scholarly journals Case Report: Combination of Olaparib With Chemotherapy in a Patient With ATM-Deficient Colorectal Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Georgios I. Papageorgiou ◽  
Evangelos Fergadis ◽  
Nikos Skouteris ◽  
Evridiki Christakos ◽  
Sergios A. Tsakatikas ◽  
...  
Keyword(s):  
Treatment Options ◽  
Stage Iv ◽  
Parp Inhibitors ◽  
Anti Cancer ◽  
Heavily Pretreated ◽  
Next Generation Sequencing Ngs ◽  
Other Neoplasms ◽  
Generation Sequencing ◽  
Current Report ◽  
Indications For Use

Poly-ADP ribose polymerase (PARP) inhibitors are constantly increasing in their indications for use as anti-cancer treatment in various neoplasms, the majority of which are linked with BRCA deficiency. Preclinical data support the investigation of PARP inhibitors in other neoplasms exhibiting “BRCAness” or homologous recombination deficiency (HRD) as monotherapy as well as in combination with chemotherapy. With the current report we present the case of a heavily pretreated 55-year-old male patient diagnosed with stage IV ATM-deficient CRC, who was effectively treated with an off-label olaparib-irinotecan combination after exhaustion of all available treatment choices; furthermore, we discuss the existing data providing evidence for the use of PARP inhibitors in ATM-deficient CRC and encourage the implementation of next-generation sequencing (NGS) in patients with no other available treatment options.

DNA damage repair (DDR) pathway defects in gastrointestinal (GI) malignancies.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 647-647
Author(s):  
Ramya Thota ◽  
Gail Fulde ◽  
Mark Andrew Lewis ◽  
Derrick S. Haslem ◽  
Lincoln Nadauld ◽  
...  
Keyword(s):  
Clinical Significance ◽  
Median Overall Survival ◽  
Parp Inhibitor ◽  
Stage Iv ◽  
Clinical History ◽  
Parp Inhibitors ◽  
Stage At Diagnosis ◽  
Damage Repair ◽  
Prostate Cancers ◽  
Generation Sequencing

647 Background: The clinical significance of the genomic alterations associated with DDR pathway in GI tumors (besides MMR defects) is largely unknown. These patients can potentially derive benefit from targeted therapy with poly ADP ribose polymerase (PARP) inhibitors, which have already shown promising activity in ovarian, breast and prostate cancers. In this study, we investigated the frequency and clinical significance of DDR repair defects (other than MMR defects) in GI tumors. Methods: We performed a retrospective analysis of all patients who had tumor next generation sequencing performed between January 2013 and August 2017 on GI cancers harboring DDR pathway defects. Data including demographics, clinical history, and treatment were extracted from patients' records. Results: Of 299 patients with GI tumors sequenced, 35 cases (12%) were noted to have DDR defects. The most commonly mutated genes – 6 (17%) BRCA2, 5 (14%) PALB2, 4 (11%) ATM, 3 (8.6%) BRCA1, 2 (5.7%) each of NBN, MUTYH, ERCC3, PARP1 amplification and 1 (2.8%) each of ERCC2, CDK12, and PARP2 amplification. Two patients had both ATM and BRCA2 mutations. Combination of ATM and MRE11, ATM and BRCA1, BRCA1 and ERCC6, BRCA2 and CDK12 were noted in 1 patient each. Of the 23 patients with available clinical data, the median age at diagnosis was 65 (range 30–85) years with male and female prevalence rates of 60.8% and 39.2%, respectively. Stage at diagnosis was I (n = 3), II (n = 3), III (n = 8), and IV (n = 9). The primary site of tumor was found in 8 (34.8%) colon, 4 (17.4%) liver, 4 (17.4%) pancreas, 2 (8.7%) esophagus, 2 (8.7%) anus, 2 (8.7%) appendix, 1 (4.3%) rectum. Seventeen patients received platinum‐based therapy, 7 were treated with PARP inhibitors and 5 patients received both platinum and PARP inhibitor. Median overall survival from diagnosis for patients with stage I/II was 65.3 months, stage III was 23.1 months, and stage IV was 22.4 months. The median survival of patients treated with olaparib was 24.5 months. Conclusions: DDR pathway defects in GI tumors are uncommon. However, they can potentially be targeted with PARP inhibitors with durable survival. Future clinical trials are warranted to explore the role to PARP inhibitors in these unique subset of patients.

scholarly journals A rare case of recurrent ovarian cancer with NTRK1-TPM3 gene rearrangement

2021 ◽  
Author(s):  
Yuta Endo ◽  
Takafumi Watanabe ◽  
Motonobu Saito ◽  
Katsuharu Saito ◽  
Rei Suzuki ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Gene Fusion ◽  
Rare Case ◽  
Multimodal Therapy ◽  
Gynecologic Cancer ◽  
Stage Iv ◽  
Recurrent Ovarian Cancer ◽  
Interval Debulking Surgery ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Abstract Background: NTRK gene fusion is rare in gynecologic cancer. Entrectinib is a novel targeted drug which is a potent inhibitor of TRK A, B and C. Here, we present a case of recurrent ovarian cancer with NTRK1-TPM3 rearrangement, which was detected by next-generation sequencing (NGS) and treated with entrectinib. Case Presentation:A 56-year-old woman was diagnosed as having stage IV ovarian cancer due to pleural effusion. Neoadjuvant chemotherapy and interval debulking surgery followed by chemotherapy were performed. Ten months after completion of chemotherapy, the patient’s disease recurred. She was treated with multimodal therapy for recurrence. DNA-based NGS detected NTRK1-TPM3 rearrangement and entrectinib was started. However, the patient’s disease progressed despite six weeks’ administration of entrectinib, and one month after discontinuation of entrectinib, she died. After her death immunohistochemistry with a pan-Trk monoclonal antibody was performed to determine the expression of NTRK. However, immunohistochemistry was negative for NTRK.Conclusion: We presented a rare case of recurrent ovarian cancer with NTRK1-TPM3 gene fusion, in which entrectinib was not effective. While NTRK gene fusion was detected by DNA-based NGS, immunohistochemistry was negative for NTRK. Immunohistchemitory should be performed for confirmation of NTRK protein expression before entrectinib administration.

Population-based screening for BRAF V600E in metastatic colorectal cancer (mCRC) to reveal true prognosis.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3579-3579
Author(s):  
Jenny E. Chu ◽  
Benny Johnson ◽  
Van K. Morris ◽  
Kanwal Pratap Singh Raghav ◽  
Lucas Swanson ◽  
...  
Keyword(s):  
Stage Iv ◽  
Population Based ◽  
Braf V600e ◽  
Baseline Characteristic ◽  
Wild Type ◽  
Md Anderson ◽  
Next Generation Sequencing Ngs ◽  
Referral Bias ◽  
Generation Sequencing ◽  
Worse Prognosis

3579 Background: BRAFV600E ( BRAF) mutations (mts) portend poor prognosis in mCRC and patients (pts) may die before ascertainment. Since 2014, Vancouver Coastal Health (VCH) has performed reflex hereditary screening of CRCs with BRAF and mismatch repair (MMR) immunohistochemistry (IHC). We evaluated this BRAF mt population-based cohort ( BRAFPOP) to establish the true prognosis of BRAF mts in mCRC. Methods: We reviewed all mCRCs from VCH between 4/2014 and 5/2018 for BRAF by IHC (VE1 antibody). Overall survival (OS) from stage IV diagnosis was compared to mCRCs with next generation sequencing (NGS) determined BRAF mts ( BRAFNGS) from BC Cancer & MD Anderson. BRAFNGS OS did not differ by center (p = 0.77). Results: See table for BRAF cohort baseline characteristic comparison. BRAFPOP pts had worse OS than BRAFNGS pts (HR 2.5, 95% CI 1.6 – 3.9, P < 0.0001). Median OS for all BRAF mt pts was 17.9 mos. Both groups had worse OS than wild type pts (P < 0.0001). 52 (81%) of BRAFPOP pts were referred to oncology, 40 (63%) received chemotherapy, and 12 (19%) had NGS BRAF testing. BRAFPOP pts who had NGS testing with BRAF mts had OS comparable to other BRAFNGS pts (P = 0.89) and better OS than BRAFPOP pts that never had NGS testing (HR 0.37, 95% CI 0.18-0.76, P = 0.030). Pts with BRAF mts and MMR deficiency (dMMR) (n = 40) had worse OS than MMR proficiency (pMMR, n = 202) (1.6, 95% CI 1.0-2.5, P = 0.011). This was driven by BRAFPOP dMMR pts (HR 1.9, 95% CI 0.9-4.0, P = 0.036) as no difference was seen by MMR in BRAFNGS pts (HR 1.3, 95% CI 0.8-2.2, P = 0.30). Conclusions: Current estimates of prognosis for mCRC with BRAF mts likely underestimate its impact due to referral bias for NGS testing. BRAF mts with dMMR are associated with worse prognosis than pMMR. This appears driven by BRAFPOP pts. [Table: see text]

A retrospective study of hepatic arterial infusion (HAI) FUDR/Dex and mitomycin C (MMC) for chemotherapy refractory unresectable intrahepatic cholangiocarcinomas (ICC).

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 432-432
Author(s):  
Gustavo Dos Santos Fernandes ◽  
Nancy E. Kemeny ◽  
Haley Hauser ◽  
James J. Harding ◽  
Thomas Boerner ◽  
...  
Keyword(s):  
Treatment Options ◽  
Hepatic Arterial Infusion ◽  
Progression Free Survival ◽  
Response Assessment ◽  
Cancer Center ◽  
Genomic Alteration ◽  
Free Survival ◽  
Heavily Pretreated ◽  
Localized Disease ◽  
Next Generation Sequencing Ngs

432 Background: ICC are aggressive tumors with approximately 6,000 cases a year in US. The 5-year survival rate is less than 30% even for localized disease. There is only one approved line of systemic (SYS) treatment and further treatment options are necessary. HAI chemotherapy is an option to treat liver predominant cancers. Methods: After obtaining IRB approval, we retrospectively reviewed patients (pts) with ICC chemo refractory unresectable liver limited (LL) or liver dominant (LD) disease who received intrahepatic chemotherapy with HAI MMC. Baseline characteristics, previous lines of therapy, toxicity profile, combinations and radiographic responses were reviewed. Tumor genomic analyses were performed on samples using an on-site next generation sequencing (NGS) assay. Results: Between January 2011 and October 2018, 19 patients ICC with LL or LD disease were treated with HAI FUDR/Dex/MMC at Memorial Sloan Kettering Cancer Center. Disease was confined to the liver in 58% of the pts. All pts had previous chemotherapy (1-4 lines) and 14 (74%) previously had HAI FUDR/Dex. Of the 19 pts, 56% had HAI with FUDR/Dex and MMC, 43% had FUDR/Dex, MCC and SYS and 5% had HAI MMC and SYS. Seventeen patients were evaluable for response, two are being treated and will have response assessment for the meeting. Response was noted in 4 (23.5%), stable disease in 6 (35.5%) and progressive disease in 7 (41%) pts. Median overall survival from treatment was 6.1months (0.36-26). Median progression free survival was 3.65 months (0.36-9.53). Four patients had dose reductions. Common toxicity attributed to MMC was grade (G) one fatigue (32%), thrombocytopenia G1(16%) and G2 (5%). Of the 12 tumors analyzed to date the most 92% of tumors harbored at least one (0-10) genomic alteration. Common genomic alterations were ARID1 (25%), RASA1 (25%), IDH1(16.6%), NTRK (16.6%), TERT (16.6%), NRAS (16.6%), CDKN2 (16. 6%). FGFR2-FOXP1 and GTL2MEt fusions were found in one patient each. Conclusions: HAI FUDR/Dex/MMC containing regimens are active in pts with heavily pretreated refractory unresectable ICC. This strategy should be further investigated. Translational data will be presented.

scholarly journals Genomic and Histopathological Tissue Biomarkers That Predict Radiotherapy Response in Localised Prostate Cancer

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Anna Wilkins ◽  
David Dearnaley ◽  
Navita Somaiah
Keyword(s):  
Prostate Cancer ◽  
External Beam Radiotherapy ◽  
Treatment Options ◽  
Cell Cycle Checkpoints ◽  
Survival Outcomes ◽  
Androgen Synthesis ◽  
Genomic Assays ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing ◽  
Tumour Proliferation

Localised prostate cancer, in particular, intermediate risk disease, has varied survival outcomes that cannot be predicted accurately using current clinical risk factors. External beam radiotherapy (EBRT) is one of the standard curative treatment options for localised disease and its efficacy is related to wide ranging aspects of tumour biology. Histopathological techniques including immunohistochemistry and a variety of genomic assays have been used to identify biomarkers of tumour proliferation, cell cycle checkpoints, hypoxia, DNA repair, apoptosis, and androgen synthesis, which predict response to radiotherapy. Global measures of genomic instability also show exciting capacity to predict survival outcomes following EBRT. There is also an urgent clinical need for biomarkers to predict the radiotherapy fraction sensitivity of different prostate tumours and preclinical studies point to possible candidates. Finally, the increased resolution of next generation sequencing (NGS) is likely to enable yet more precise molecular predictions of radiotherapy response and fraction sensitivity.

scholarly journals The treatment of Burkitt lymphoma in adults

Blood ◽  
2020 ◽  
Author(s):  
Jennifer L. Crombie ◽  
Ann S. LaCasce
Keyword(s):  
Burkitt Lymphoma ◽  
Randomized Trials ◽  
Treatment Options ◽  
Unmet Need ◽  
Cns Involvement ◽  
Non Hodgkin Lymphoma ◽  
Genomic Landscape ◽  
Relapsed Disease ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Burkitt lymphoma (BL) is a highly aggressive, B-cell, non-Hodgkin lymphoma (NHL) categorized into endemic, sporadic and immunodeficiency-associated subtypes. BL has distinct pathologic and clinical features, characterized by rapidly progressive tumors with high rates of extranodal involvement. Next generation sequencing (NGS) analyses have further characterized the genomic landscape of BL and our understanding of disease pathogenesis, though these findings have yet to influence treatment. Although the majority of patients are cured with intensive combination chemotherapy, given the paucity of randomized trials, optimal therapy has not been defined. Furthermore, treatment for elderly patients, patients with central nervous system (CNS) involvement, or those with relapsed disease, remains an unmet need. In this review, we highlight the clinical, pathologic, and genomic features, as well as standard and emerging treatment options for adult patients with BL.

Phase II study of single-agent copanlisib in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 7536-7536 ◽  
Author(s):  
Georg Lenz ◽  
Eliza Hawkes ◽  
Gregor Verhoef ◽  
Corinne Haioun ◽  
Lim Soon Thye ◽  
...  
Keyword(s):  
Single Agent ◽  
B Cell Lymphoma ◽  
Cell Of Origin ◽  
Phosphatidylinositol 3 Kinase ◽  
Heavily Pretreated ◽  
Full Analysis ◽  
Status Analysis ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing ◽  
Clinical Trial Information

7536 Background: Relapsed/refractory (r/r) DLBCL patients (pts) are characterized by poor prognosis. Copanlisib is a pan-Class I phosphatidylinositol 3-kinase (PI3K) inhibitor, with modest single-agent activity in unselected DLBCL pts. Here we report the treatment effect of copanlisib in r/r DLBCL pts with regards to cell of origin (COO) and molecular biomarker profiles (NCT02391116). Methods: Patients with r/r DLBCL and ≥1 prior lines of therapy were eligible. Copanlisib (60 mg IV infusion) was administered on days 1, 8 and 15 of a 28-day cycle. Tumor samples were evaluated for COO, CD79B mutations and > 400 genes by next generation sequencing (NGS). The primary endpoint was objective tumor response rate (ORR; per Lugano Classification, 2014) by COO and CD79B status. Results: The full-analysis (FAS) and per-protocol sets (PPS; ≥3 doses, post-baseline scans and NGS/COO data) included 67 and 40 pts, respectively. Pts were 58% male, median age 69 (range 25-93), ECOG status 0/1/2 22%/57%/21%, and heavily pretreated (median prior lines = 3, range 1-13). In the PPS, COO (and mutant CD79B status) analysis identified 22 GCB DLBCL (2 mutant), 16 ABC DLBCL (6 mutant), and 2 unclassifiable. The ORR in the PPS was 25% (10 of 40), with 5 complete responses (CR) and 5 partial responses (PR); stable disease in 12 pts. The ORR was 13.6% with 1 CR in GCB pts and 37.5% with 4 CRs (25%) in ABC pts. Response to copanlisib was 25% in pts with (2/8) and without (8/32) CD79B mutations. Five of 10 ABC DLBCL-wtCD79B pts and one GCB DLBCL-mCD79B responded (ongoing > 17 cycles). NGS analysis in 54 pts detected 348 mutations; BCL2 (54% of pts), TP53 (41%), BCL6 (30%), MYC (22%), CD79B (19%)/A (6%), MYD88 (19%), TNFAIP3 (17%), CARD11 (13%), and NFKBIA (9%). Response to copanlisib was not significantly different based on BCL2, BCL6, MYC, and MYD88 mutations. With a median of 6 cycles (range 1-29), the most common AEs (% all grade/gr3+4) were diarrhea (36/2), nausea (31/2), fatigue (31/3), fever (21/2) and transient hypertension (40/33) and hyperglycemia (34/31). There were 14 gr5 AEs (none drug-related). Conclusions: Copanlisib treatment of r/r DLBCL pts resulted in encouraging responses, especially in the ABC subtype, with a manageable toxicity. Clinical trial information: NCT02391116.

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