bims-preonc 2024-12-08 papers

bims-preonc

Biomed News

on Precision oncology

Issue of 2024–12–08
eleven papers selected by
Ankita Daiya, OneCell Diagnostics Inc.

Circulating Tumor DNA as a Prognostic Biomarker for Recurrence in Patients With Locoregional Esophagogastric Cancers With a Pathologic Complete Response.
Circulating Tumor DNA: A New Research Frontier in Urological Oncology from Localized to Metastatic Disease.
Evaluation of circulating tumor DNA as a prognostic and predictive biomarker in BRAF V600E mutated colorectal cancer-results from the FIRE-4.5 study.
Adrenocortical carcinoma with circulating tumor DNA analysis at post-operative recurrence: a case report with review of literature.
Toripalimab plus anlotinib in patients with recurrent or metastatic nasopharyngeal carcinoma: A multicenter, single-arm phase 2 trial (TORAL).
Long term efficacy of first-line afatinib and the clinical utility of ctDNA monitoring in patients with suspected or confirmed EGFR mutant non-small cell lung cancer who were unsuitable for chemotherapy.
Discovery of Gene Fusions in Driver-Negative Cancer Samples From the National Cancer Institute-Molecular Analysis for Therapy Choice Screening Cohort.
Evolution of Rapid Clonal Dynamics and Non-Cross-Resistance in Response to Alternating Targeted Therapy and Chemotherapy in BRAF-V600E-Mutant Colon Cancer.
Influence of Epithelial-Mesenchymal Transition on Risk of Relapse and Outcome to Eribulin or Cyclin-Dependent Kinase Inhibitors in Metastatic Breast Cancer.
Blood-based tumor mutational burden impacts clinical outcomes of immune checkpoint inhibitor treated breast and prostate cancers.
Molecular Characterization and Clinical Relevance of MGMT-Silenced Pancreatic Cancer.

JCO Precis Oncol. 2024 Dec;8 e2400288

Circulating Tumor DNA as a Prognostic Biomarker for Recurrence in Patients With Locoregional Esophagogastric Cancers With a Pathologic Complete Response.

Eric Michael Lander, Vasily N Aushev, Brandon M Huffman, Diana Hanna, Punashi Dutta, Jenifer Ferguson, Shruti Sharma, Adham Jurdi, Minetta C Liu, Cathy Eng, Samuel J Klempner, Michael K Gibson.

PURPOSE: After neoadjuvant therapy (NAT) and surgery, up to one third and one half of patients with esophagogastric adenocarcinoma with a pathologic complete response (pCR; tumor regression grade 0 [TRG-0]) and near-pCR (TRG-1) will recur, respectively. Our study aims to evaluate postoperative circulating tumor DNA (ctDNA) as a predictor of recurrence in patients with pCR or near-pCR after curative-intent neoadjuvant chemotherapy or neoadjuvant chemoradiation and surgery.
METHODS: We retrospectively identified patients from 11 institutions with stages I-IV esophagogastric cancers (EGCs) who completed NAT and had TRG-0/1 scores at the time of curative-intent surgery. Postoperative plasma samples were collected for ctDNA analysis within a 16-week molecular residual disease (MRD) window after definitive surgery, and during surveillance from January 7, 2020, to November 9, 2023, at the provider's discretion. ctDNA was assessed using a clinically validated, personalized, tumor-informed ctDNA assay (Signatera, Natera, Inc). The primary outcome was recurrence-free survival (RFS).
RESULTS: We obtained 309 blood samples from 42 patients with esophagogastric adenocarcinoma with a pCR after neoadjuvant treatment over a median follow-up time of 28.5 months (range, 0.2-81.7). Detectable ctDNA in the 16-week MRD window (N = 23) correlated with higher rates of recurrence (67%; 2/3) compared with undetectable ctDNA (15%; 3/20). Detectable ctDNA within the MRD window was associated with a significantly shorter RFS (hazard ratio [HR], 6.2; P = .049). Among 32 patients who had ctDNA analyzed in the surveillance setting, the recurrence rate was 100% (5/5) in the ctDNA-positive cohort compared with 7.4% (2/27) in ctDNA-negative patients and was associated with shorter RFS (HR, 37.6; P < .001).
CONCLUSION: Within the subgroup of patients with EGC and favorable pathologic responses (TRG 0-1) after NAT, the presence of postoperative ctDNA identified patients with elevated recurrence risk.

DOI: https://doi.org/10.1200/PO.24.00288
Eur Urol Oncol. 2024 Dec 02. pii: S2588-9311(24)00270-0. [Epub ahead of print]

Circulating Tumor DNA: A New Research Frontier in Urological Oncology from Localized to Metastatic Disease.

Marianna Garofoli, Brigida Anna Maiorano, Giuseppina Bruno, Guido Giordano, Ugo Giovanni Falagario, Andrea Necchi, Giuseppe Carrieri, Matteo Landriscina, Vincenza Conteduca.

   BACKGROUND AND OBJECTIVE: Circulating tumor DNA (ctDNA) testing provides valuable prognostic and predictive information for guiding therapeutic choices and monitoring disease progression and drug resistance for urological tumors. Our review focuses on emerging opportunities for ctDNA analysis in urological tumors and the development of potential circulating biomarkers within a multidisciplinary framework to improve personalized treatment.
METHODS: A nonsystematic literature review was conducted in the PubMed and MEDLINE databases. Prospective and retrospective peer-reviewed studies, review articles, and research abstracts on the use of ctDNA for urological tumors were included.
KEY FINDINGS AND LIMITATIONS: Several studies have demonstrated that ctDNA analysis is a promising tool that can help clinicians in the diagnosis and clinical management of urological tumors. In prostate and urothelial cancers, the ctDNA fraction increases proportionally from localized to metastatic disease, indicating a higher tumor burden and more aggressive behavior. Thus, ctDNA seems to be a useful tool for improving prognostic risk stratification and treatment selection. Data on the use of liquid biopsy in renal cell carcinoma are still limited, and assessment of prognostic and predictive biomarkers is a critical unmet need.
CONCLUSIONS AND CLINICAL IMPLICATIONS: ctDNA analysis promises to revolutionize the management of urological tumors in different disease settings. Integration of ctDNA testing in routine clinical practice will require a multidisciplinary approach that involve patients, clinicians, and molecular biologists.
PATIENT SUMMARY: We reviewed how testing for tumor DNA in blood (circulating tumor DNA, ctDNA) is used in urological cancers. A great deal of evidence supports the usefulness of this noninvasive test. However, further research via a multidisciplinary approach is needed before ctDNA testing becomes part of routine patient care.

Keywords:  Circulating tumor DNA; Prostate cancer; Renal cell carcinoma; Urothelial cancer

DOI:  https://doi.org/10.1016/j.euo.2024.11.008
Mol Oncol. 2024 Dec 04.

Evaluation of circulating tumor DNA as a prognostic and predictive biomarker in BRAF V600E mutated colorectal cancer-results from the FIRE-4.5 study.

Susanne Klein-Scory, Alexander Baraniskin, Wolff Schmiegel, Thomas Mika, Roland Schroers, Swantje Held, Kathrin Heinrich, David Tougeron, Dominik P Modest, Ingo Schwaner, Jan Eucker, Rudolf Pihusch, Martina Stauch, Florian Kaiser, Christoph Kahl, Meinolf Karthaus, Christian Müller, Christof Burkart, Sebastian Stintzing, Volker Heinemann.

  The randomized FIRE-4.5 (AIO KRK0116) trial compared first-line therapy with FOLFOXIRI (folinic acid, fluorouracil, oxaliplatin, and irinotecan) plus either cetuximab or bevacizumab in B-Raf proto-oncogene, serine/threonine kinase (BRAF) V600E-mutant metastatic colorectal cancer (mCRC) patients. This study was accompanied by a prospective translational project analyzing cell-free circulating tumor DNA (ctDNA) in plasma to test whether ctDNA analysis may help to guide clinical treatment decision making. FIRE-4.5 included mCRC patients with BRAF V600E mutation detected by tissue-based analyses. Liquid biopsies (LBs) were collected at baseline (pre-treatment) and during therapy. Digital droplet PCR (ddPCR) technology was applied for determination of BRAF mutations and the in vitro diagnostics (IVD)-certified ONCOBEAM RAS procedure for analysis of RAS mutations. The BRAF V600E variants in ctDNA were analyzable in 66 patients at start of the therapy, at baseline. No BRAF V600E mutations were detected in 26% (17/66) of patients and was associated with a significantly longer progression-free survival (PFS: 13.2 vs 6.5 months; HR 0.47; P = 0.014) and overall survival (OS: 36.8 vs 13.2 months; HR 0.35; P = 0.02) as compared to ctDNA mutant patients. Patients with detectable BRAF mutations showed a clear superiority of FOLFOXIRI plus bevacizumab with regard to PFS (10.4 vs 5.7 months; HR 0.4; P = 0.009) and OS (16.6 vs 11.6 months; HR 0.5; P = 0.15), while this was not the case for BRAF wild-type patients. Follow-up LBs were obtained from 51 patients. Patients converting from BRAF V600E mutant to a BRAF V600 wild-type status (36%, N = 18) had a superior PFS (8.6 vs 2.3 months; P = 0.0002) and OS (17.4 vs 5.1 months; P < 0.0001) compared to patients with stable or increased mutational allele frequency (12%, N = 6). Those patients also achieved a significantly greater disease control rate (89% vs 20%; P = 0.008). In conclusion, LB evaluating ctDNA is informative and may help to guide treatment in patients with BRAF V600E-mutated mCRC.

Keywords:  FOLFOXIRI; bevacizumab; cetuximab; circulating tumor DNA; liquid biopsy; mutational load

DOI:  https://doi.org/10.1002/1878-0261.13778
Endocr J. 2024 Nov 30.

Adrenocortical carcinoma with circulating tumor DNA analysis at post-operative recurrence: a case report with review of literature.

Daisuke Aono, Toshiaki Kato, Akina Morisawa, Sakuya Kimata, Seigo Konishi, Mitsuhiro Kometani, Takashi Yoneda, Kazuyoshi Hosomichi, Shigehiro Karashima.

  Recently, the usefulness of circulating tumor DNA (ctDNA) analysis in various malignancies has been reported. However, reports on ctDNA analysis in adrenocortical carcinoma (ACC) are few. Therefore, this study aimed to examine the detectability of genetic mutations in ctDNA and the association between ctDNA allelic ratio and disease progression in a patient with post-operative recurrence of ACC. A 77-year-old woman presented with a 5.4 cm left adrenal mass, which was clinically diagnosed as subclinical cortisol-producing ACC on close examination. She underwent left adrenalectomy and was diagnosed with stage II (T2N0M0) ACC. Post-operatively, adjuvant chemotherapy with mitotane was commenced because of histologically high-grade ACC. However, 17 months post-operatively, she had a local recurrence at the left adrenalectomy site. FoundationOne® CDx Cancer Genome Profile showed CTNNB1 G34A mutation in the resected adrenal tumor. She had heart failure and interstitial pneumonia and was treated with radiotherapy for local recurrence. Subsequently, lung and liver metastasis appeared post-operatively at 21 and 23 months, respectively. Serum dehydroepiandrosterone sulfate and computed tomography findings at 27 months post-operatively showed disease progression. We collected the peripheral blood at 23 and 27 months post-operatively and analyzed 18 genes associated with adrenal disease in plasma cell-free DNA and the resected adrenal tumor using a next-generation sequencer. At both time-points, CTNNB1 mutations consistent with the primary tumor were observed in ctDNA, with the allelic ratio increasing over time from 8% to 27%. In conclusion, monitoring the ctDNA allelic ratio may be useful for evaluating disease progression in advanced ACC.

Keywords:  Adrenal cancer; Adrenocortical carcinoma; Circulating tumor DNA; Genetic mutations; Next-generation sequencing

DOI:  https://doi.org/10.1507/endocrj.EJ24-0346
Cell Rep Med. 2024 Nov 20. pii: S2666-3791(24)00604-9. [Epub ahead of print] 101833

Toripalimab plus anlotinib in patients with recurrent or metastatic nasopharyngeal carcinoma: A multicenter, single-arm phase 2 trial (TORAL).

Yuchen Zhang, Qihua Zou, Baitian Zhao, Ning Su, Zhihua Li, Xicheng Wang, Panpan Liu, Xiaopeng Tian, Xiaojie Fang, Jun Cai, Lirong Li, Yingxian Liu, Yi Xia, Qingqing Cai.

  Treatment options for patients with recurrent or metastatic nasopharyngeal carcinoma (RM-NPC) after failure of platinum-based therapy are limited. In this phase 2 trial, 40 patients with RM-NPC who failed platinum-based chemotherapy receive toripalimab plus anlotinib regimen. The objective response rate is 37.5%, and the disease control rate is 85.0%. With a median follow-up of 17.4 months, the median progression-free survival (PFS) is 9.5 months and 1-year overall survival rate is 73.3%. The most common treatment-related grade 3-4 adverse events are hand-foot syndrome (22.5%) and oral mucositis (17.5%). Analyses of plasma circulating tumor DNA (ctDNA) demonstrate that the blood tumor mutation burden at cycle 1/2 is associated with response and PFS, and disease progression indicated by ctDNA precedes radiological progression by a median of 2.3 months. In conclusion, toripalimab plus anlotinib is well tolerated and shows promising efficacy in patients with RM-NPC, and ctDNA could be a potential predictive biomarker. The trial is registered at ClinicalTrials.gov (NCT04996758).

Keywords:  anlotinib; circulating tumor DNA; clinical trial; nasopharyngeal carcinoma; recurrent or metastatic; toripalimab

DOI:  https://doi.org/10.1016/j.xcrm.2024.101833
Br J Cancer. 2024 Dec 05.

Long term efficacy of first-line afatinib and the clinical utility of ctDNA monitoring in patients with suspected or confirmed EGFR mutant non-small cell lung cancer who were unsuitable for chemotherapy.

Sanjay Popat, Adam Januszewski, Mary O'Brien, Tanya Ahmad, Conrad Lewanski, Ulrike Dernedde, Petra Jankowska, Clive Mulatero, Riyaz Shah, Jonathan Hicks, Tom Geldart, Mathilda Cominos, Gill Gray, James Spicer, Karen Bell, Simon Roitt, Clive Morris, Yenting Ngai, Laura Hughes, Allan Hackshaw, William Wilson.

BACKGROUND: Here we present long-term outcomes of first line afatinib in comorbid patients with suspected or confirmed EGFR mutant NSCLC otherwise considered unsuitable for chemotherapy, and the clinical utility of serial ctDNA monitoring.
METHODS: TIMELY (NCT01415011) was a multicentre, single arm, phase II trial conducted in the UK. Patients aged ≥18 were treated with daily oral afatinib (40 mg) until disease progression or unacceptable toxicity. Blood samples for ctDNA analysis were obtained at baseline and 12-weekly until treatment discontinuation. The primary endpoint was PFS.
RESULTS: Thirty-nine patients were enrolled between March 2013 and August 2015. Median follow-up was 98 months (range 69-101). Median PFS was 7.9 months (95% CI 4.6-10.5). Seven patients (18%) continued afatinib beyond 18 months, 3 beyond 36 months and 2 were still on treatment at last follow-up 101 months post-treatment initiation. Analysis of baseline ctDNA samples identified 8 EGFR mutant cases that were not identified by tissue genotyping and ctDNA clearance was associated with improved PFS and OS.
CONCLUSION: Afatinib is a viable treatment option for tissue or ctDNA-detected EGFR mutant NSCLC comorbid patients, with a proportion achieving long-term clinical benefit. Plasma ctDNA testing improved EGFR mutant identification and its clearance predicted improved PFS and OS.

DOI: https://doi.org/10.1038/s41416-024-02901-6
JCO Precis Oncol. 2024 Dec;8 e2400493

Discovery of Gene Fusions in Driver-Negative Cancer Samples From the National Cancer Institute-Molecular Analysis for Therapy Choice Screening Cohort.

Stefan T Kaluziak, Elizabeth M Codd, Rashi Purohit, Beatrice Melli, Prinjali Kalyan, Jo Anne Fordham, Grace Kirkpatrick, Lisa M McShane, Ting-Chia Chang, Guangxiao Yang, Jinglan Wang, P Mickey Williams, Chris Karlovich, Jeffrey Sklar, A John Iafrate.

PURPOSE: The National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH) trial was implemented to identify actionable genetic alterations across cancer types and enroll patients accordingly onto treatment arms, irrespective of tumor histology. Using multiplex polymerase chain reaction (PCR) next-generation sequencing, NCI-MATCH genotyped 5,540 patients, discovering gene fusions in 202/5,540 tumors (3.65%). This result, substantially lower than the fusion detection prevalence of 8.5% across all patients with cancer screened at Massachusetts General Hospital's (MGH) clinical laboratories, supported reanalysis of NCI-MATCH samples identified as mutations-of-interest (MOI)-negative. The assay used by NCI-MATCH requires previous knowledge of both fusion genes, cannot detect novel fusions, and may underestimate fusion-positive patients. Anchored multiplex PCR (AMP) technology permits fusion detection with knowledge of just one gene of the fusion partners.
METHODS: Using AMP-based kits, we reprocessed 663 MOI-negative samples. 200 ng of RNA per sample were shipped from the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network biorepository to MGH (n = 319) and Yale University (n = 344), processed, and sequenced on the NextSeq550. Reported fusions were manually reviewed, and novel fusions orthogonally verified via reverse-transcription PCR and Sanger sequencing.
RESULTS: AMP identified 148 fusions in 142/663 MOI-negative patients (21% [95% CI, 18 to 25]), of which 28 were covered by the Oncomine Comprehensive Assay (OCA) panel but missed, while 120 were not covered by OCA. Among AMP-identified positive patients, 32 had actionable fusions, 24 contained novel fusions, and six had two fusion events. We identified fusions in 12/34 (35% [95% CI, 20 to 54]) cholangiocarcinomas and 43/109 (39% [95% CI, 30 to 49]) sarcomas.
CONCLUSION: Technology and awareness of actionable fusions have improved since the NCI-MATCH trial. With AMP-based technology, we identified 142 patients with fusions not detected during NCI-MATCH screening, many potentially actionable. These striking data underscore the need to optimize the fusion-detection capabilities of genotyping assays used in precision medicine.

DOI: https://doi.org/10.1200/PO-24-00493
JCO Precis Oncol. 2024 Dec;8 e2300260

Evolution of Rapid Clonal Dynamics and Non-Cross-Resistance in Response to Alternating Targeted Therapy and Chemotherapy in BRAF-V600E-Mutant Colon Cancer.

Srilatha Simhadri, Jillian N Carrick, Susan Murphy, Om A Kothari, Husam Al-Hraishami, Atul Kulkarni, Nahed Jalloul, Katarina Stefanik, Manisha Bandari, Kavya Chettur, Ming Yao, Vasudeva Ginjala, Roman Groisberg, Howard Hochster, Janice Mehnert, Gregory Riedlinger, Hossein Khiabanian, Michael P Verzi, Kevin Tong, Shridar Ganesan.

PURPOSE: Combined BRAF, MEK, and EGFR inhibition can induce clinical responses in BRAF-V600E-mutant colon cancer, but rapid resistance often occurs.
METHODS: We use serial monitoring of circulating tumor DNA cell-free plasma DNA (cfDNA) in a patient case study in addition to organoids derived from mouse models of BRAF-V600E-mutant intestinal cancer, which emulated the patient's mutational profile to assess drug treatment efficacy.
RESULTS: We demonstrate dynamic evolution of resistance to combined EGFR/BRAF/MEK inhibition in a pediatric patient with metastatic BRAF-V600E-mutant, mismatch repair-stable colon cancer. Initial resistance to targeted therapy was associated with development of MET amplification. Sequential treatment with chemotherapy and targeted therapy resulted in clearing of the resistant MET-amplified clone. Rechallenge with combined BRAF/EGFR inhibition resulted in clinical and radiographic response, demonstrating these treatments may be non-cross-resistant. Tumor organoids were used to model clinical findings and demonstrated effectiveness of combined targeted therapy and chemotherapy.
CONCLUSION: These findings suggest rational strategies for combining sequential chemotherapy and BRAF-/EGFR-directed therapy in BRAF-V600E-mutant colon cancer to prevent resistance and improve outcome. The data demonstrate rapid clonal dynamics in response to effective therapies in BRAF-V600E-mutant colon cancer that can be monitored by serial cfDNA analysis. Moreover, in mismatch repair-proficient BRAF-V600E-mutant colon cancers, combined EGFR and BRAF/MEK therapy is not cross-resistant with standard chemotherapy, suggesting new rational combination treatment strategies.

DOI: https://doi.org/10.1200/PO.23.00260
JCO Precis Oncol. 2024 Dec;8 e2400274

Influence of Epithelial-Mesenchymal Transition on Risk of Relapse and Outcome to Eribulin or Cyclin-Dependent Kinase Inhibitors in Metastatic Breast Cancer.

Arlene Chan, Jespal Gill, HuiJun Chih, Sarah Christine Elisabeth Wright, Natali Vasilevski, Pieter Johan Adam Eichhorn.

PURPOSE: The presence of epithelial-mesenchymal transition (EMT) in breast cancer (BC) cells has been linked to worse prognosis and may influence response to systemic treatment. We explored the effect of EMT in tumor samples of patients with metastatic BC on disease-free interval and overall survival in those patients receiving eribulin or cyclin-dependent kinase 4/6 inhibitors (CDK4/6i).
MATERIALS AND METHODS: Key inclusion criteria included available archived primary BC tissue and, where available, matched metastatic biopsy. Patients received eribulin and/or a CDK4/6i in the metastatic setting. Specimens were assessed for biomarkers by immunohistochemistry (CDH1, AE1/3, VIM, CDH2, ZEB1, pSMAD2, and SMAD4) and gene expression by droplet digital polymerase chain reaction (CDH1, CDH2, SNAI1 & 2, TWIST1, VIM, PTEN, and ZEB1 & 2).
RESULTS: Between 2002 and 2020, 127 patients were included (95 early-stage disease at diagnosis with metastatic relapse, 32 de novo metastatic disease). In metastatic samples, presence of ZEB1 overexpression was associated with shorter time to recurrence (48.1 months shorter; P = .003), with pSMAD2 overexpression suggesting clinical significance of 52.0 months shorter; P = .01. High gene expression levels for SNAIL1, TWIST1, and PTEN in the primary BC were associated with significantly longer survival in patients who received eribulin (P < .05); high VIM was associated with a clinically relevant trend toward shorter survival after a CDK4/6i (P = .013).
CONCLUSION: We demonstrate in our exploratory study that biomarkers involved in the process of EMT could have a prognostic impact in a cohort of patients with BC uniformly treated and with long-term follow-up. Genes known to be involved in EMT were associated with improved eribulin efficacy, while suggesting a poorer outcome with CDK4/6i.

DOI: https://doi.org/10.1200/PO.24.00274
Commun Med (Lond). 2024 Dec 02. 4(1): 256

Blood-based tumor mutational burden impacts clinical outcomes of immune checkpoint inhibitor treated breast and prostate cancers.

Reagan M Barnett, Albert Jang, Sree Lanka, PIngfu Fu, Leslie A Bucheit, Hani Babiker, Alan Bryce, Haley M Meyer, Yujin Choi, Casey Moore, Rohan Garje, Xin Gao, Dae Won Kim, Richard Y Chang, Pat Gulhati, Ryne Ramaker, Rani Bansal, Tian Zhang, A Oliver Sartor, Andrew J Armstrong, Mehmet A Bilen, Pedro Barata.

BACKGROUND: Breast and prostate tumors are known to be less responsive to immune checkpoint inhibitors (ICIs). Tissue-based tumor mutation burden (tTMB) has emerged as a predictive biomarker of response to ICIs, including in these "cold tumors". In clinical practice, when tTMB is not available, blood-based TMB score (bTMB) can be used to consider treatment with ICIs.
METHODS: This retrospective, real-world study included a final cohort of metastatic breast and prostate cancer patients treated with an ICI following a liquid biopsy test. Multiple bTMB-High cut-offs were assessed. Clinical, genomic, and outcomes data were collected. We hypothesized that a cut-off of bTMB ≥10 mut/Mb is not a strong predictor of response to ICIs in this setting. The Guardant Health genomic database (GHGD) was then queried (N = 13,992) for associations of bTMB with genomic alterations.
RESULTS: In the clinical cohort (N = 48), ICI treatment is offered after a median of 3 (1-9) lines of treatment. The median bTMB is 16.4 (10-186) mut/Mb. The median time on ICI and PFS is 2.1 (0-1.7) and 3.1 months (95%CI, 1.6-4.6) respectively; no difference by MSI/MMR status (p = 0.152). Response rate among eligible patients (n = 36) is 16.7%; only N = 1/6 in bTMB <16 mut/Mb. High bMSI is associated with higher bTMB (correlation test, r = 0.66, p = 0.000). In the GHGD, patients with bTMB high have significantly more alterations than bTMB low and TP53, PIK3CA, ATM, ESR1, NF1, BRCA2, ARID1A, and APC were the most frequently altered genes.
CONCLUSIONS: In this study, the practice of offering an ICIs based on bTMB was uncommon and did not independently predict ICI benefits in patients with refractory, advanced breast and prostate cancers.

DOI: https://doi.org/10.1038/s43856-024-00687-5
Cancer Med. 2024 Dec;13(23): e70393

Molecular Characterization and Clinical Relevance of MGMT-Silenced Pancreatic Cancer.

Federico Nichetti, Marco Silvestri, Luca Agnelli, Andrea Franza, Chiara Pircher, Simone Rota, Paolo Ambrosini, Giuseppe Fotia, Jennifer Hüllein, Giovanni Randon, Panna Lajer, Federica Perrone, Elena Tamborini, Giuseppe Leoncini, Jorgelina Coppa, Michele Droz Dit Busset, Sara Pusceddu, Massimo Milione, Federica Morano, Filippo Pietrantonio, Giancarlo Pruneri, Vincenzo Mazzaferro, Daniel B Lipka, Bruno Christian Köhler, Daniel Hübschmann, Stefan Fröhling, Filippo de Braud, Monica Niger.

   BACKGROUND: The identification of actionable molecular targets of pancreatic cancer (PAC) is key to improving patient outcomes. We hypothesized O6-methylguanine-DNA methyltransferase (MGMT) silencing may occur in a subset of PAC tumors, with unexplored clinical and molecular correlates.
EXPERIMENTAL DESIGN: We leveraged sequencing data from The Cancer Genome Atlas (TCGA), the Clinical Proteomic Tumor Analysis Consortium 3 (CPTAC-3), and the (Australian Pancreatic Cancer Genome Initiative) PACA-AU cohorts to characterize MGMT-silenced PAC. Genomic, transcriptomic, methylation, and clinical data were investigated, and findings were validated in silico using methylation, transcriptomic and drug sensitivity data from Cancer Cell Line Encyclopedia (CCLE) project, and in a real-world cohort of PAC patients profiled for MGMT status at Istituto Nazionale Tumori of Milan (INT).
RESULTS: On the basis of Human Methylation 450k data, MGMT silencing was identified in ~6% of PAC cases and was enriched in tumors with non-ductal histology, with a trend toward longer overall survival. MGMT-silenced tumors were associated with a lower frequency of KRAS mutations and showed features of immune exclusion. In the INT cohort, MGMT-silencing was confirmed in ~7% of cases and prevalent in KRAS wild type tumors, with a favorable prognostic impact. In silico analysis suggested a higher sensitivity to alkylating and DNA damaging agents in MGMT-silenced PAC cell lines.
CONCLUSIONS: MGMT silencing occurs in a small subgroup of PACs and is enriched in KRAS wild type cases, with a favorable prognostic impact. Our findings provide the rationale to explore combinations of alkylating with DNA damaging agents in MGMT-silenced PAC.

Keywords:  KRAS wild type; MGMT; biomarker; molecular profiling; pancreatic cancer; temozolomide

DOI:  https://doi.org/10.1002/cam4.70393