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|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|ATM inact mut||mantle cell lymphoma||sensitive||Olaparib||Preclinical - Cell line xenograft||Actionable||In a preclinical study, a mantle cell lymphoma cell line with ATM inactivation demonstrated sensitivity to Lynparza (olaparib) in culture and in xenograft models (PMID: 20739657).||20739657|
|ATM inact mut||prostate cancer||sensitive||Olaparib||Phase II||Actionable||In a Phase II clinical trial, 80% (4/5) of metastatic, castration-resistant prostate cancer patients harboring an ATM inactivating mutation responded to Lynparza (olaparib) (PMID: 26510020).||26510020|
|ATM inact mut||prostate cancer||sensitive||Olaparib||FDA approved - On Companion Diagnostic||Actionable||In a Phase III trial (PROfound) that supported FDA approval, Lynparza (olaparib) treatment improved progression-free survival (7.4 vs 3.6 mo, HR=0.34, p<0.001), objective response rate (33%, 28/84 vs 2%, 1/43, OR=20.86, p<0.001), and median time to pain progression (HR=0.44, p=0.02) compared to control in patients with metastatic castration-resistant prostate cancer harboring deleterious or suspected deleterious mutations in BRCA1/2 or ATM who progressed on hormone therapy (PMID: 32343890; NCT02987543).||detail... 32343890 detail...|
|ATM inact mut||prostate cancer||sensitive||Olaparib||Guideline||Actionable||Lynparza (olaparib) is included in guidelines as second-line therapy post androgen receptor-directed therapy for patients with metastatic castration-resistant prostate cancer harboring pathogenic mutations in ATM (NCCN.org).||detail...|
|ATM inact mut||prostate cancer||sensitive||Olaparib||Phase II||Actionable||In a Phase II (TOPARP-B) trial, Lynparza (olaparib) treatment resulted in a composite overall response rate of 36.8% (7/19) and a RECIST objective response rate of 8.3% (1/12) in patients with castration-resistant prostate cancer harboring deleterious ATM mutations (PMID: 31806540; NCT01682772).||31806540|
|ATM inact mut||mantle cell lymphoma||sensitive||Fludarabine + Olaparib||Preclinical - Cell culture||Actionable||In a preclinical study, Lynparza (olaparib) sensitized a mantle cell lymphoma cell line harboring an ATM inactivating mutation to Fludara (fludarabine) in cell culture, resulting in decreased cell survival (PMID: 20739657).||20739657|
|ATM inact mut||lymphoid leukemia||sensitive||Olaparib||Preclinical - Patient cell culture||Actionable||In a preclinical study, lymphoblastoid cell lines with ATM inactivation derived from ataxia-telangiectasia patients demonstrated increased sensitivity to Lynparza (olaparib) in culture, compared to ATM wild-type cell lines (PMID: 20739657).||20739657|
|ATM inact mut||mantle cell lymphoma||sensitive||Olaparib + Valproic acid||Preclinical - Cell culture||Actionable||In a preclinical study, the combination of Lynparza (olaparib) and valproic acid worked synergistically to inhibit growth of a mantle cell lymphoma cell line harboring an ATM inactivating mutation in culture (PMID: 20739657).||20739657|
|ATM inact mut||Advanced Solid Tumor||predicted - sensitive||Radiotherapy||Clinical Study||Actionable||In a clinical study, treatment with radiotherapy resulted in greater therapeutic efficacy in advanced solid tumor patients harboring an ATM inactivating mutation (n=177) compared to those who harbored an ATM variant of unknown significance (n=180), demonstrating a significantly decreased 2-year cumulative incidence of irradiated progression, 13.2% versus 27.5% (p=0.001), respectively, and the greatest clinical benefit was observed in tumors with bi-allelic ATM inactivating mutations (PMID: 32726432).||32726432|
|ATM inact mut||Advanced Solid Tumor||sensitive||E7449||Preclinical||Actionable||In a preclinical study, E7449 inhibited proliferation of a ATM-deficient cell line in culture, which demonstrated increased sensitivity compared to cells without DNA repair pathway mutations (PMID: 26513298).||26513298|
|ATM inact mut||mantle cell lymphoma||sensitive||Bendamustine + Olaparib||Preclinical - Cell culture||Actionable||In a preclinical study, Lynparza (olaparib) sensitized a mantle cell lymphoma cell line harboring an ATM inactivating mutation to Treanda (bendamustine) in cell culture, resulting in growth inhibition (PMID: 20739657).||20739657|
|ATM inact mut||chronic lymphocytic leukemia||sensitive||Olaparib||Preclinical - Patient cell culture||Actionable||In a preclinical study, patient-derived chronic lymphocytic leukemia cells with inactivating mutations in ATM, that had been induced to proliferate in culture, demonstrated increased sensitivity to growth inhibition by Lynparza (olaparib) compared to ATM wild-type cells (PMID: 20739657).||20739657|
|ATM inact mut||Advanced Solid Tumor||predicted - sensitive||BAY1895344||Phase I||Actionable||In a Phase I trial, BAY1895344 treatment was tolerated and resulted in an objective response rate of 36.4% (4/11, all partial responses) and a disease control rate of 63.6% (7/11) in patients with advanced solid tumors harboring ATM inactivating mutations and/or ATM protein expression loss (PMID: 32988960; NCT03188965).||32988960|
|ATM inact mut||prostate cancer||no benefit||Rucaparib||Phase II||Actionable||In a Phase II trial (TRITON2), activity of Rubraca (rucaparib) was limited in the cohort of patients with metastatic castrate-resistant prostate cancer harboring an ATM mutation presumed to be inactivating, with a radiographic response rate of 10.5% (2/19, including 1 patient with co-occurring CHEK2 alteration) and PSA response rate of 4.1% (2/49), and no radiographic responses in 11 patients with biallelic alterations in ATM or 11 patients with germline ATM alterations (PMID: 32086346; NCT02952534).||32086346|
|ATM inact mut||Advanced Solid Tumor||sensitive||Veliparib||Preclinical - Cell culture||Actionable||In a preclinical study, an ATM-deficient cell line demonstrated increased sensitivity to Veliparib (ABT-888) compared to an ATM-reconstituted cell line, in culture (PMID: 21300883).||21300883|
|ATM mutant||mantle cell lymphoma||predicted - sensitive||Ibrutinib + Venetoclax||Phase II||Actionable||In a Phase II trial (AIM), distinct molecular profiles were identified in mantle cell lymphoma patients responded to Imbruvica (ibrutinib) and Venclexta (venetoclax) combination therapy compared to those did not respond, with all patients harboring mutations in NSD2 (n=4), UBR5 (n=3), KMT2D (n=3), and 12 of 13 patients harboring mutations in ATM responded to the therapy, while SMARCA4 (n=4), CCND1 (n=2), and NOTCH1 (n=3) alterations were exclusively observed in nonresponders (PMID: 30455436; NCT02471391).||30455436|
|ATM mutant||prostate cancer||not applicable||N/A||Guideline||Risk Factor||Germline ATM mutations are associated with increased risk of developing prostate cancer (NCCN.org).||detail...|
|ATM mutant||prostate cancer||sensitive||Olaparib||Phase II||Actionable||In a Phase II clinical trial, 80% (4/5) of metastatic castration-resistant prostate cancer patients with ATM truncation mutations demonstrated response to Lynparza (olaparib) treatment (Cancer Res August 1, 2015 75:CT322).||detail...|
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