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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.

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. Mutations in BRCA1/2 are associated with a homologous recombination deficiency phenotype in BRCA-associated cancers. Reversion mutations can restore BRCA1/2 function and result in treatment resistance in these cancer-types. Here, the authors show that, in select cases, reversion mutations in BRCA1/2 can indicate prior BRCA-mediated tumorigenesis in non-canonical histologies.

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.

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. Analysis of more than 17,000 tumours suggests that the contribution of germline and somatic mutations in the BRCA1 and BRCA2 genes to oncogenesis depends on tumour lineage.

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. The results of the phase 1/2 LIBRETTO-001 clinical trial has recently established the efficacy of the RET inhibitor selpercatinib in RET-driven cancers. Here, the authors characterize the molecular determinants of response and resistance in 72 LIBRETTO-001 lung and thyroid cancer patients treated at a single site.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.An Amendment to this paper has been published and can be accessed via a link at the top of the paper.

The majority of human breast cancers are dependent on hormone-stimulated estrogen receptor alpha (ER) and are sensitive to its inhibition. Treatment resistance arises in most advanced cancers due to genetic alterations that promote ligand independent activation of ER itself or ER target genes. Whereas re-targeting of the ER ligand binding domain (LBD) with newer ER antagonists can work in some cases, these drugs are largely ineffective in many genetic backgrounds including ER fusions that lose the LBD or in cancers that hyperactivate ER targets. By identifying the mechanism of ER translation, we herein present an alternative strategy to target ER and difficult to treat ER variants. We find that ER translation is cap-independent and mTOR inhibitor insensitive, but dependent on 5' UTR elements and sensitive to pharmacologic inhibition of the translation initiation factor eIF4A, an mRNA helicase. EIF4A inhibition rapidly reduces expression of ER and short-lived targets of ER such as cyclin D1 and other components of the cyclin D-CDK complex in breast cancer cells. These effects translate into suppression of growth of a variety of ligand-independent breast cancer models including those driven by ER fusion proteins that lack the ligand binding site. The efficacy of eIF4A inhibition is enhanced when it is combined with fulvestrant-an ER degrader. Concomitant inhibition of ER synthesis and induction of its degradation causes synergistic and durable inhibition of ER expression and tumor growth. The clinical importance of these findings is confirmed by results of an early clinical trial (NCT04092673) of the selective eIF4A inhibitor zotatifin in patients with estrogen receptor positive metastatic breast cancer. Multiple clinical responses have been observed on combination therapy including durable regressions. These data suggest that eIF4A inhibition could be a useful new strategy for treating advanced ER+ breast cancer.

RET fusion–positive lung cancer accounts for 1 to 2% of non–small-cell lung cancers. Among previously treated patients with RET fusion–positive lung cancer, 64% of those who received selpercatinib, a RET kinase inhibitor, had a response, and among previously untreated patients, 85% had a response. Approximately one third of the patients had adverse events of grade 3 or higher.

Objective: To evaluate a new treatment for dysmenorrhea by mechanically inducing menstrual fluid streaming. Setting: A 4-month randomized double-blind, placebo-controlled, crossover study. Participants: Study participants included women experiencing dysmenorrhea monthly (for the 6 preceding months) at a level >5 on the visual analog scale (0–10), who were otherwise healthy. The study participants also collected their menstrual fluid for 2 baseline months, while recording their pain levels (primary outcome) systematically. A correlation between menstrual fluid characteristics and menstrual pain was studied as well. Intervention: A newly invented device was used to attenuate dysmenorrheic pain level. Results: From September 2011 to December 2013, 28 study participants were enrolled; three withdrew and three were excluded for protocol non-adherence. Twenty-two study participants (132 menstrual cycles) who used the device reported an average reduction of 55 ± 7.6% in pain levels vs. 22 ± 12% reported with placebo (p = 0.008). In addition, analysis of menstrual fluid collected from 19 study participants (38 menstrual cycles) showed that high pain levels necessarily involve tissue fragments or a viscous menstrual fluid, supporting the idea that dysmenorrhea is associated with the rheological characteristics of the menstrual fluid. Conclusions: The new device is highly effective in relieving menstrual pain. Rheological characteristics of the menses are correlated with severity of dysmenorrhea.