFR and ERBB2 (HER2) alterations. MATERIALS AND METHODS: Tumour specimens from 3753 patients with advanced UC were assayed with hybrid capture-based comprehensive genomic profiling of 180-395 genes. Tumour mutational burden (TMB) was assessed on 0.8 or 1.1 Mb of DNA, and is reported as mutations per megabase. RESULTS: In 3753 cases of UC, EGFR alterations were detected in 4.1% (154) and were most commonly amplifications (64%; 99/154), while exon 20 insertions (EGFRexon20ins ) were the second most common alteration (18%; 27/154). Alterations in ERBB2 were observed in 15% (552/3753) of cases and, similarly, ERBB2 amplification was the most commonly observed alteration (278/552; 50%); ERBB2exon20ins occurred in 3.6% (20/552) of cases. EGFRexon20ins and ERBB2exon20ins occurred in younger patients (median age 62 vs 69 years, P = 2.6E-2 and 60 vs 68 years, P = 7.8E-4), and these cases had significantly lower TMB (median 3.6 vs 7.2, P = 2.7E-4 and 2.5 vs 10, P = 1.2E-7) and less frequent TP53 alterations (3.7% vs 83%, P = 4.3E-14 and 20% vs 68%, P = 9.8E-4) compared to cases with other EGFR or ERBB2 alterations. CONCLUSION: EGFR and ERBB2 alterations occur in 4% and 15% of UC, respectively. EGFRexon20ins and ERBB2exon20ins were present in 0.7% and 0.5% of UC overall and collectively define a small, but distinct, subset of UC with infrequent co-occurrence of other drivers and low TMB. Given recent promising clinical studies of inhibitors with activity against exon 20 insertions in non-small cell lung cancer, consideration should be given to developing a trial inclusive of patients with UC harbouring these alterations.

Immunoprofiles and Oncologic Outcomes of 15 Patients with Androgen Receptor-Positive Salivary Duct Carcinoma.

BACKGROUND: Salivary duct carcinomas (SDC) are a rare and aggressive subtype of salivary gland neoplasm. They can present with distinct immunoprofiles, such as androgen receptor (AR) and HER-2/Neu-positivity. To date, no consensus exists on how to best manage this entity. METHODS: All patients diagnosed with nonmetastatic AR+ SDC of the parotid from 2013 to 2019 treated with curative intent were included. Immunologic tumor profiling was conducted using 24 distinct markers. Kaplan-Meier analyses were used to estimate locoregional recurrence (LRR), distant control, and overall survival (OS). RESULTS: Fifteen patients were included. Nine (60%) patients presented with T4 disease and eight (53%) had positive ipsilateral cervical lymphadenopathy. Ten (67%) patients underwent trimodality therapy, including surgery followed by adjuvant radiation and concurrent systemic therapy. The median follow-up was 5.5 years (interquartile range, 4.8-6.1). The estimated 5-year rates of LRR, distant progression, and OS were 6%, 13%, and 87%, respectively. CONCLUSION: Despite only including AR+ SDC of the parotid, immunoprofiles, such as expression of HER-2, were highly variable, highlighting the potential to tailor systemic regimens based on individual histologic profiles in the future. Studies with larger patient numbers using tumor-specific molecular profiling and tumor heterogeneity analyses are justified to better understand the biology of these tumors. Molecularly informed treatment approaches, including the potential use of AR- and HER-2/Neu-directed therapies upfront in the definitive setting, may hold future promise to further improve outcomes for these patients.

Activity of osimertinib in a patient with stage IV non-small cell lung cancer harboring HER2 exon 19, p.L755P mutation: case report.

Background: Recurrent in-frame insertions within exon 20 causing duplication of amino acids Tyrosine-Valine-Methionine-Alanine (YVMA) represent 80% of all HER2 alterations in non-small cell lung cancer (NSCLC). HER2 tyrosine kinase inhibitors (TKI), anti-HER2 monoclonal antibodies and HER2 directed antibody-drug conjugates have been evaluated in patients with HER2 mutated NSCLC. Limited data are available regarding the activity of these agents in exon 19 alterations. Osimertinib, a 3rd generation EGFR-TKI, has been found in pre-clinical studies to decrease growth of NSCLC with HER2 exon 19 aberrations. Case Description: A 68-year-old female with a past medical history of type 2 diabetes and minimal smoking was diagnosed with stage IV NSCLC. Next generation sequencing on tumor tissue demonstrated an ERBB2 exon 19 c.2262_2264delinsTCC, p.(L755P) mutation. After five lines of treatment that included chemotherapy, chemoimmunotherapy and investigational agents the patient's disease was progressing. At this time her functional status remained good, therefore clinical trials were explored however, none were available. Based on findings from pre-clinical studies, the patient was commenced on osimertinib 80 mg OD and achieved a partial response (PR) according to RESIST criteria both intra- and extracranially. Conclusions: This is the first report to our knowledge to demonstrate activity of osimertinib in a patient with NSCLC harboring HER2 exon 19, p.L755P mutation resulting in intra- and extracranial response. In the future, osimertinib could become a targeted treatment for patients harboring exon19 ERBB2 point mutations.