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There is significant improvement in the outcomes following treatment with PARP inhibitors among patients with certain tumors that have BRCA mutations (BRCAm), homologous recombination repair (HRR) gene mutations, or homologous recombination deficiency (HRD) positivity. We performed a literature review and meta-analysis to evaluate the prevalence of BRCA1/2m, HRR gene mutations, and HRD positivity across multiple cancers. There were 265 publications on BRCA1/2 mutation prevalence, 189 on HRR gene mutation prevalence, and 7 on HRD positivity prevalence. The prevalences of germline BRCA1m and BRCA2m were 7.8% and 5.7% for breast cancer, 13.5% and 6.6% for ovarian cancer, 0.5% and 3.5% for prostate cancer, and 1.1% and 4.1% for pancreatic cancer, respectively. The prevalences of somatic BRCA1m and BRCA2m were 3.4% and 2.7% for breast cancer, 4.7% and 2.9% for ovarian cancer, 5.7% and 3.2% for prostate cancer, and 1.2% and 2.9% for pancreatic cancer, respectively. We identified 189 studies with over 418,649 samples across 25 tumor types that examined mutations in one or more HRR genes other than BRCA1/2. The prevalence of mutations among HRR genes remained low (less than 1%), with ATM (5.2%), CHEK2 (1.6%), and PALB2 (0.9%) exhibiting the highest prevalence. Seven studies evaluated HRD positivity in breast, ovarian, and prostate cancer patients. The prevalence of HRD positivity was 56% overall (95% CI = 48%-64%). The understanding of biomarker prevalence across tumor types and standardization of biomarker assays could have important clinical implications.

Objective: To describe chemotherapy treatments, associated health care use and costs, and survival for women diagnosed with cervical cancer in the United States.Methods: This was a retrospective co...

Patients with BRCA1/2 mutations (BRCAm), loss-of-function mutations in other homologous recombination repair (HRRm) genes, or tumors that are homologous recombination deficiency positivity (HRD+) demonstrate a robust response to PARPi therapy. We conducted a systematic literature review and meta-analysis to evaluate the prognostic value of BRCAm, HRRm, and HRD+ on overall survival (OS) among those treated by chemotherapy or targeted therapy other than PARPi across tumor types. A total of 135 eligible studies were included. Breast cancer (BC) patients with BRCA1/2m had a similar overall survival (OS) to those with wild-type BRCA1/2 (BRCA1/2 wt) across 18 studies. Ovarian cancer (OC) patients with BRCA1/2m had a significantly longer OS than those with BRCA1/2 wt across 24 studies reporting BRCA1m and BRCA2m, with an HR of 0.7 (0.6–0.8). Less OS data were reported for other tumors: 6 studies for BRCA2m compared with BRCA2 wt in prostate cancer with an HR of 1.9 (1.1–3.2) and 2 studies for BRCA1/2m compared with BRCA1/2 wt in pancreatic cancer with an HR of 1.5 (0.8–3.1). Only 4 studies reported HRD+ by either BRCA m or genomic instability score (GIS) ≥ 42 and OS by HRD status. The HR was 0.67 (0.43–1.02) for OS with HRD+ vs. HRD−. A total of 15 studies reported the association between HRRm and OS of cancers in which one or more HRR genes were examined. The HR was 1.0 (0.7–1.4) comparing patients with HRRm to those with HRR wild-type across tumors. Our findings are useful in improving the precision and efficacy of treatment selection in clinical oncology.

Most cases of small cell lung cancer (SCLC) are diagnosed at an advanced stage. The objective of this study was to investigate patient characteristics, survival, chemotherapy treatments, and health care use after a diagnosis of advanced SCLC in subjects enrolled in a health system network. This was a retrospective cohort study of patients aged ≥ 18 years who either were diagnosed with stage III/IV SCLC or who progressed to advanced SCLC during the study period (2005–2015). Patients identified from the Indiana State Cancer Registry and the Indiana Network for Patient Care were followed from their advanced diagnosis index date until the earliest date of the last visit, death, or the end of the study period. Patient characteristics, survival, chemotherapy regimens, associated health care visits, and durations of treatment were reported. Time-to-event analyses were performed using the Kaplan-Meier method. A total of 498 patients with advanced SCLC were identified, of whom 429 were newly diagnosed with advanced disease and 69 progressed to advanced disease during the study period. Median survival from the index diagnosis date was 13.2 months. First-line (1L) chemotherapy was received by 464 (93.2%) patients, most commonly carboplatin/etoposide, received by 213 (45.9%) patients, followed by cisplatin/etoposide (20.7%). Ninety-five (20.5%) patients progressed to second-line (2L) chemotherapy, where topotecan monotherapy (20.0%) was the most common regimen, followed by carboplatin/etoposide (14.7%). Median survival was 10.1 months from 1L initiation and 7.7 months from 2L initiation. Patients in a regional health system network diagnosed with advanced SCLC were treated with chemotherapy regimens similar to those in earlier reports based on SEER-Medicare data. Survival of patients with advanced SCLC was poor, illustrating the lack of progress over several decades in the treatment of this lethal disease and highlighting the need for improved treatments.

e18802 Background: BRCAm, HRRm, or HRD+ may be predictive of response to poly (ADP-ribose) polymerase inhibitors (PARPi) with/without immunotherapy (IO). However, there is limited data on the prevalence of these biomarkers and their impact on overall survival (OS) among patients who are not treated with PARPi or IO. Methods: This is a retrospective observational study across 15 available tumor types, using data from the de-identified Flatiron Health - Foundation Medicine (FMI) clinicogenomic database collected up to Dec 31, 2020. The de-identified data originated from ̃280 US cancer clinics (̃800 sites of care). Eligible patients were aged ≥ 18 years, diagnosed with advanced/metastatic solid tumors in 2018-2019. BRCAm, HRRm, and HRD were assessed by FMI F1CDx. HRD+ was defined as genomic loss of heterozygosity (gLOH) ≥16. OS analysis from second line therapy initiation (2L, primary index date) was performed as primary analysis since this population had high unmet medical need, and most patients were sequenced after 1L. Patients were excluded if PARPi/IO started on the index date or earlier or if patients died before the index date; and patients were censored as of PARPi/IO initiation if PARPi/IO was started later than the index date. OS was analyzed using the Kaplan-Meier method and Cox proportional hazards model, adjusted for age, sex, and tumor type. Results: A total of 9,462 patients with advanced/metastatic solid tumors were included, with 52% women and mean age of 66 years. The top five tumor types represented more than 75% of the patients, including non-small cell lung cancer (27%), colorectal (19%), breast (13%), pancreatic (8%) and gastric (8%) cancers. Known or suspected deleterious BRCAm was observed in 4.6% of patients across tumors and varied by tumor type, with the highest prevalence in ovarian cancer (13.0%). Total HRRm prevalence was 13.2% across tumor types with prostate cancer (25.9%) as the highest, and the prevalence of HRD+ was 20.6% cross tumor types with breast cancer (34.4%) as the highest. The adjusted hazard ratio (aHR) for OS from initiation of 2L therapy for patients with BRCAm vs BRCA wild type (BRCAwt) was 0.81 (95%CI, 0.61-1.07). Comparable results were observed when calculating OS from 1L or 3L therapy. The aHR of OS from 2L therapy with HRRm vs HRRwt was 0.92 (0.78-1.09) and 1.20 (1.01-1.43) for patients with HRD+ vs HRD negative (HRD-). Conclusions: The prevalence of BRCAm, HRRm, and HRD+ varies widely by tumor type. There was no association between BRCA/HRRm status and OS, yet HRD+ might be associated with shorter OS among patients who were not treated with PARPi or IO across the evaluated tumor types.[Table: see text]

Aim: We evaluated the relationship between clinical and genomic characteristics and tumor mutational burden (TMB) in small cell lung cancer. Materials & methods: In a retrospective analysis of small cell lung cancer patients aged ≥18, we assessed treatment patterns and survival in relation to TMB; the association of clinical and genomic characteristics with TMB was determined by multivariate regression. High TMB (TMB-H) was defined as ≥10 mutations/megabase. Results: Among 186 patients, treatment patterns and overall survival were similar for TMB-H and non-TMB-H patients. TMB was determined for 179 patients, 41.9% of whom were TMB-H. Short variants of LRP1B, FAT3, MLL3, MED12 and NOTCH3 were significantly associated with TMB-H (p ≤ 0.01). Conclusion: Neither treatment patterns nor survival differed by TMB status.

Data are limited on the real-world utilization and costs of brentuximab vedotin (BV) among patients with relapsed/refractory Hodgkin lymphoma (rrHL) in the United States. A total of 219 BV patients identified from the Truven MarketScan® databases were followed up for a median of 2.9 years before and 1.0 year after initiation of BV. Of these patients, 109 (50.6%) received systemic therapy after BV (post-BV ST). Median duration of treatment was short for BV (2.1 months) and post-BV ST treatment (1.3 months); time to next treatment was 6.2 and 9.1 months, respectively. Average total US dollar 2014 costs/person for BV and post-BV ST line of therapy were $167,152 and $132,115, respectively; mean per-patient-per-month costs for BV and post-BV ST were $30,434 and $29,138, respectively. Findings underscore the unmet medical need and substantial economic burden in BV-treated patients with rrHL.

3125 Background: Poly (ADP-ribose) polymerase inhibitor (PARPi) may have broad application in the treatment of cancer patients with mutations of BRCA (BRCAm) or other homologous recombination repair genes (HRRm) or HR deficiency positive (HRD+). A literature review and meta-analysis were conducted to evaluate the clinical prognostic outcomes by total BRCAm, HRRm, and HRD+ status across tumor types among patients treated with non-PARPi treatment. Methods: Comprehensive searches for eligible studies in Ovid MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Cochrane reviews were performed in May 2020 to capture studies published in English within 10 years for manuscripts and 3 years for abstracts across geographic regions. A summary estimate with corresponding 95% CI was calculated using random-effects models due to varying effects sizes across studies. Results: A total of 135 eligible studies were included. Breast cancer (BC) patients with either BRCA1m or BRCA2m (BRCA1/2m) had a similar overall survival (OS) to those with wild-type BRCA1 and BRCA2 (BRCA1/2wt) across 18 studies reporting data on BRCA1m and BRCA2m. The pooled estimates of hazard ratio (HR) was 1.0 (95% CI: 0.8-1.3) overall and was 1.0 (0.7-1.5) for triple-negative BC (TNBC, 7 studies). Similarly, the HR was 1.1 (0.9-1.3) across all 10 studies reporting BRCA1m data and 1.1 (0.8-1.3) across all 7 studies reporting BRCA2m data. Ovarian cancer (OC) patients with BRCA1/2m had a significantly longer OS than those with BRCA1/2wt across 24 studies reporting BRCA1m and BRCA2m, with a HR of 0.7 (0.6-0.8). The HR was 0.6 (0.4, 0.8) across 4 studies on stage III-IV ovarian cancer. The HR was 0.8 (0.6-1.1) across 13 studies reporting BRCA1m and 0.5 (0.3-0.9) across 8 studies reporting BRCA2m. Less OS data were reported for other tumors, 6 studies for BRCA2m in prostate cancer with a HR of 1.9 (1.1-3.2) and 2 studies for BRCA1/2m in pancreatic cancer with a HR of 1.5 (0.8-3.1). Only 4 studies reported HRD+ by either BRCAm or genomic instability score (GIS) ≥ 42 and OS by HRD status; 3 on TNBC and 1 on high-grade serous ovarian cancer. The HR was 0.67 (0.43-1.02) for OS with HRD+ vs. HRD-. A total of 15 studies reported the association between HRRm and OS of cancers (5 on prostate, 4 on pancreas, 3 on ovary, 2 on breast and 1 on urothelial cancer), in which one or more HRR genes were examined. The HR was 1.0 (0.7-1.4) comparing patients with HRRm to those with HRRwt across tumor types. Due to the limited study number and inconsistent methodology/definitions of HRRm and HRD+, these results should be interpreted with caution. Conclusions: The effects of BRCA1/2m on OS in patients treated with chemotherapy varies by cancer type with no effect in BC and a positive association in OC. More study is required in other cancer types. There was no significant association found between HRD+ or HRRm with OS. These findings could help inform evidence-based treatment decisions.

e18698 Background: Endometrial cancer (EC) is the most common gynecologic cancer in the US, yet real-world disease burden is poorly understood. To address this, we conducted a retrospective study exploring patient (pt) characteristics, treatment patterns, overall survival (OS), and healthcare resource utilization (HCRU) among elderly US pts with EC. Methods: Using Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data, we identified beneficiaries aged ≥65 y with newly diagnosed EC between Jan 1, 2007–Dec 31, 2013. Pts were followed from the EC diagnosis date to the earliest of death, loss to follow-up, or Dec 31, 2014. Descriptive analyses were conducted for pt characteristics assessed in the 6-mo baseline period and for treatment patterns and HCRU assessed during follow-up. Median OS was estimated from the start of each line of systemic therapy using the Kaplan-Meier method. Lines of therapy started when pts received a new systemic therapy regimen and ended when pts switched to another regimen, after a 90-d treatment gap, or at end of follow-up. For pts with surgery, systemic therapy starting >120 d after surgery or after discontinuation of adjuvant therapy was defined as first-line (1L) therapy. Adjuvant therapy was defined as any systemic therapy starting ≤120 d after surgery for EC and ending after a 90-d treatment gap following the last prescription. Results: There were 12,710 eligible pts with EC during 2007–2013 in the SEER-Medicare database; median age at diagnosis was 73 y. At initial diagnosis, 9395 (73.9%) pts had stage I/II EC, 2042 (16.1%) had stage III, and 1273 (10.0%) had stage IV. 778 pts did not receive surgery/radiation, 1230 pts received surgery/radiation plus adjuvant therapy, 9729 pts received surgery/radiation only, and 973 (7.7%) pts received 1L systemic therapy. Of these 973 pts, 370 (38.0%) received second-line (2L) and 157 (16.1%) received third-line (3L) treatment. Pts receiving 1L therapy had a mean of 5.6 outpatient physician office visits per month, 22.1% had ≥1 hospitalization, and 38.5% had ≥1 emergency room visit during follow-up. Carboplatin-based regimens were the most frequently used 1L therapies (56.8%), typically combined with paclitaxel (43.5%). Median OS was generally short, particularly for those diagnosed with stage III/IV EC (Table). Conclusions: Medicare beneficiaries receiving systemic chemotherapy for EC generally had high HCRU and poor survival, particularly among pts diagnosed at later stages. This highlights the underlying disease burden and unmet need for more effective treatments in these pts.[Table: see text]

10589 Background: Poly (ADP-ribose) polymerase inhibitor (PARPi) may have broad application in the treatment of cancer patients with mutations in BRCA (BRCAm) or other homologous recombination repair genes (HRRm) or with homologous recombination deficiency positive (HRD+). A literature review and meta-analysis were conducted to evaluate the prevalence of BRCAm, HRRm, and HRD+ across tumor types. Methods: Comprehensive searches for eligible studies in Ovid MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Cochrane reviews were performed in May 2020 to capture studies published in English, within 10 years for manuscripts and 3 years for abstracts across geographic regions. A weighted summary estimate was calculated for BRCAm. A summary estimate with corresponding 95% CI was calculated using random-effects models for HRD+ and HRRm. Results: A total of 342 eligible studies with at least 100 samples were included in the review of BRCA1/2m prevalence, containing a total of over 469,000 samples across 24 tumor types. The most frequent indications examined in the included studies were breast (study number n = 144), ovarian (53), prostate (17) and pancreatic (11) cancers. The prevalence of germline BRCA1m (gBRCA1m) and gBRCA2m was 5% and 4% for breast, 12% and 5% for ovarian, 1% and 3% for prostate, and 1% and 4% for pancreatic cancer, respectively. The prevalence of somatic BRCA1m (sBRCA1m) and somatic BRCA2m (sBRCA2m) was 3% and 3% for breast, 7% and 5% for ovarian, 3% and 5% for prostate, and 1% and 3% for pancreatic cancer, respectively. Few studies evaluated endometrial, lung and colon cancers, the prevalence of gBRCA1m or gBRCA2m was generally less than 1%, and the prevalence of sBRCA1m and sBRCA2 ranged 1 to 3%. Seven publications were identified where HRD+ was defined by either BRCAm or genomic instability score (GIS) ≥ 42 across breast, ovarian and pancreatic cancers. The overall HRD+ prevalence was 56% (95%CI: 48, 64), with similar prevalence observed across the 3 tumor types and was 50% (34, 66) for the 3 studies only counting GIS≥ 42. 194 studies across 26 tumor types were identified that examined HRRm as mutations in one or more HRR genes other than BRCA1/2m. The definitions of HRRm varied substantially across the studies, and ATM (2.8%), CHEK2 (1.6%), and PALB2 (1.6%) accounted for most of the observed mutations among HRR genes. Conclusions: Prevalence of BRCAm, HRRm and HRD+ varied by cancer type. This comprehensive meta-analysis enriches the knowledge in this field and demonstrates the need to standardize the measurement of HRRm and HRD.Understanding the prevalence of these biomarkers could have important clinical implications.

Importance Tumor mutational burden (TMB) is a potential biomarker associated with response to immune checkpoint inhibitor therapies. The prognostic value associated with TMB in the absence of immunotherapy is uncertain. Objective To assess the prevalence of high TMB (TMB-H) and its association with overall survival (OS) among patients not treated with immunotherapy with the same 10 tumor types from the KEYNOTE-158 study. Design, setting, and participants This retrospective cohort study evaluated the prognostic value of TMB-H, assessed by Foundation Medicine (FMI) and defined as at least 10 mutations/megabase (mut/Mb) in the absence of immunotherapy. Data were sourced from the deidentified Flatiron Health-FMI clinicogenomic database collected up to July 31, 2018. Eligible patients were aged 18 years or older with any of the following solid cancer types: anal, biliary, endometrial, cervical, vulvar, small cell lung, thyroid, salivary gland, mesothelioma, or neuroendocrine tumor. Patients with microsatellite instability-high tumors were excluded from primary analysis. For OS analysis, patients were excluded if immunotherapy started on the FMI report date or earlier or if patients died before January 1, 2012, and patients were censored if immunotherapy was started later than the FMI report date. Data were analyzed from November 2018 to February 2019. Main outcomes and measures Overall survival was analyzed using the Kaplan-Meier method and Cox proportional hazards model, adjusting for age, sex, cancer types, practice type, and albumin level. Results Of 2589 eligible patients, 1671 (64.5%) were women, and the mean (SD) age was 63.7 (11.7) years. Median (interquartile range) TMB was 2.6 (1.7-6.1) mut/Mb, and 332 patients (12.8%) had TMB-H (≥10 mut/Mb). Prevalence of TMB-H was highest among patients with small cell lung cancer (40.0%; 95% CI, 34.7%-45.6%) and neuroendocrine tumor (29.3%; 95% CI, 22.8%-36.6%) and lowest was among patients with mesothelioma (1.2%; 95% CI, 0.3%-4.4%) and thyroid cancer (2.7%; 95% CI, 1.2%-5.7%). Adjusted hazard ratio for OS of patients not treated with immunotherapy with TMB-H vs those without TMB-H was 0.94 (95% CI, 0.77-1.13). Comparable results were observed when including patients with high microsatellite instability tumors and calculating OS from first observed antineoplastic treatment date. Conclusions and relevance These findings suggest that prevalence of TMB-H varies widely depending on tumor type and TMB-H does not appear to be a factor associated with OS among patients across these cancer types treated in the absence of immunotherapy.

Background Little is known about the prognostic effect of TMB-H among patients with less common cancers who did not receive an immunotherapy (IO). Methods The de-identified Flatiron Health-Foundation Medicine (FMI) Clinico-Genomic Database was used to select patients (pts) with any of 10 solid cancers (Table). 109 Pts with confirmed microsatellite instability-high (MSIH) cancers were excluded, of which 101 pts were endometrial cancer. TMB-H was defined as ≥ 10 mutations per megabase (Mut/Mb) with an additional analysis using a cutoff of 13 Mut/Mb. For overall survival (OS) analysis, Pts with IO were excluded if start of IO earlier than or equal to FMI report date (69 pts), or censored if start of IO later than FMI report date (243 pts). OS was analyzed using Kaplan-Meier method and Cox proportional hazard model, adjusting for age, gender, cancer types, practice type and albumin. A non-inferiority test of TMB-H having longer OS than TMB-low (-L) was carried out with a prespecified hazard ratio (HR) of 0.75. Results Of the 2,589 pts (table), average age at diagnosis was 64 years and 65% were female. Median TMB was 2.6 Mut/Mb overall, ranged from 1.7 (Meso, salivary, thyroid) to 8.7 (SCLC) Mut/Mb. Overall 12.8% were TMB-H with the highest in SCLC (40.0%) and lowest in meso (1.2%). The adjusted HR (AHR) of TMB-H vs. -L was 0.94 (95% CI: 0.77-1.13) for OS from FMI report date, which met the prespecified threshold for non-inferiority by rejecting the null hypothesis. The AHR was 0.84 (0.67-1.05) using alternative cutoff of 13 Mut/Mb. Comparable results were observed when including MSI-H pts and calculating OS from 1st observed antineoplastic treatment date. Table: 1877PD . N TMB-H OS (month, 95%CI) HRadjust Padjust n % TMB-H TMB-L Total 2,589 332 12.8 8.4 (7.4; 11.4) 10.5 (9.5; 11.5) 0.94 (0.77; 1.13) 0.491 SCLC 305 122 40.0 6.4 (5.4; 7.5) 7.4 (5.5; 10.5) 1.03 (0.74; 1.44) 0.863 Neuroendocrine 164 48 29.3 10.4 (6.4; NA) 6.4 (4.5; 10.5) 0.83 (0.48; 1.44) 0.506 Cervical 114 17 14.9 NA (6.4; NA) 7.4 (4.4; 11.5) 0.32 (0.08; 1.31) 0.113 Anal 125 17 13.6 7.4 (2.5; NA) 7.5 (5.5; 15.4) 0.84 (0.40; 1.79) 0.659 Vulvar 30 4 13.3 8.5 (0.5; NA) 6.5 (2.5; NA) 1.18 (0.22; 6.29) 0.848 Salivary 169 22 13.0 4.5 (3.5; NA) 15.5 (10.5; 21.5) 1.20 (0.48; 2.99) 0.691 Endometrial 590 66 11.2 11.4 (8.5; 26.5) 13.5 (11.5; 15.4) 1.15 (0.75; 1.75) 0.522 Biliary 706 28 4.0 11.5 (7.4; NA) 8.4 (7.4; 10.4) 0.65 (0.35; 1.19) 0.162 Thyroid 223 6 2.7 10.2 (1.5; NA) 27.5 (21.5; NA) 1.64 (0.39; 6.96) 0.502 Meso 163 2 1.2 NA 12.5 (8.5; 15.5) - 0.997 Conclusions There is a wide range of TMB among these cancers. Non-inferiority testing and HR estimates comparing OS for TMB-H (≥10 Mut/Mb) vs. -L did not support an effect of TMB on OS in the absence of IO for these cancers. Further research is needed to explore whether the prognostic effect of TMB varies by tumor type or threshold. Legal entity responsible for the study Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure D. Backenroth: Shareholder / Stockholder / Stock options, Full / Part-time employment: Flatiron Health Inc. C. Shao: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co. G. Li: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. L. Huang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co.. S.K. Pruitt: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. E. Castellanos: Full / Part-time employment: Flatiron Health Inc.. G.M. Frampton: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. K.R. Carson: Full / Part-time employment: Flatiron Health Inc.. T. Snow: Full / Part-time employment: Flatiron Health Inc.. G. Singal: Full / Part-time employment: Foundation Medicine. D. Fabrizio: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. B.M. Alexander: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. F.J. Jin: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. W. Zhou: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc..

Pseudoxanthoma elasticum (PXE), an autosomal recessive disorder characterized by ectopic mineralization, is caused by mutations in the ABCC6 gene. We examined clinically 29 Chinese PXE patients from unrelated families, so far the largest cohort of Asian PXE patients. In a subset of 22 patients, we sequenced ABCC6 and another candidate gene, ENPP1, and conducted pathogenicity analyses for each variant. We identified a total of 17 distinct mutations in ABCC6, 15 of them being, to our knowledge, previously unreported, including 5 frameshift and 10 missense variants. In addition, a missense mutation in combination with a recurrent nonsense mutation in ENPP1 was discovered in a pediatric PXE case. No cases with p.R1141X or del23-29 mutations, common in Caucasian patient populations, were identified. The 10 missense mutations in ABCC6 were expressed in the mouse liver via hydrodynamic tail-vein injections. One mutant protein showed cytoplasmic accumulation indicating abnormal subcellular trafficking, while the other nine mutants showed correct plasma membrane location. These nine mutations were further investigated for their pathogenicity using a recently developed zebrafish mRNA rescue assay. Minimal rescue of the morpholino-induced phenotype was achieved with eight of the nine mutant human ABCC6 mRNAs tested, implying pathogenicity. This study demonstrates that the Chinese PXE population harbors unique ABCC6 mutations. These genetic data have implications for allele-specific therapy currently being developed for PXE.

e18226 Background: Limited chemotherapy data is available for elderly cervical cancer patients (pts). This study aimed to investigate real-world use of systemic therapies, survival, and costs among elderly pts in U.S. Methods: Pts who aged 65+ years and initially diagnosed with cervical cancer between 2007 and 2013 were identified using the SEER-Medicare data. Regimens were classified into 3 mutually-exclusive categories, i.e. cisplatin (Cis), carboplatin (Car), and Other based therapies. Chemotherapy within 90 days of surgery or radiation therapy were not considered as first line (1L) systemic therapy. All costs were converted to 2016 US dollars. Results: A total of 1 651 eligible pts were identified with 430 (26%) being stage IV at diagnosis. Among pts received systemic therapies, the median overall survival (OS) was 14 m from 1L initiation and 10 m from 2L initiation. Among 225 pts who received 1L, 58% pts received Cis-based therapy, and 17% pts received Car-based therapy. Car + paclitaxel was the most commonly used regimen (44%). Among 73 pts who received 2L, 34% and 15% pts received Cis- and Car-based therapy, respectively. Pts with 2L therapy received a variety of regimens with the top 3 being Car + paclitaxel (19%), gemcitabine (11%), and topotecan (9.6%). Median duration of treatment (DOT) was 4-6 m across line of therapies (LOTs), yet median time to next treatment (TTNT) ranged 10-32 m for 1L, and 9-11 m for 2L. The average per person per month (PPPM) costs were 7.1k for 1L and 8.8k for 2L with primary drivers of spending being outpatient and emergency room visits. Conclusions: Elderly pts with advanced cervical cancer requiring chemotherapy had poor prognosis and had no standard of care for 2L therapy. Per-patient economic burden is substantial for both 1L and 2L therapy, exceeding 7k dollars per month. [Table: see text]

e20647 Background: Given a dearth of literature, this study aimed to investigate real-world use of systemic therapies, survival, and costs among elderly SCLC patients (pts) in U.S. Methods: Pts (65+ years old) with an initial diagnosis of SCLC during 2007-2013 were identified using the SEER-Medicare data. Overall survival (OS), duration of treatment (DOT) and time to next treatment (TTNT) were estimated based on the Kaplan-Meier method. Costs (2016 US dollars) were derived from Medicare claims. Results: A total of 11 812 pts were identified with 7 797 (66%) being stage IV at diagnosis. During an average of 10 months (m) follow-up post diagnosis, 6 509 (55%), 2 238 (19%) and 679 (6%) received first line (1L), 2L and 3L therapy, respectively. The median OS was 9 m from 1L start and 6 m from 2L or 3L start, suggesting existing treatment providing limited survival benefit. Majority pts (93%) received platinum-based therapy for 1L with Car + etoposide (Eto, 59%) being the most commonly used regimen, followed by Cis + Eto (18%) and Car monotherapy (8%). Car + Eto, Top and Pac were the top 3 regimens used in 2L and 3L. Median DOTs were 4-6 m, yet TTNT ranged from 7 to 18 m across lines of therapy. The average per person per month (PPPM) costs were $9.4k for 1L, $8.9k for 2L, and $8.8k for 3L. Conclusions: Advanced SCLC remains an aggressive malignancy with poor prognosis, lack of ideal therapy and high medical cost, which highlighted high unmet medical need of SCLC among elderly pts. [Table: see text]

Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder manifesting with ectopic connective tissue mineralization, caused by mutations in the ABCC6 gene, with ∼35% of all mutations being premature termination mutations. In this study, we investigated the therapeutic potential of the nonsense codon read-through-inducing drug, PTC124, in treating PXE. The ability of this drug to facilitate read-through of nonsense mutations was examined in HEK293 cells transfected with human ABCC6 expression constructs harboring seven different PXE-associated nonsense mutations, and was evaluated by immunofluorescence and In-Cell ELISA. Our data demonstrated that PTC124 did not exhibit cytotoxicity in concentrations up to 20μgml −1 , and the facilitated read-through varied not only with dose but also with sequence context. Considering the redundancy of the genetic code, it was postulated that in case of the most common recurrent nonsense mutation, p.R1141X, the read-through may result in substitution of the arginine 1,141 by glycine, tryptophan, or cysteine. Their potential pathogenicity was tested in a recently developed zebrafish messenger RNA (mRNA) rescue assay, and demonstrated that all three mRNA transcripts were able to rescue abcc6a morpholino-induced phenotype of zebrafish. Thus, our results suggest that read-through of nonsense mutations in ABCC6 by PTC124 may have potential for pharmacologic treatment of PXE.

Staphylococcus aureus is an important human pathogen whose virulence relies on the secretion of many different proteins. In general, the secretion of most proteins in S. aureus, as well as other bacteria, is dependent on the type I signal peptidase (SPase)-mediated cleavage of the N-terminal signal peptide that targets a protein to the general secretory pathway. The arylomycins are a class of natural product antibiotics that inhibit SPase, suggesting that they may be useful chemical biology tools for characterizing the secretome. While wild-type S. aureus (NCTC 8325) is naturally resistant to the arylomycins, sensitivity is conferred via a point mutation in its SPase. Here, we use a synthetic arylomycin along with a sensitized strain of S. aureus and multidimensional protein identification technology (MudPIT) mass spectrometry to identify 46 proteins whose extracellular accumulation requires SPase activity. Forty-four possess identifiable Sec-type signal peptides and thus are likely canonically secreted proteins, while four also appear to possess cell wall retention signals. We also identified the soluble C-terminal domains of two transmembrane proteins, lipoteichoic acid synthase, LtaS, and O-acyteltransferase, OatA, both of which appear to have noncanonical, internal SPase cleavage sites. Lastly, we identified three proteins, HtrA, PrsA, and SAOUHSC_01761, whose secretion is induced by arylomycin treatment. In addition to elucidating fundamental aspects of the physiology and pathology of S. aureus, the data suggest that an arylomycin-based therapeutic would reduce virulence while simultaneously eradicating an infection.

Leptomycin B (LMB) and/or its derivatives are considered a novel class of cancer therapeutics through blocking chromosome maintenance region 1, which mediates p53 nuclear export. The objectives of the present study were to first evaluate the cytotoxic effects of LMB on a normal human lung epithelial cell line (BEAS-2B) and three human lung adenocarcinoma cell lines with various p53 status (wild type: A549, mutant: NCI-H522, and null: NCI-H358) and then to identify LMB-induced gene expression alterations in human p53 signaling pathway.Cells were treated with 0.01-100 nM LMB or 0.1% ethanol (vehicle control) for 4-72 h. Gene expression analyses using gene array for 84 genes involved in p53-mediated signaling pathways were performed in A549 and NCI-H358 after treatment with 20 nM LMB or vehicle control for 24 h.Cytotoxic results from MTS assays revealed a significant dose- and time-dependent effect of LMB on all cell lines. However, this effect was more pronounced in cancer cells than in normal cells, and cancer cells with p53 wild type tended to be less sensitive than those with p53 mutant or null. A total of 23 genes, predominantly involved in apoptosis and cell cycle/proliferation, were significantly altered in A549 after LMB treatment, while no strong modulating effects were observed in NCI-H358. The protein expression of two selected genes, p21 and survivin, was further confirmed by Western blots.Our results suggest that LMB has anti-cancer potential and provides a new regimen of individualized therapy for lung cancer treatment.

Background: Real-world data on treatment patterns and economic burden associated with rrHL are limited. The study aimed to describe BV utilization, post-BV therapies, health care resource utilization (HCRU) and costs among rrHL patients treated with BV in US clinical practice. Methods: This is a retrospective database analysis of the Truven Health MarketScan Commercial and Medicare Database. Patients were included if they initiated BV treatment for HL between Jan 1, 2012 and Jun 30, 2014, were ≥18 yrs, and had ≥6 mos continuous enrollment before and after the 1st BV dose (index date). If two or more drugs were started within 30 days, they were considered as one regimen. Line of therapy (LOT) was defined when a new treatment was introduced or there was a treatment gap >60 days. Time to next treatment (TTNT) was defined from initiation of the LOT to initiation of subsequent LOT. Duration of treatment (DOT) and TTNT were evaluated based on Kaplan-Meier method. HCRU (events/person-months) and costs (per patient per month, PPPM) were calculated by LOT. The total costs included inpatient costs, outpatient costs and pharmacy costs. Results: A total of 219 patients were included in the study. On average, patients were observed for 2.7 yrs prior to and 1.1 yrs post to initiation of BV. During the observational period, 88 patients had transplant (SCT), including 50 having SCT prior to initiation of BV. Median age at index date was 46 yrs among all patients and 40 yrs among patients with SCT. For BV, median DOT was 2.1 mos and TTNT was 6.2 mos. Rate of outpatient visits, inpatient visits, ER visits and hospice care visits, per person-month, were 5.04, 0.08, 0.09, and 0.09, respectively. Mean total costs per person was $167,152, with outpatient costs being the largest cost driver ($144,583). Mean PPPM cost was $24,593. Of the 219 patients, 126 (57.5%) patients received subsequent systemic therapy (ST) after discontinuing BV. For subsequent ST post-BV, median DOT was 1.5 mos with BV (12.8%a), GVD/GV (10.5%), bendamustine (6.8%) gemcitabine (4.6%) and fludarabine (1.8%) being most common. Rate of outpatient visits, inpatient visits, ER visits and hospice care visits, per person-month, were 5.84, 0.18, 0.10, and 0.01, respectively. Mean total costs per person were $139,146, inpatient costs were $69,043, and outpatient costs were $65,233. Mean PPPM cost was $28,290. Conclusions: Short duration of therapy was observed for both BV and subsequent ST post-BV. Costs over $24K per month were incurred for each patient during BV treatment course and over $28K per month during subsequent ST post-BV course. Findings underscore substantial economic burden in rrHL patients treated with BV. Table Table. Disclosures Shao: Merck & Co., Inc.: Employment. Liu:Merck & Co., Inc.: Employment. Zhou:Merck & Co.: Employment. Raut:Merck & Co.: Employment. Monberg:Merck & Co.: Employment. Cao:Merck & Co.: Employment. Ricart:Pfizer: Equity Ownership; Merck & Co.: Employment. Balakumaran:Merck & Co.: Employment, Other: stock, stock options.

Background: Carfilzomib (Car, 2012), pomalidomide (Pom, 2013), and panobinostat (Pano, 2015) were approved for the treatment of rrMM patients after failure of at least two prior standard therapies. There is limited real-world data on utilization of these medications, health care resource utilization (HCRU) and costs in patients with rrMM at the US population level. This study aimed to describe treatment pattern, HCRU, and costs in rrMM patients who received at least two prior therapies using a large administrative claims database. Methods: This was a retrospective database analysis using the Truven Health MarketScan Commercial and Medicare Database. Patients (pts) were included if they were diagnosed with MM between Jan 1, 2006 and May 31, 2015, were ≥18 yrs, had no claim for stem cell transplant, and had ≥6 mos continuous enrollment before and ≥1 mos after the 1st MM diagnosis (index date) and treatment initiation (TI). Only patients who had ≥6 mos continuous enrollment after TI were included in HCRU and cost evaluation. If two or more drugs started within 90 days, they were considered as 1 regimen. End of a line of therapy (LOT) was defined when a new treatment was introduced or there was a treatment gap >90 days or end of follow-up, whichever occurred first. Third line of therapy (3L) was identified following 2 prior lines of therapy. Time to next treatment (TTNT) was defined from initiation of the LOT to initiation of subsequent LOT. Duration of treatment (DOT) and TTNT were estimated based on Kaplan-Meier method. Regimens were classified into 6 mutually-exclusive categories, including bortezomib (Bor), lenalidomide (Len), Pom, Car, thalidomide (Thal), and Other based therapies. HCRU and cost (per patient per month, PPPM) were calculated. The total costs included inpatient costs, outpatient costs and pharmacy costs. Results: A total of 9,960 pts were identified with initiation of 1L therapy. Median age was 67 yrs. And 57.4% were male. During an average of 20.0 mos follow-up post TI, 3,282 (33.0%), 1,103 (11.1%) and 400 (4%) pts initiated 2L, 3L, and 4L therapies, respectively. During 3L therapy, Bor (43.5%, including 10.5% for Bor-Len) and Len based regimens (29.8%) were most commonly observed. Median DOTs ranged from Car (3.7 mos) to Len (8.1 mos) based regimens. Median TTNT from short to long was Car, Pom, Bor, Len, Other, and Thal based regimens. On average, each patient with rrMM had 4.5 outpatient visits, 0.1 inpatients visits, 0.1 ER visits and 0.004 hospice care visits per month. The average PPPM costs were $14,286, $13,377, $11,919, for Bor, Len, Thal based regimens and $25,850 and $21,180 for Pom and Car based regimens, respectively. Conclusions: Although novel agents were added to rrMM treatment, Bor and/or Len based regimens remained the most commonly used therapies in 3L setting. Compared to Bor, Len and Thal based therapies, PPPM costs were higher for Pom and Car based regimens. These data could be useful for treatment consideration and economic evaluation. Table Table. Disclosures Shao: Merck & Co., Inc.: Employment. Monberg:Merck & Co.: Employment. Cao:Merck & Co.: Employment. Zhou:Merck & Co.: Employment. Zhong:Merck & Co., Inc.: Employment. Marinello:Merck & Co., Inc.: Employment.

e19019Background: BV was associated with a 75% ORR in a single-arm trial of patients with relapsed HL. Yet real-world BV utilization data is limited. This study aimed to describe BV utilization, ad...

The p53 tumor suppressor gene plays an essential role in tumorigenesis, and the chromosomal region maintenance 1 (CRM1) has been suggested to export p53 protein from the nucleus to the cytoplasm. The objectives of the present study were to evaluate p53 expression and subcellular localization as well as CRM1 expression using immunohistochemistry in our established bitransgenic mouse lung tumor model. In this model, expression of the mutant human Ki-rasG12C allele was regulated in a doxycycline (DOX)-inducible, lung-specific manner. Following treatment with curcumin, we found that although overall p53 expression levels were not significantly changed among the three groups, lung lesions in mice treated with DOX alone had the highest proportion of N>C (nucleus predominant) p53 staining (46±7%), followed by lung lesions in mice co-treated with DOX and curcumin (31±12%) and controls (17±4%). CRM1 expression was dramatically inhibited in lung lesions in mice treated with DOX (0±0) as compared to controls (90±17, P=0.001), and could be partially reversed after curcumin treatment (47±21, P=0.028, DOX vs. DOX+curcumin). Collectively, the results from this study demonstrated that p53 accumulated in the nucleus in lung lesions in mice expressing the mutant Ki-rasG12C transgene as a result of down-regulation of CRM1. Furthermore, these alterations could be partially reversed by curcumin treatment. p53 subcellular localization resulting from CRM1 alterations may play an important role in lung tumorigenesis.

4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone [corrected] (NNK), a known tobacco-specific human lung carcinogen, is notorious for causing DNA damage. The tumor suppressor gene p53 has multiple functions in response to DNA damage. Besides being regulated by posttranslational modifications (PTMs), p53 function is modulated by nucleocytoplasmic shuttling factors (NSFs). In this study, the alterations of p53 protein after NNK exposure and the molecular mechanisms involved p53 PTMs and NSFs in human bronchial epithelial cells BEAS-2B were investigated. NNK induced p53 nuclear accumulation and upregulated the expression of p21, a p53 target gene. Among the five NSFs examined, chromosomal region maintenance 1 (CRM1), interacting with p53 and exporting p53 from nucleus to cytoplasm, was significantly downregulated after NNK exposure. Increases of p53 phosphorylation and poly(ADP-ribosyl)ation were found in NNK-treated cells as compared with the controls. The upregulation of p53 poly(ADP-ribosyl)ation was induced by the enhanced expression of poly(ADP-ribose) polymerase 1 after NNK exposure. Collectively, p53 went through PTMs in response to DNA damage, and the modified p53 had a tendency for nuclear accumulation, which could result from CRM1 downregulation. Consequently, the activation of p53 led to subsequent induction of its downstream targets. These data could facilitate the better understanding of chemical carcinogenesis induced by NNK.

Objective: Our recent study demonstrated the protective action of green tea polyphenols (GTPs) against bone loss in ovariectomized (OVX) rats through their antioxidant capacities to scavenge reactive oxygen species. The objective of the present study was to evaluate the alterations of liver protein profiles in estrogen-deficient middle-aged rats after GTP treatment by a gel-based proteomic approach. This may lead to understanding the mechanisms of GTPs in promoting bone health. Methods: Liver samples were obtained from 14-mo-old female OVX rats treated with no GTPs (OVX) or 0.5% (w/v) GTPs (OVX þ GTP) in drinking water for 16 wk (n ¼ 10/group). Twodimensional difference gel electrophoresis combined with mass spectrometry was used to compare the liver protein profiles of pooled samples from the OVX and OVX þ GTP groups. Liver proteins were labeled in duplicate by reversing the fluorescent dyes. Results: Approximately 800 protein spots were detected. The expression levels of superoxide dismutase-1 and adenosine triphosphate synthase were 2.0-fold and 1.5-fold higher in the OVX þ GTP group versus the OVX group, respectively, whereas the expression level of catecholO-methyltransferase was 1.5-fold lower in the OVX þ GTP group versus the OVX group. The changes of superoxide dismutase-1 and catechol-O-methyltransferase in individual liver samples were confirmed by western blots. Conclusion: Our data provide further evidence for the antioxidant role of GTPs by increasing superoxide dismutase-1 and adenosine triphosphate synthase and the estrogen-associated effect of GTPs by decreasing catechol-O-methyltransferase.

The objective of this study was to characterize specific serum glycan profile in esophageal squamous cell carcinoma (ESCC) cases and matched controls. A recently developed lectin-based antibody array was applied to detect various cancer-associated glycotopes in sera from 23 cases and 23 controls. Glycan levels were highly expressed in sera of ESCC patients as compared with controls. These included fucosylation level on interleukin (IL) 8; mannose level on haptoglobin; N-acetylglucosamine levels on IL6, mucin (MUC)1, and von Willebrand factor (vWf); sialyl Lewis a (sLea) levels on blood group Lewis X, IL6, IL10, MUC1, and serum amyloid A (SAA); sialyl Tn antigen (sTn) levels on cathepsin D, gelsolin, IL10, and vWf; T antigen levels on IL8, IL10, blood group Lewis X, vitronectin, and vWf (p

Leptomycin B (LMB), a metabolite of Streptomyces, is a specific and potent inhibitor of chromosome maintenance region 1 (CRM1), which mediates the nuclear export of p53. LMB and/or its derivatives are being considered as a novel class of cancer therapeutics. Our previous data showed that cell growth inhibitory effects of LMB were more pronounced in human lung cancer cell lines than the normal human bronchial epithelial cell line. In addition, the inhibitory effects varied among lung cancer cell lines with different p53 status. For instance, the inhibitory effect was more remarkable in p53 null/mutated cell lines like NCI-H358 than p53 wild-type cell lines like A549. The objectives of the present study were to evaluate the mechanism for p53-mediated tumor inhibitory effect of LMB and to identify the mechanistic difference in tumor inhibitory effect of LMB between lung cancer cells with p53 wild type (A549) and p53-null (NCI-H358) by profiling gene expression in human p53 signaling pathway. Cells were treated with 20 nM LMB or 0.1% ethanol vehicle control for 24 h. p53 and p21 protein expression levels were evaluated by Western blots. RNA was extracted and used to perform the RT2 Profiler™ PCR array for analyzing gene expression of 84 genes involved in human p53 signaling pathway. Treatment of cancer cells with LMB led to increased p53 protein expression in A549 but not NCI-H358. LMB treatment significantly altered p53-dependent transcription for 23 genes predominantly involved in apoptosis and cell cycle/proliferation in A549, including 13 down-regulated genes, such as CDC2, CDC25C, PRC1, and survivin, and 10 up-regulated genes, such as BTG2, MDM2, p21, and SESN1. These results suggested that the cell growth inhibition effects of LMB on A549 could be closely related to the CRM1-dependent p53 nuclear accumulation to induce cell cycle arrest and/or apoptosis. On the other hand, LMB treatment did not show strong modulating effects on p53-mediated genes in NCI-H358. In comparison to A549, some p53 regulated genes, such as BAX, CCNE2, HK2, MDM2, p21, and SESN1, had significantly different expression in NCI-H358. The more pronounced cell growth inhibitory effects of LMB on NCI-H358 as compared to A549 could result from signal transduction pathways other than p53. In addition, the p21 gene expression data were further confirmed by protein expression analyses, which showed selectively significant up-regulation in A549 while no change in NCI-H358 after LMB treatment. Collectively, these findings suggest the involvement of p53 in cellular response of A549 to LMB but not NCI-H358. The abilities of LMB to induce p53 protein expression and modulate its responsive genes that lead to cell growth inhibition and/or apoptosis may be useful in lung cancer treatment. The different cellular responses of cells with distinct p53 status suggest the importance of individualized therapy for lung cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2484.