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Simultaneous presentation of two separate primary breast cancers of differing histology at initial diagnosis is an uncommon phenomenon; it is even rarer to find these pathologically distinct populations within the same biopsy. Here we report the case of a patient diagnosed with clearly demarcated, pathologically heterogenous triple negative breast cancer (TNBC) and HER2+ breast cancer that was treated with a hybrid chemoimmunotherapy regimen combining elements of Keynote-522 and a standard HER2-directed neoadjuvant regimen, yielding apathologic complete response by the time of surgery with no notable adverse events. Molecular analysis of the histologically distinct tumor populations confirmed molecular evidence of differential HER2 expression but also suggested clonal relatedness of the two tumor populations based upon mutational profile, with phenotypic divergence potentially resulting from copy number alterations in NF1. Overall, this case highlights a rare histologic phenomenon that was successfully treated by combining both TNBC and HER2 directed neoadjuvant therapies., (© 2024. The Author(s).)

The association between loss of BRCA1/2 and a homologous recombination deficiency phenotype is lineage dependent. In BRCA-associated cancers such as breast, ovarian, pancreas and prostate, this phenotype confers sensitivity to PARP inhibitors and platinum-therapies. Somatic reversion mutations restoring BRCA1/2 function mediate resistance, and have exclusively been reported in BRCA-associated tumors. In this study, we analyze matched tumor and normal sequencing from 31,927 patients and identify 846 (2.7%) patients with germline BRCA1/2 variants across 43 different cancer types, including 11 with somatic reversion mutations. While nine are in BRCA-associated tumors, we find two reversion mutations in non-BRCA-associated histologies, namely lung and esophagogastric adenocarcinomas. Both were detected following platinum therapy. Whole exome sequencing confirms the homologous recombination deficiency phenotype of these tumors. While reversion mutations arise in all BRCA-associated cancer types, here we show that reversion mutations arising post-platinum in non-BRCA associated histologies, while rare, may indicate BRCA1/2 mediated tumorigenesis., (© 2022. The Author(s).)

The efficacy of the highly selective RET inhibitor selpercatinib is now established in RET-driven cancers, and we sought to characterize the molecular determinants of response and resistance. We find that the pre-treatment genomic landscape does not shape the variability of treatment response except for rare instances of RAS-mediated primary resistance. By contrast, acquired selpercatinib resistance is driven by MAPK pathway reactivation by one of two distinct routes. In some patients, on- and off-target pathway reactivation via secondary RET solvent front mutations or MET amplifications are evident. In other patients, rare RET-wildtype tumor cell populations driven by an alternative mitogenic driver are selected for by treatment. Multiple distinct mechanisms are often observed in the same patient, suggesting polyclonal resistance may be common. Consequently, sequential RET-directed therapy may require combination treatment with inhibitors targeting alternative MAPK effectors, emphasizing the need for prospective characterization of selpercatinib-treated tumors at the time of monotherapy progression., (© 2022. The Author(s).)

Purpose: Selpercatinib and pralsetinib induce deep and durable responses in patients with advanced RET fusion-positive lung and thyroid cancer. RET fusion testing strategies with rapid and reliable results are critical given recent FDA approval. Here, we assess various clinical assays in a large pan-cancer cohort., Experimental Design: Tumors underwent DNA-based next-generation sequencing (NGS) with reflex to RNA-based NGS if no mitogenic driver or if a RET structural variant of unknown significance (SVUS) were present. Canonical DNA-level RET fusions and RNA-confirmed RET fusions were considered true fusions. Break-apart FISH and IHC performance were assessed in subgroups., Results: A total of 171 of 41,869 patients with DNA NGS harbored RET structural variants, including 139 canonical fusions and 32 SVUS. Twelve of 32 (37.5%) SVUS were transcribed into RNA-level fusions, resulting in 151 oncogenic RET fusions. The most common RET fusion-positive tumor types were lung (65.6%) and thyroid (23.2%). The most common partners were KIF5B (45%), CCDC6 (29.1%), and NCOA4 (13.3%). DNA NGS showed 100% (46/46) sensitivity and 99.6% (4,459/4,479) specificity. FISH showed 91.7% (44/48) sensitivity, with lower sensitivity for NCOA4 - RET (66.7%, 8/12). A total of 87.5% (7/8) of RET SVUS negative for RNA-level fusions demonstrated rearrangement by FISH. The sensitivity of IHC varied by fusion partner: KIF5B sensitivity was highest (100%, 31/31), followed by CCDC6 (88.9%, 16/18) and NCOA4 (50%, 6/12). Specificity of RET IHC was 82% (73/89)., Conclusions: Although DNA sequencing has high sensitivity and specificity, RNA sequencing of RET SVUS is necessary. Both FISH and IHC demonstrated lower sensitivity for NCOA4 - RET fusions., (©2020 American Association for Cancer Research.)

Purpose: The RET proto-oncogene encodes a receptor tyrosine kinase that is activated by gene fusion in 1%-2% of non-small cell lung cancers (NSCLC) and rarely in other cancer types. Selpercatinib is a highly selective RET kinase inhibitor that has recently been approved by the FDA in lung and thyroid cancers with activating RET gene fusions and mutations. Molecular mechanisms of acquired resistance to selpercatinib are poorly understood., Patients and Methods: We studied patients treated on the first-in-human clinical trial of selpercatinib (NCT03157129) who were found to have MET amplification associated with resistance to selpercatinib. We validated MET activation as a targetable mediator of resistance to RET-directed therapy, and combined selpercatinib with the MET/ALK/ROS1 inhibitor crizotinib in a series of single patient protocols (SPP)., Results: MET amplification was identified in posttreatment biopsies in 4 patients with RET fusion-positive NSCLC treated with selpercatinib. In at least one case, MET amplification was clearly evident prior to therapy with selpercatinib. We demonstrate that increased MET expression in RET fusion-positive tumor cells causes resistance to selpercatinib, and this can be overcome by combining selpercatinib with crizotinib. Using SPPs, selpercatinib with crizotinib were given together generating anecdotal evidence of clinical activity and tolerability, with one response lasting 10 months., Conclusions: Through the use of SPPs, we were able to offer combination therapy targeting MET -amplified resistance identified on the first-in-human study of selpercatinib. These data suggest that MET dependence is a recurring and potentially targetable mechanism of resistance to selective RET inhibition in advanced NSCLC., (©2020 American Association for Cancer Research.)

Purpose: TRK inhibitors achieve marked tumor-agnostic efficacy in TRK fusion-positive cancers and consequently are now an established standard of care. Little is known, however, about the demographics, outcomes, response to alternative standard therapies, or genomic characteristics of TRK fusion-positive cancers., Experimental Design: Utilizing a center-wide screening program involving more than 26,000 prospectively sequenced patients, genomic and clinical data from all cases with TRK fusions were extracted. An integrated analysis was performed of genomic, therapeutic, and phenomic outcomes., Results: We identified 76 cases with confirmed TRK fusions (0.28% overall prevalence) involving 48 unique rearrangements and 17 cancer types. The presence of a TRK fusion was associated with depletion of concurrent oncogenic drivers ( P < 0.001) and lower tumor mutation burden ( P < 0.001), with the exception of colorectal cancer where TRK fusions cooccur with microsatellite instability (MSI-H). Longitudinal profiling in a subset of patients indicated that TRK fusions were present in all sampled timepoints in 82% (14/17) of cases. Progression-free survival on first-line therapy, excluding TRK inhibitors, administered for advanced disease was 9.6 months [95% confidence interval (CI), 4.8-13.2]. The best overall response rate achieved with chemotherapy containing-regimens across all lines of therapy was 63% (95% CI, 41-81). Among 12 patients treated with checkpoint inhibitors, a patient with MSI-H colorectal cancer had the only observed response., Conclusions: TRK fusion-positive cancers can respond to alternative standards of care, although efficacy of immunotherapy in the absence of other predictive biomarkers (MSI-H) appears limited. TRK fusions are present in tumors with simple genomes lacking in concurrent drivers that may partially explain the tumor-agnostic efficacy of TRK inhibitors., (©2019 American Association for Cancer Research.)

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With the FDA approval of larotrectinib, NTRK fusion assessment has recently become a standard part of management for patients with locally advanced or metastatic cancers. Unlike somatic mutation assessment, the detection of NTRK fusions is not straightforward, and various assays exist at the DNA, RNA, and protein level. Here, we investigate the performance of immunohistochemistry and DNA-based next-generation sequencing to indirectly or directly detect NTRK fusions relative to an RNA-based next-generation sequencing approach in the largest cohort of NTRK fusion positive solid tumors to date. A retrospective analysis of 38,095 samples from 33,997 patients sequenced by a targeted DNA-based next-generation sequencing panel (MSK-IMPACT), 2189 of which were also examined by an RNA-based sequencing assay (MSK-Fusion), identified 87 patients with oncogenic NTRK1-3 fusions. All available institutional NTRK fusion positive cases were assessed by pan-Trk immunohistochemistry along with a cohort of control cases negative for NTRK fusions by next-generation sequencing. DNA-based sequencing showed an overall sensitivity and specificity of 81.1% and 99.9%, respectively, for the detection of NTRK fusions when compared to RNA-based sequencing. False negatives occurred when fusions involved breakpoints not covered by the assay. Immunohistochemistry showed overall sensitivity of 87.9% and specificity of 81.1%, with high sensitivity for NTRK1 (96%) and NTRK2 (100%) fusions and lower sensitivity for NTRK3 fusions (79%). Specificity was 100% for carcinomas of the colon, lung, thyroid, pancreas, and biliary tract. Decreased specificity was seen in breast and salivary gland carcinomas (82% and 52%, respectively), and positive staining was often seen in tumors with neural differentiation. Both sensitivity and specificity were poor in sarcomas. Selection of the appropriate assay for NTRK fusion detection therefore depends on tumor type and genes involved, as well as consideration of other factors such as available material, accessibility of various clinical assays, and whether comprehensive genomic testing is needed concurrently.

Purpose: Matching patients to investigational therapies requires new tools to support physician decision making. We designed and implemented Precision Insight Support Engine (PRECISE), an automated, just-in-time, clinical-grade informatics platform to identify and dynamically track patients on the basis of molecular and clinical criteria. Real-world use of this tool was analyzed to determine whether PRECISE facilitated enrollment to early-phase, genome-driven trials., Materials and Methods: We analyzed patients who were enrolled in genome-driven, early-phase trials using PRECISE at Memorial Sloan Kettering Cancer Center between April 2014 and January 2018. Primary end point was the proportion of enrolled patients who were successfully identified using PRECISE before enrollment. Secondary end points included time from sequencing and PRECISE identification to enrollment. Reasons for a failure to identify genomically matched patients were also explored., Results: Data were analyzed from 41 therapeutic trials led by 19 principal investigators. In total, 755 patients were accrued to these studies during the period that PRECISE was used. PRECISE successfully identified 327 patients (43%) before enrollment. Patients were diagnosed with 29 tumor types and harbored alterations in 43 oncogenes, most commonly ERBB2 (21.3%), PIK3CA (14.1%), and BRAF (8.7%). Median time from sequencing to enrollment was 163 days (interquartile range, 66 to 357 days), and from PRECISE identification to enrollment 87 days (interquartile range, 37 to 180 days). Common reasons for failing to identify patients before enrollment included accrual on the basis of molecular alterations that did not match pre-established PRECISE genomic eligibility (140 [33%] of 428) and external sequencing not available for parsing (127 [30%] of 428)., Conclusion: PRECISE identified 43% of all patients accrued to a diverse cohort of early-phase, genome-matched studies. Purpose-built informatics platforms represent a novel and potentially effective method for matching patients to molecularly selected studies., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or po.ascopubs.org/site/ifc. Ezra Y. RosenResearch Funding: BayerJaclyn F. HechtmanHonoraria: Medscape Consulting or Advisory Role: Navigant Consulting, Axiom Biotechnologies Research Funding: BayerJames J. HardingConsulting or Advisory Role: Bristol-Myers Squibb, CytomX Therapeutics, Eli Lilly, Eisai Research Funding: Bristol-Myers Squibb (Inst), Pfizer (Inst), Eli Lilly (Inst), Novartis (Inst), Incyte (Inst), Calithera Biosciences (Inst), Polaris (Inst)Lillian M. SmythHonoraria: AstraZeneca, Pfizer Consulting or Advisory Role: AstraZeneca, Genentech Research Funding: AstraZeneca (Inst), Genentech (Inst), Puma Biotechnology (Inst) Travel, Accommodations, Expenses: Pfizer, Genentech, Puma BiotechnologyKomal L. JhaveriConsulting or Advisory Role: Novartis, Pfizer, Spectrum Pharmaceuticals, AstraZeneca, Taiho Pharmaceutical, Jounce Therapeutics, ADC Therapeutics, Synthon, Intellisphere, Bristol-Myers Squibb Research Funding: Novartis (Inst), Genentech (Inst), Debio Pharmaceuticals (Inst), ADC Therapeutics (Inst), Pfizer (Inst), Novita Pharmaceuticals (Inst), Clovis Oncology (Inst), Eli Lilly (Inst), Zymeworks (Inst) Travel, Accommodations, Expenses: Taiho Pharmaceutical, Jounce Therapeutics, Pfizer, AstraZeneca Other Relationship: Novartis, Pfizer, Taiho Pharmaceutical, Jounce TherapeuticsAlexander DrilonHonoraria: Medscape, OncLive, PeerVoice, Physicians Education Resources, Targeted Oncology, MORE Health, Research to Practice, Foundation Medicine, Peerview Consulting or Advisory Role: Ignyta, Loxo, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Genentech, Helsinn Therapeutics, BeiGene, Hengrui Therapeutics, Exelixis, Bayer, Tyra Biosciences, Verastem, Takeda, ARIAD Pharmaceuticals, Millennium Pharmaceuticals, BerGenBio, MORE Health, Eli Lilly Research Funding: Foundation Medicine Patents, Royalties, Other Intellectual Property: Wolters Kluwer (royalties for Pocket Oncology) Other Relationship: Merck, GlaxoSmithKline, Teva Pharmaceuticals, Taiho Pharmaceutical, Pfizer, PharmaMar, Puma BiotechnologyMarc LadanyiHonoraria: Merck (I) Consulting or Advisory Role: National Comprehensive Cancer Network/AstraZeneca Tagrisso RFP Advisory Committee, Takeda, Bristol-Myers Squibb, Bayer, Merck (I) Research Funding: Loxo (Inst), Helsinn TherapeuticsDavid B. SolitStock and Other Ownership Interests: Loxo Consulting or Advisory Role: Pfizer, Loxo, Illumina, Intezyne Technologies, Vivideon Therapeutics Travel, Accommodations, Expenses: MerckMichael F. BergerConsulting or Advisory Role: Roche Research Funding: IlluminaDavid M. HymanConsulting or Advisory Role: Chugai Pharma, CytomX Therapeutics, Boehringer Ingelheim, AstraZeneca, Pfizer, Bayer, Genentech Research Funding: AstraZeneca, Puma Biotechnology, Loxo, Bayer Travel, Accommodations, Expenses: Genentech, Chugai Pharma No other potential conflicts of interest were reported., (© 2019 by American Society of Clinical Oncology.)

Mutations in BRCA1 and BRCA2 predispose individuals to certain cancers 1-3 , and disease-specific screening and preventative strategies have reduced cancer mortality in affected patients 4,5 . These classical tumour-suppressor genes have tumorigenic effects associated with somatic biallelic inactivation, although haploinsufficiency may also promote the formation and progression of tumours 6,7 . Moreover, BRCA1/2-mutant tumours are often deficient in the repair of double-stranded DNA breaks by homologous recombination 8-13 , and consequently exhibit increased therapeutic sensitivity to platinum-containing therapy and inhibitors of poly-(ADP-ribose)-polymerase (PARP) 14,15 . However, the phenotypic and therapeutic relevance of mutations in BRCA1 or BRCA2 remains poorly defined in most cancer types. Here we show that in the 2.7% and 1.8% of patients with advanced-stage cancer and germline pathogenic or somatic loss-of-function alterations in BRCA1/2, respectively, selective pressure for biallelic inactivation, zygosity-dependent phenotype penetrance, and sensitivity to PARP inhibition were observed only in tumour types associated with increased heritable cancer risk in BRCA1/2 carriers (BRCA-associated cancer types). Conversely, among patients with non-BRCA-associated cancer types, most carriers of these BRCA1/2 mutation types had evidence for tumour pathogenesis that was independent of mutant BRCA1/2. Overall, mutant BRCA is an indispensable founding event for some tumours, but in a considerable proportion of other cancers, it appears to be biologically neutral-a difference predominantly conditioned by tumour lineage-with implications for disease pathogenesis, screening, design of clinical trials and therapeutic decision-making.

Progranulin (GRN) mutations cause frontotemporal dementia (FTD), but GRN's function in the CNS remains largely unknown. To identify the pathways downstream of GRN, we used weighted gene coexpression network analysis (WGCNA) to develop a systems-level view of transcriptional alterations in a human neural progenitor model of GRN-deficiency. This highlighted key pathways such as apoptosis and ubiquitination in GRN deficient human neurons, while revealing an unexpected major role for the Wnt signaling pathway, which was confirmed by analysis of gene expression data from postmortem FTD brain. Furthermore, we observed that the Wnt receptor Fzd2 was one of only a few genes upregulated at 6 weeks in a GRN knockout mouse, and that FZD2 reduction caused increased apoptosis, while its upregulation promoted neuronal survival in vitro. Together, these in vitro and in vivo data point to an adaptive role for altered Wnt signaling in GRN deficiency-mediated FTD, representing a potential therapeutic target., (Copyright © 2011 Elsevier Inc. All rights reserved.)