HER2 Alterations Research Articles

Effect of germline mutations on somatic alteration landscapes in BRCA-associated cancers.

10509 Background: The interaction between germline alterations in homologous recombination repair (gHRR) genes and tumoral genomic landscapes is poorly understood. We hypothesized that gHRR alterations may influence somatic mutational landscapes in BRCA-associated cancers. Methods: Using a large de-identified real-world dataset of patients undergoing matched tumor/normal next-generation DNA sequencing (Tempus xT), we compared somatic genomic landscapes of tumors arising in individuals with germline HRR mutations (g BRCA1, g BRCA2, g PALB2, g ATM, g CHEK2) versus their sporadic counterparts, across four BRCA-associated cancers (breast, ovary, pancreas, prostate). Results: In breast cancer (N = 6955; gHRR-altered 5.9%, sporadic 94.1%), somatic TP53 muts were enriched in g BRCA1 pts, and depleted in g ATM and g CHEK2 pts (all P < 0.001). ESR1 muts were depleted in g BRCA1 pts, and enriched in g ATM and g CHEK2 pts (all P < 0.05). PIK3CA muts were depleted in g BRCA1/ 2 pts, and enriched in g ATM and g CHEK2 pts (all P < 0.05). FGFR1 muts were depleted in g BRCA1/2 and g PALB2 pts, and enriched in g ATM pts (all P < 0.01). HER2 and CDH1 alterations were depleted in g BRCA1 pts (P < 0.05). In ovarian cancer (N = 4244; gHRR-altered 6.2%, sporadic 93.8%), somatic TP53 muts were enriched in g BRCA1/ 2 pts, and depleted in g ATM and g CHEK2 pts (all P < 0.05). ESR1 muts were enriched in g ATM pts (P < 0.001). PIK3CA muts were depleted in g BRCA1/ 2 pts, and enriched in g ATM pts (all P < 0.05). KRAS muts were depleted in g BRCA1/ 2 pts (P < 0.05). In pancreatic cancer (N = 5386; gHRR-altered 3.9%, sporadic 96.1%), somatic TP53 muts were enriched in g BRCA1 pts, and depleted in g ATM and g PALB2 pts (all P < 0.05). KRAS muts were enriched in g BRCA1/2 and g ATM pts (P < 0.05). Unexpectedly, ESR1 muts were enriched in g PALB2 and g CHEK2 pts (P < 0.05). In prostate cancer (N = 4378; gHRR-altered 4.5%, sporadic 95.5%), somatic TP53 muts trended higher in g BRCA1 pts, and lower in g ATM and g PALB2 pts (P = NS). TMPRSS2-ERG fusions were depleted in g BRCA1 and g BRCA2 pts (P < 0.05). FOXA1 muts were enriched in g BRCA2 pts (P < 0.05), while BRAF and CDK12 muts were enriched in g CHEK2 pts (P < 0.05 and P = 0.07). Median TMB was higher in BRCA-associated cancers with g BRCA1/2 and gPALB2 muts relative to sporadic cancers (all P < 0.05), but not in pts with g ATM or g CHEK2 muts. There were no differences in MMR mutations or MSI status. Conclusions: Across four BRCA-associated cancers, TP53 muts are enriched in BRCA1 pts and depleted in g ATM pts. In breast/ovarian cancers, PIK3CA muts are depleted in g BRCA1/ 2 pts, while ESR1 muts are enriched in g ATM pts. KRAS muts are enriched in g BRCA1/2-altered pancreas cancers, but are depleted in g BRCA1/2-altered ovarian cancers. g BRCA2-altered prostate cancers are enriched in FOXA1 muts, and depleted in ERG fusions. These data suggest that gHRR-mutated cancers have distinct genomic landscapes compared to their sporadic counterparts; this may influence therapeutic considerations.

The Role of HER2 Status in the Biliary Tract Cancers.

Despite recent advances, biliary tract cancer (BTC) is traditionally known as being hard to treat with a poor prognosis. Recent state-of-the-art genomic technologies such as next-generation sequencing (NGS) revolutionized cancer management and shed light on the genomic landscape of BTCs. There are ongoing clinical trials to assess the efficacy of HER2-blocking antibodies or drug conjugates in BTCs with HER2 amplifications. However, HER2 amplifications may not be the sole eligibility factor for these clinical trials. In this review, we aimed to comprehensively examine the role of somatic HER2 alterations and amplifications in patient stratification and provide an overview of the current state of ongoing clinical trials.

Abstract 4017: TAS2940 inhibits intracranial tumor growth and prolongs survival in HER2-aberrant and EGFR-amplified patient-derived xenograft models

Abstract Patients with brain tumors and metastases have poor prognosis and overall survival rates despite the advancements in neurosurgery, radiotherapy, and chemotherapy. Genomic alterations in HER2 are present in brain metastases of breast cancer (BC; ~20%) and non-small cell lung cancer (NSCLC; 13-20%), and EGFR alterations occur frequently in glioblastoma multiforme (GBM; >50%). Despite the advancements in standard of care options, optimal treatment management for these patients remains an unmet medical need. Recent evidence suggests activity of systemic therapy for immune and targeted therapies in the brain, including agents targeting HER2/EGFR. HER2-targeted tyrosine kinase inhibitors lapatinib, neratinib, and tucatinib and the HER2-targeted antibodies trastuzumab and pertuzumab, in combination with chemotherapy, have been shown to improve survival of patients with HER2 overexpressing BC in the presence of brain metastases. The limited penetration of these compounds into the CNS, however, limits their efficacy. TAS2940 is an irreversible pan-ErbB inhibitor with greater brain-penetrability than poziotinib, tucatinib, and neratinib. Here, we demonstrate that TAS2940 induces downregulation of phosphorylated HER2/EGFR, reduces tumor burden, and promotes a significant increase in survival in intracranial xenograft mouse models with HER2-amplification (BC), HER2-Exon20 insertion mutation (NSCLC), and EGFR-amplification (GBM). These promising preclinical data highlight potential novel therapeutic strategies for patients with EGFR-aberrant GBM and brain metastases harboring HER2/EGFR alterations, and may help support the advancement of the ongoing first-in-human clinical trial (NCT04982926) for TAS2940 in solid tumors with EGFR and/or HER2 alterations. Citation Format: Jing Han, Mikhila Mahendra, Poojabahen Gandhi, Joseph R. Daniele, Caroline C. Carrillo, Benjamin J. Bivona, Ningping Feng, John V. Heymach, Funda Meric-Bernstam, Kei Oguchi, Shinji Mizuarai, Timothy P. Heffernan, Christopher P. Vellano, Joseph R. Marszalek. TAS2940 inhibits intracranial tumor growth and prolongs survival in HER2-aberrant and EGFR-amplified patient-derived xenograft models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4017.

Abstract 1031: Specific gene alterations of HER2 positive single circulating tumor cell (CTC) compared to autologous leukocytes in metastatic breast cancer (MBC)

Abstract Introduction: Monitoring of CTC in MBC showed ability to predict treatment resistance and outcome. HER2 is one of the most important tumor markers which is associated with rapid cell division and the metastasis and prognosis of MBC in the clinic. More recently, we reported single CTC gene mutation is a key point to distinguish metastasis capability in MBC (2022 AACR and 2022 ASCO). Herein, we report specific gene alterations in HER2+ single CTC compared to autologous leukocytes in MBC. Methods: Whole blood sample (7.5ml/each) was collected from MBC patient before therapy. CTC enumeration was performed in FDA approved CellSearch™ System and then the single HER2+ CTC and leukocytes were isolated by using DEPArrayTM System (Menarini). The single cell DNA was isolated and then the initial library was prepared by using Ampli1™ Whole Genome Amplification, Ampli1™ QC Kit (Menarini) and AMPure XP kit (Beckman Coulter). The exome capture was performed by TruSeq DNA Exome kit (illumine). The sequencing was prepared by NextSeq 500 mid output V2.5 kit and was performed on the NextSeq 500 (Illumina). Results: We identified 107 CTCs including 55 HER2+ CTCs and 14 CTC-clusters. Autologous single HER2+ CTC (HER2+CK+CD45−, Group 1), HER2+CK−CD45+ leukocyte (Group 2) and HER2−CK−CD45+ leukocyte (Group 3) were isolated and sequenced respectively. The sequencing data was processed following the GATK pipeline and annotated using SnpEff. There were 486,119 counts (56.69%) for intron variants, 175,819 counts (20.51%) for intergenic variants, 70,334 counts (8.20%) for exon variants, 50,370 counts (5.87%) for downstream genes, 45,915 counts (5.36%) for upstream genes and others (3.37%) in HER2+ CTC. Meanwhile, there were 71,848 (8.76%) and 0 counts for exon variants found in Group 2 and Group 3 respectively. There were 79 gene variants ((SNP and Ins-Del) identified to have the highest impact effect (≥20) on HER2+ CTC chromosome, when there were 85 and 0 highest impact gene variants were identified in Group 2 and Group 3 respectively. The specific gene alterations in Group 1 compared to Group 2 includes CCNA2, FOLH1, BRD4, SAMHD1, CYP17A1, IDE, HPGDS and CTNNB1 Among the top 50 high impact gene variants, there were 26 genes alteration sites are same in both Group 1 and Group 2, including FECH, HDAC8, CYP11B2, TTN(6 sites), RAN, CD207, HK1, CASP1(2 sites), BRCA1, PIK3CG (3 sites), APEX1(4 sites), KIF11, SIRT5 (2 sites), XYLB and CHKA. Conclusion: Genomic characterization of HER2 positive single CTCs elucidated specific gene alterations associated with disease metastasis compared to autologous leukocytes in MBC. The newfound HER2+CK−CD45+ cells with gene alterations maybe a new kind of cancer transformed leukocytes which need further validation. Specific gene alterations will help to develop novel drugs aimed at the eradication of CTCs using molecularly driven therapies for disease metastasis. Citation Format: Qiang Zhang, Lorenzo Gerratana, Zhe Ji, Xinkun Wang, Paolo D’Amico, Seema Singhal, Youbin Zhang, Andrew A. Davis, Ami N. Shah, William Gradishar. Specific gene alterations of HER2 positive single circulating tumor cell (CTC) compared to autologous leukocytes in metastatic breast cancer (MBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1031.

Genomic landscape and efficacy of HER2-targeted therapy in patients with HER2-mutant non-small cell lung cancer.

HER2-targeted therapy provides survival benefits to HER2-mutant non-small cell lung cancer (NSCLC). A better understanding of the clinical and genomic characterization of treatment-naïve HER2-positive NSCLC, as well as the efficacy of and resistance to HER2-targeted therapy in HER2-altered NSCLC, could promote further improvement of HER2 targeted therapy. HER2-altered NSCLC patients was retrospectively included and their genomic profiles were performed by next-generation sequencing. The clinical outcomes included overall response rate, disease control rate and progression-free survival. Among 176 treatment-naïve patients with HER2 alterations, 64.8% harbored HER2 mutations with/without HER2 amplification, and 35.2% carried HER2 amplification only. Molecular characterization was correlated with tumor stage that late-stage NSCLC with HER2 oncogenic mutations showed a higher prevalence of TP53 mutations and a higher tumor mutation burden. However, this correlation was not found in patients with HER2 amplification only. Twenty-one patients with HER2 alterations treated with pyrotinib or afatinib were retrospectively enrolled. Pyrotinib yielded a longer median progression-free survival than afatinib (5.9 [95% CI, 3.8-13.0] vs. 4.0 months [95% CI, 1.9-6.3], P = 0.06) in these patients. Analysis of the genomic profiles before and after anti-HER2 targeted therapies identified de novo HER2 copy number gain and G518W mutation, as well as mutations involving DNA damage repair signaling, SWI-SNF complex, and epigenetic regulations as potential resistance mechanisms. HER2-mutant NSCLC had different molecular features from HER2-amplified NSCLC, and its genomic profile was dependent of tumor stage. Pyrotinib had superior therapeutic effects than afatinib in HER2-altered NSCLC, although larger cohorts are warranted to validate it. HER2-dependent and -independent resistance mechanisms to afatinib and pyrotinib were unveiled.

HER2 Expression Associated with Clinical Characteristics and Prognosis of Urothelial Carcinoma in a Chinese Population.

The frequency of HER2 overexpression in bladder cancer is reported as 9%-61%. HER2 alteration correlates with aggressive disease in bladder cancer. Traditional anti-HER2 targeted therapy has failed to show clinical benefits in patients with advanced urothelial carcinoma . The information on pathologically proven patients with urothelial carcinoma with detected HER2 status was collected from the database of Peking University Cancer Hospital. The HER2 expression, as well as its association with clinical characteristics and prognosis, was analyzed. A total of 284 consecutive patients with urothelial carcinoma were enrolled. HER2 was positive (IHC 2+/3+) in 44% of urothelial carcinoma. HER2 positivity was found more frequent in UCB than in UTUC (51% vs. 38%). Stage, radical surgery, and histological variant were associated with survival (P < .05). For metastatic patients, multivariate analysis shows that 3 indicators, including liver metastasis, the number of involved organs, and anemia, are independent risk factors of prognosis. Receiving immunotherapy or disitamab vedotin (DV) treatment is an independent protecting factor. The survival of patients with low HER2 expression was also significantly improved by the treatment of DV (P < .001). HER2 expression (IHC 1+, 2+, 3+) was associated with a better prognosis in this population. DV has improved the survival of patients with urothelial carcinoma in the real world. With the new-generation anti-HER2 ADC treatment, HER2 expression is no longer a poor prognostic factor.

Poziotinib in Treatment-Naive NSCLC Harboring HER2 Exon 20 Mutations: ZENITH20-4, A Multicenter, Multicohort, Open-Label, Phase 2 Trial (Cohort 4)

IntroductionERBB2 or HER2 alterations are found in approximately 2% to 5% of NSCLCs; most are exon 20 insertion mutations. The efficacy and safety of poziotinib, an oral tyrosine kinase inhibitor, were assessed in patients with treatment-naive NSCLC whose tumors harbor HER2 exon 20 insertions. MethodsZENITH20 is an open-label, multicohort, multicenter, global, phase 2 trial. ZENITH20-C4 enrolled treatment-naive patients with NSCLC with tumors harboring HER2 exon 20 insertions. Poziotinib was administered 16 mg once daily (QD) or 8 mg twice daily (BID). The primary end point was objective response rate (ORR) by independent central review. Secondary and exploratory end points included disease control rate, duration of response, progression-free survival, and safety. ResultsA total of 80 patients (16 mg QD, n = 47; 8 mg BID, n = 33) were treated in ZENITH20-C4. ORR was 39% (95% confidence interval [CI]: 28%–50%; 31 of 80), with a disease control rate of 73% (95% CI: 61%–82%; 58 of 80); 80% of the patients experienced tumor reduction. Median duration of response was 5.7 (95% CI: 4.6–11.9) months, and median progression-free survival was 5.6 (95% CI: 5.4–7.3) months. The most common grade 3 treatment-related adverse events were rash (QD, 45%; BID, 39%), stomatitis (QD, 21%; BID, 15%), and diarrhea (QD, 15%; BID, 21%). Among all subtypes of HER2 exon 20 insertions, seven patients (9%) harboring tumors with G778_P780dupGSP had the best clinical outcomes (ORR, 71%). ConclusionsPoziotinib was found to have clinically meaningful efficacy with a manageable toxicity profile for patients with treatment-naive NSCLC harboring HER2 exon 20 mutations.

Abstract P1-05-27: Liquid Biopsy for HER2 Status Assessment in Breast Cancer Using Surrogate DNA Methylation Markers

Abstract Background: Emerging HER2-targeted drugs especially antibody–drug conjugates (ADCs) are promising and provide more options for breast cancer management. Current assessment of HER2 status and treatment decisions are mainly dependent on immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) on the primary tumor tissues. With the disease progression, the molecular status of the tumor may evolve and become discordant with the primary site. However, longitudinal monitoring of HER2 status is limited by infeasible repeated sampling of the tumor tissues. A non-invasive and accurate approach to obtaining real-time samples for measuring HER2 alterations is thus an unmet need for surveillance and guiding treatment selection in breast cancer. Detecting HER2 aberration in cell-free DNA (cfDNA) can allow repeated sampling and avoid effects from tumor heterogeneity of tissue biopsy. Previous approaches for HER2 status determination using liquid biopsy were mostly dependent on the detection of copy number changes in cfDNA, but the limited signal-to-noise ratio poses a great challenge to the accuracy and robustness of the tests. In this study, we identified a group of DNA methylation markers for determining HER2 status in cfDNA for breast cancer. Methods: Genome-wide DNA methylation sequencing was conducted in tissue (25 HER2-positive and 35 HER2-negative) and plasma (32 HER2-positive and 107 HER2-negative) samples to identify specific methylation markers for HER2 status. HER2-positive samples were defined by IHC 3+ and 2+ with FISH positive, while HER2-negative ones were IHC 0/1+ and 2+ with FISH negative. Candidate markers were verified in another two sets of plasma samples (1. 30 HER2-positive and 40 HER2-negative; 2. 33 HER2-positive and 53 HER2-negative) by using quantitative methylation-specific PCR (qMSP). The performance of the markers was estimated by the Wilcoxon test, receiver operating characteristic curve, and logistic regression modelling. Results: 36 HER2 status-specific markers were discovered from genome-wide DNA methylation sequencing. Based on the qMSP results, 11 markers were verified by the performance analyses. The individual area under the curve (AUC) of these markers was from 0.58 to 0.68. From logistic regression modelling and 2-fold cross-validation, a 7-marker diagnostic model was built and validated on plasma samples, with the highest AUC of 0.812. Conclusion: cfDNA methylation detection inferring HER2 overexpression is a novel and non-invasive option for monitoring HER2 status in breast cancer patients, with a potential application in response prediction of HER2-targeted treatments. Further validation of the test is undergoing in large multi-centre cohorts in China. Citation Format: Xianyu Zhang, Shiyao Lu, Hui Li, Xin Liu, Jun Wang, Liuhong Zeng, Zhipeng Lu, Siyu Liu, Yanling Yin, Marina Bibikova, Zhiwei Chen, Jian-Bing Fan, Da Pang. Liquid Biopsy for HER2 Status Assessment in Breast Cancer Using Surrogate DNA Methylation Markers [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-05-27.

A phase 2 basket study of tucatinib and trastuzumab in previously treated solid tumors with HER2 alterations: Urothelial cancer cohort (SGNTUC-019).

TPS587 Background: Tucatinib, a highly selective human epidermal growth factor receptor 2 (HER2)-directed tyrosine kinase inhibitor approved in multiple regions for HER2-positive (HER2+) metastatic breast cancer, is being investigated as a novel therapy for metastatic colorectal cancer, gastric cancer, and other solid tumors. In xenograft models of HER2+ and HER2-mutated tumors, dual targeting of HER2 with tucatinib plus trastuzumab showed superior activity to either alone (Kulukian 2020; Peterson 2020). Despite development of several new therapies for metastatic urothelial cancer (UC), most patients are refractory to subsequent therapies and die from the disease, highlighting the need for additional therapeutic approaches. Given that 20%–30% of metastatic UCs have molecular alterations of the ErbB family, tucatinib plus trastuzumab warrants further evaluation. SGNTUC-019 (NCT04579380) is a multi-cohort, open-label, phase 2 study evaluating tucatinib plus trastuzumab in patients with previously treated solid tumors displaying HER2+ or HER2-mutated solid tumors, including a cohort with locally advanced or metastatic UC. Methods: Eligible patients in the UC cohort must have HER2+ locally advanced or metastatic disease, with progression during or after, or intolerance of, the most recent line of systemic therapy. Patients must have an ECOG PS ≤1; adequate hepatic, hematologic, renal, and cardiac function; and no prior exposure to HER2-directed therapy. HER2 alterations can be demonstrated by HER2 overexpression/amplification in tumor tissue by prior IHC/ISH or by HER2 amplification in prior or prescreening NGS assay of ctDNA or prior tissue NGS assay. The HER2 overexpression/amplification UC cohort will enroll 12 response-evaluable patients per RECIST 1.1. If ≥2 responses are observed, the cohort will be expanded to 30. The primary objective is antitumor activity, with confirmed ORR as the primary endpoint and DCR, duration of response, PFS, and OS as secondary efficacy endpoints. Confidence intervals (CIs) will be calculated for confirmed ORR and DCR. For time-to-event endpoints, median survival time will be estimated by the Kaplan-Meier method, and the associated 95% CI will be calculated using complementary log-log transformation. Safety endpoints will be assessed using descriptive statistics. Patients will receive tucatinib 300 mg orally twice daily and trastuzumab 8 mg/kg intravenously on Cycle 1 Day 1 and 6 mg/kg every 21 days from Cycle 2 Day 1. Disease assessments per RECIST 1.1 will occur every 6 weeks for 24 weeks, then every 12 weeks. Trough concentrations of tucatinib will be evaluated in Cycles 2–6, with peak concentration sampled in Cycle 3. Quality of life will be evaluated every second cycle using the EQ-5D-5L. Sites are currently enrolling within the US, EU, and Asia Pacific. Clinical trial information: NCT04579380 .

Immunohistochemical based molecular subtypes of muscle-invasive bladder cancer: association with HER2 and EGFR alterations, neoadjuvant chemotherapy response and survival

Muscle-invasive bladder cancers (MIBCs) is a group of molecularly heterogonous diseases that could be stratified into subtypes with distinct clinical courses and sensitivities to chemotherapy. Clinical application of molecular subtypes could help in prediction of neoadjuvant chemotherapy (NAC) responders. Immunohistochemical (IHC) markers such as GATA3, cytokeratin (CK) 5/6, and p53 are associated with these subtypes and are widely available. Human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR) are mutated in multiple cancers including MIBC and are potential therapeutic targets. HER2/EGFR status of MIBC subtypes has not been investigated. Tissue microarrays (TMAs) were constructed from transurethral resection of the bladder tumor (TURB) specimens and stained with GATA3,CK5/6,p53 and HER2 in addition to Quantitative Reverse Transcription PCR for detection of EGFR gene. Of the total cases, 45% were luminal, 36.7% basal and 18.3% p53 wild subtype (p53-WT). Univariate analysis showed that overall survival (OS) and disease-free progression survival (DFS) were significantly longer for luminal subtype. In multivariate analysis, molecular subtype, HER2 status and LV invasion were independent prognostic factors for DFS and OS. Basal subtype showed a significantly better response to NAC. HER2 expression was significantly higher in luminal while EGFR expression was significantly higher in basal subtype. Kaplan-Meier survival curves revealed a significant longer OS and DFS for HER2 negative than positive cases. MIBC can be stratified using a simple IHC panel [GATA3,CK5/6,P53] into clinically relevant prognostic molecular subtypes. Basal tumors are aggressive and respond well to NAC while luminal have better OS. P53-WT tumors are chemoresistant and require further treatments. HER2 and EGFR are potential therapeutic targets for molecular subtypes of MIBC where luminal tumors are more likely to benefit from HER2 and basal from EGFR directed therapies.

Primary Mucinous Tumors of the Ovary: An Interobserver Reproducibility and Detailed Molecular Study Reveals Significant Overlap Between Diagnostic Categories

Primary ovarian mucinous tumors represent a heterogeneous group of neoplasms, and their diagnosis may be challenging. We analyzed 124 primary ovarian mucinous tumors originally diagnosed as mucinous borderline tumors (MBTs) or mucinous carcinomas (MCs), with an emphasis on interobserver diagnostic agreement and the potential for diagnostic support by molecular profiling using a next-generation sequencing targeted panel of 727 DNA and 147 RNA genes. Fourteen experienced pathologists independently assigned a diagnosis from preset options, based on a review of a single digitized slide from each tumor. After excluding 1 outlier participant, there was a moderate agreement in diagnosing the 124 cases when divided into 3 categories (κ = 0.524, for mucinous cystadenoma vs MBT vs MC). A perfect agreement for the distinction between mucinous cystadenoma/MBT as a combined category and MC was found in only 36.3% of the cases. Differentiating between MBTs and MCs with expansile invasion was particularly problematic. After a reclassification of the tumors into near-consensus diagnostic categories on the basis of the initial participant results, a comparison of molecular findings between the MBT and MC groups did not show major and unequivocal differences between MBTs and MCs or between MCs with expansile vs infiltrative pattern of invasion. In contrast, HER2 overexpression or amplification was found only in 5.3% of MBTs and in 35.3% of all MCs and in 45% of MCs with expansile invasion. Overall, HER2 alterations, including mutations, were found in 42.2% of MCs. KRAS mutations were found in 65.5% and PIK3CA mutations in 6% of MCs. In summary, although the diagnostic criteria are well-described, diagnostic agreement among our large group of experienced gynecologic pathologists was only moderate. Diagnostic categories showed a molecular overlap. Nonetheless, molecular profiling may prove to be therapeutically beneficial in advanced-stage, recurrent, or metastatic MCs.

Molecular alterations of driver genes in non-small cell lung cancer: from diagnostics to targeted therapy.

Lung cancer is the leading cause of cancer death all over the world. The majority (80-85 %) of lung cancer cases are classified as non-small cell lung cancer (NSCLC). Within NSCLC, adenocarcinoma (AC) and squamous cell carcinoma (SCC) are the most often recognized. The histological and immunohistochemical examination of NSCLC is a basic diagnostic tool, but insufficient for comprehensive therapeutic decisions. In some NSCLC patients, mainly adenocarcinoma, molecular alterations in driver genes, like EGFR, KRAS, HER2, ALK, MET, BRAF, RET, ROS1, and NTRK are recognized. The frequency of some of those changes is different depending on race, and between smokers and non-smokers. The molecular diagnostics of NSCLC using modern methods, like next-generation sequencing, is essential in estimating targeted, personalized therapy. In recent years, a breakthrough in understanding the importance of molecular studies for the precise treatment of NSCLC has been observed. Many new drugs were approved, including tyrosine kinase and immune checkpoint inhibitors. Clinical trials testing novel molecules like miRNAs and trials with CAR-T cells (chimeric antigen receptor - T cells) dedicated to NSCLC patients are ongoing.

Evolution of Treatment in Advanced Cholangiocarcinoma: Old and New towards Precision Oncology.

Cholangiocarcinoma (CCA) is a malignant neoplasm arising in the epithelium of the biliary tract. It represents the second most common primary liver cancer in the world, after hepatocellular carcinoma, and it constitutes 10-15% of hepatobiliary neoplasms and 3% of all gastrointestinal tumors. As in other types of cancers, recent studies have revealed genetic alterations underlying the establishment and progression of CCA. The most frequently involved genes are APC, ARID1A, AXIN1, BAP1, EGFR, FGFRs, IDH1/2, RAS, SMAD4, and TP53. Actionable targets include alterations of FGFRs, IDH1/2, BRAF, NTRK, and HER2. "Precision oncology" is emerging as a promising approach for CCA, and it is possible to inhibit the altered function of these genes with molecularly oriented drugs (pemigatinib, ivosidenib, vemurafenib, larotrectinib, and trastuzumab). In this review, we provide an overview of new biologic drugs (their structures, mechanisms of action, and toxicities) to treat metastatic CCA, providing readers with panoramic information on the trajectory from "old" chemotherapies to "new" target-oriented drugs.

Antibody drug conjugates targeting HER2: Clinical development in metastatic breast cancer

The identification of the HER2 alteration as an actionable oncogenic driver in breast cancer has propelled the development of HER-targeting monoclonal antibodies (mAb) such as trastuzumab and pertuzumab, which led to dramatic improvements in survival outcomes. Lately, the great strides made toward developing antibody-conjugation methods have led to the development of a new class of compelling compounds, the antibody-drug conjugates (ADCs) targeting HER2 which have profoundly transformed the treatment landscape of breast cancer. HER2-targeting ADCs, trastuzumab-emtansine and trastuzumab-deruxtecan, have improved the overall survival in the second and third-line settings with manageable adverse events. Other HER2-targeting ADCs using novel technological advances in the antibody, linker and/or payload conception have shown promising activity in preclinical and clinical studies and some of them are now being evaluated in larger clinical trials. Multiple challenges still impede the success of ADCs in breast cancer namely the lack of a comprehensive understanding of resistance mechanisms as well as the mechanisms of action of ADCs in special subgroups of patients such as those with low or ultra-low HER2 expression and patients with brain or leptomeningeal metastases (BM). In this framework, we review the approved indications and ongoing trials for HER2-targeting ADCs, across patient subgroups, including those with BM and discuss the associated potential mechanisms of action and resistance. Last, we provide an overview of the future perspectives involving HER2-targeting ADCs in breast cancer.

Deciphering the Impact of HER2 Alterations on Non-Small-Cell Lung Cancer: From Biological Mechanisms to Therapeutic Approaches.

Despite the recent increase in the number of types of treatments, non-small-cell lung cancer (NSCLC) remains the major cause of death from cancer worldwide. So, there is an urgent need to develop new therapeutic strategies. The HER2 gene codes for tyrosine kinase receptor whose alterations are known to drive carcinogenesis. HER2 alterations, including amplification, mutations, and overexpression, have been mainly described in breast and gastric cancers, but up to 4% of NSCLC harbor actionable HER2 mutations. HER2-targeted therapy for NSCLC with trastuzumab, pertuzumab, and trastuzumab emtansine has failed to demonstrate an improvement in survival. Nevertheless, recent data from phase II trials have shed light on promising specific therapies for HER2-mutant NSCLC such as trastuzumab deruxtecan. Herein, we aimed to provide an updated review on the biology, epidemiology, molecular testing, and therapeutic strategies for NSCLC with HER2 molecular alterations.

HER2 in Uterine Serous Carcinoma: Testing platforms and implications for targeted therapy

ObjectiveHER2 is an important prognostic and therapeutic target in uterine serous carcinoma (USC). Optimal HER2 testing platforms have not been defined and guidelines for testing have changed over time. Our objective is to assess the concordance of HER2 positivity based on chromogenic in situ hybridization (CISH), immunohistochemistry (IHC), and next generation sequencing (NGS) and to determine the rate of downstream mutations that may affect response to HER2 directed therapy. MethodsUtilizing the Caris tumor registry, 2192 USC tumors were identified and analyzed using NGS (NextSeq, 592 Genes and WES, NovaSEQ), IHC, and CISH. PD-L1 expression was tested by IHC. Microsatellite instability was tested by fragment analysis, IHC, and NGS. Tumor mutational burden (TMB) was measured by totaling somatic mutations per tumor. HER2 positivity through IHC and CISH was determined based on 2007 and 2018 ASCO/CAP HER2 breast cancer guidelines. ResultsThere was a higher rate of HER2 positivity by IHC when using the 2018 guidelines compared to the 2007 guidelines (16.3% vs 12.3%). Concordance between IHC and CISH was 98.9%. ERBB2 amplification was identified by NGS in 10.5% of tumors. Compared to CISH results, this corresponds to a concordance rate of 91.6% and a positive predictive value (PPV) of 60.3%. Single gene alterations in HER2 amplified tumors that may implicate HER2 therapy resistance included PI3K (33.1%), KRAS (2.5%), and PTEN (1.3%). ConclusionsThere was high concordance between HER2 positivity based on CISH and IHC. Rate of HER2 positivity is the lowest by NGS. Ultimately these testing platforms need to be validated by response to targeted therapy.

HER2 in Metastatic Colorectal Cancer: Pathology, Somatic Alterations, and Perspectives for Novel Therapeutic Schemes.

Simple SummaryIn the current clinical practice, HER2 status is tested in breast and gastroesophageal cancers to select patients eligible for anti-HER2 treatment. However, HER2 is an emerging biomarker in colorectal cancer (CRC), one of the big killers in oncology. The most frequent types of HER2 alterations in CRC include gene amplification and mutations and often involve protein overexpression. In this review, we discuss the current knowledge of HER2 testing in CRC and the immediate future perspectives for HER2 targeting in the metastatic setting.HER2 is an emerging biomarker in colorectal cancer (CRC). This oncogene plays an essential role in regulating cell proliferation, differentiation, migration, and, more in general, tumorigenesis and tumor progression. The most frequent types of HER2 alterations in CRC include gene amplification and missense mutations in 7–8% of CRC, often being mirrored by HER2 protein overexpression, representing founder events in solid tumors, including CRC. There are currently no approved HER2-targeted therapy guidelines for CRC; however, several studies have shown that HER2 can be effectively targeted in meta-static CRC settings. In this review, we discuss the current knowledge of HER2 testing in CRC and the immediate future perspectives for HER2 targeting in the metastatic setting.

EP08.01-105 Efficacy of First-Line Immune Checkpoint Inhibitors in Patients with Advanced NSCLC harboring KRAS, MET, FGFR, RET, BRAF, and HER2 Alterations

In patients with NSCLC harboring molecular alterations, the efficacy of immune checkpoint inhibitors (ICI) remains unknown. The aim of our study was to examine the efficacy of first-line ICI among patients having NSCLC with KRAS, MET, FGFR, RET, BRAF, and HER2 alterations, compared to those with driver-unknown.

EP08.01-051 Clinical Characterization and Outcomes of Non Small Cell Lung Cancer with HER2 Alterations in the Era of Immunotherapy

HER2-altered Non Small Cell Lung Cancer (NSCLC) is a rare subgroup (2-4%) of NSCLC. Previous studies, using small cohorts, report poor outcomes and shorter survival in HER2-altered NSCLC compared to the other subtypes of NSCLC. However, most studies were done before immunotherapy is used as the first-line therapy in stage IV NSCLC. The detailed outcomes of those patients treated under the most recent guidelines are largely unknown.

Pyrotinib combined with apatinib for targeting metastatic non-small cell lung cancer with HER2 alterations: a prospective, open-label, single-arm phase 2 study (PATHER2)

BackgroundAlthough targeted agents have been gradually applied in the treatment of HER2-mutated non-small cell lung cancer (NSCLC) in recent years, patients’ therapeutic demands are far from being met. PATHER2 was the first phase 2 trial to explore the efficacy and safety of the HER2-targeted tyrosine kinase inhibitor (TKI) pyrotinib plus the antiangiogenic agent apatinib in previously treated HER2-altered metastatic NSCLC patients.MethodsHER2-mutated or HER2-amplified metastatic NSCLC patients who had failed at least first-line chemotherapy or HER2-targeted TKIs received oral pyrotinib 400 mg plus apatinib 250 mg once daily until disease progression, intolerable toxicity, or death. The primary endpoint was the investigator-assessed objective response rate (ORR).ResultsBetween March 2019 and December 2020, 33 patients were enrolled; 13 (39.4%) presented brain metastases, and 16 (48.5%) had received at least two lines of prior chemotherapy or HER2-targeted TKIs. As of September 20, 2021, the median follow-up duration was 11.3 (range, 3.5–26.0) months. The investigator-assessed ORR was 51.5% (17/33; 95% CI, 33.5 to 69.2%), and the disease control rate was 93.9% (31/33; 95% CI, 79.8 to 99.3%). The median duration of response, progression-free survival, and overall survival were 6.0 (95% CI, 4.4 to 8.6) months, 6.9 (95% CI, 5.8 to 8.5) months, and 14.8 (95% CI, 10.4 to 23.8) months, respectively. The most frequent grade ≥ 3 treatment-related adverse events included diarrhea (3.0%) and hypertension (9.1%). No treatment-related deaths were reported.ConclusionsPyrotinib plus apatinib demonstrated promising antitumor activity and a manageable safety profile in HER2-mutated or HER2-amplified metastatic NSCLC patients.Trial registrationChinese Clinical Trial Registry Identifier: ChiCTR1900021684.