Citations

Abstract Background LIV-1, a transmembrane protein and downstream target of STAT3, is highly expressed in breast cancer cells. It is associated with lymph node involvement and metastatic progression. SGN-LIV1A is an anti-LIV-1 antibody conjugated via a protease-cleavable linker to monomethyl auristatin E (MMAE). Upon binding to cell-surface LIV-1, SGN-LIV1A is internalized and releases MMAE, which disrupts microtubulin and induces apoptosis. Methods This ongoing, phase 1 study evaluates safety, tolerability, pharmacokinetics, and antitumor activity of SGN-LIV1A (q3wks IV) in women with LIV-1-positive, unresectable, locally advanced or metastatic breast cancer (LA/MBC) (NCT01969643). Patients (pts) with measurable disease and ≥2 prior cytotoxic regimens for LA/MBC are eligible. Pts with ≥ Grade 2 neuropathy are excluded. Response is assessed per RECIST v1.1; pts with stable disease (SD) or better can continue treatment until disease progression or intolerable toxicity. At completion of dose escalation in hormone receptor-positive/HER2-negative (HR+/HER2–) and triple-negative (TN) pts, expansion cohorts were opened to further evaluate safety and antitumor activity of monotherapy in TN pts. Tumor biopsies are evaluated for LIV-1 expression. Results To date, 69 pts (18 HR+/HER2–, 51 TN) have received a median of 3 cycles (range, 1–12) of SGN-LIV1A at doses of 0.5–2.8 mg/kg. Median age was 56 yrs. Pts had a median of 3 prior cytotoxic regimens for LA/MBC; 58 had visceral disease and 37 had bone metastases. No dose-limiting toxicities (DLTs) occurred in 19 DLT-evaluable pts; maximum tolerated dose was not exceeded at 2.8 mg/kg. Expansion cohorts of TN pts were opened at 2.0 and 2.5 mg/kg. Treatment-emergent adverse events (AEs) reported in ≥25% of pts were fatigue (59%), nausea (51%), peripheral neuropathy (44%), alopecia (36%), decreased appetite (33%), constipation (30%), abdominal pain, diarrhea, and neutropenia (25% each). Most AEs were Grade 1/2; AEs ≥ Grade 3 included neutropenia (25%) and anemia (15%). Febrile neutropenia occurred in 2 pts whose total dose exceeded 200 mg per cycle, including 1 treatment-related death due to sepsis. No other treatment-related deaths occurred on-study. Seven pts discontinued treatment due to AEs. In dose escalation, activity was observed in 17 efficacy evaluable (EE) HR+/HER2- pts, with a disease control rate (DCR= CR+PR+SD) of 59% (10 SD), including 1 pt with SD ≥24 wks. Among the 44 EE TN pts (dose escalation plus expansion cohorts), the objective response rate (ORR) was 32% (14 PR) with a confirmed PR rate of 21%, DCR was 64% (14 PR, 14 SD), and clinical benefit rate (CBR=CR+PR+SD ≥24 wks) was 36% (16 pts). For TN pts, median PFS was 11.3 wks (95% CI: 6.1, 17.1); 10 pts remain on treatment. Of 631 MBC tumor samples of all clinical subtypes evaluated for LIV-1, 91% were positive; 75% had moderate-to-high expression (H-score ≥100). Conclusions LIV-1 is expressed in almost all MBC tumors. SGN-LIV1A monotherapy was generally well tolerated and showed encouraging antitumor activity in heavily pretreated TN MBC, with a PR rate of 32%, confirmed PR rate of 21%, and CBR (≥24 wks) of 36%. Response duration data continue to evolve. Enrollment continues in the TN monotherapy expansion cohort. Citation Format: Modi S, Pusztai L, Forero A, Mita M, Miller KD, Weise A, Krop I, Burris III H, Kalinsky K, Tsai M, Liu MC, Hurvitz SA, Wilks S, Ademuyiwa F, Diab S, Han HS, Kato G, Nanda R, O'Shaughnessy J, Kostic A, Li M, Specht J. Phase 1 study of the antibody-drug conjugate SGN-LIV1A in patients with heavily pretreated triple-negative metastatic breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD3-14.

Abstract Estrogen receptor positive (ER+) breast cancer is treated with endocrine therapy but intrinsic resistance occurs in ˜1/3 of patients and acquired resistance in ˜1/5 of the remainder. While many resistance mechanisms have been explored, clinical trials testing associated therapeutics have had mixed outcomes. Understanding mechanisms of resistance and finding therapeutic strategies to target them, therefore, remain important challenges. In this study we discover an intriguing link between mismatch repair (MMR) deficiency, specifically of the MutL complex (MLH1/3, PMS1/2), and endocrine therapy resistance in ER+ disease. We find a direct role for MutL loss in inducing endocrine therapy resistance in vitro and in vivo by knocking down multiple MutL genes using CRISPR and stable shRNA approaches validated using standard rescue experiments. We identify the underlying mechanism: MutL deficiency in ER+ breast cancer abrogates Chk2-mediated feedback inhibition of CDK4/6 that appears necessary for endocrine therapy responsiveness. Consequently, pharmacological targeting of CDK4/6 in vitro and in vivo significantly inhibits growth of endocrine therapy resistant MutL-deficient ER+ breast cancer cells. These results are corroborated by data from a neoadjuvant clinical trial demonstrating that cell cycle regulation of MutL-mutant tumors is estrogen-independent but CDK4/6 dependent. The results of this study provide important biological and clinically relevant insights. 1) a novel role for MMR in endocrine therapy resistance 2) A mechanism underlying the effectiveness of CDK4/6 inhibitors in some de novo endocrine therapy resistant tumors. While there are currently no biomarkers to guide the use of CDK4/6 inhibitors for ER+ breast cancer, markers of MMR dysregulation could identify patients in whom CDK4/6 inhibition may, most effectively, prevent disease recurrence. Citation Format: Haricharan S, Punturi N, Singh P, Holloway KR, Anurag M, Schmelz J, Schmidt C, Lei JT, Suman V, Hunt K, Olson Jr JA, Hoog J, Li S, Huang S, Edwards DP, Kavuri SM, Bainbridge MN, Ma CX, Ellis MJ. Loss of mismatch repair predicts resistance to endocrine therapy and sensitivity to CDK4/6 inhibitors in ER+ breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-04-01.

Abstract Stereotactic Radiosurgery ( SRS ) is considered standard of care for patients with 1–3 brain metastases ( BM ). Recent observational studies have shown equivalent OS in patients with 5+ BM compared to those with 2–4, suggesting SRS alone may be appropriate in these patients. We aim to review outcomes of patients treated with SRS with 2–4 versus 5+ BM . This analysis included consecutive patients from 1994 to 2015 treated with SRS . Of 1017 patients, we excluded patients with a single BM and patients without adequate survival data, resulting in 391 patients. All risk factors were entered into univariate analysis using Cox proportional hazards model, and significant factors were entered into multivariate analysis ( MVA ). We additionally analyzed outcomes after excluding patients with prior surgery or whole‐brain radiotherapy ( WBRT ). Median follow‐up was 7.1 months. Median KPS was 90, mean age was 59, and most common histologies were melanoma and lung. Median tumor volume was 3.41 cc. Patients with 2–4 BM had a median OS of 8.1 months compared to 6.2 months for those with 5+ BM ( P = 0.0136). On MVA , tumor volume, KPS , and histology remained significant for OS , whereas lesion number did not. Similar results were found when excluding patients with prior surgery or WBRT . Rather than lesion number, the strongest prognostic factors for patients undergoing SRS were tumor volume >10 cc, KPS , and histology. BM number may therefore not be the most important criterion for candidacy for SRS . Patients with 5 or more BM should be considered for SRS .

Objective: The purpose of this study was to evaluate injury characteristics by position groups. Design: Prospective, observational study. Setting: A single, major Division I collegiate football program. Participants: All players on a collegiate football program each fall regular season. Independent Variables: Exposure to Division I collegiate football and position groups. Main Outcome Measures: Injury rates (IRs) per 1000 athlete exposures (AEs) and injury rate ratios (IRRs) were calculated and analyzed for all monitored injury variables, which included time in the season, body part, type of injury, game and practice injuries, mechanism of injury, and type of exposure. Results: During the 2012 to 2016 fall regular seasons, there were 200 reported injuries sustained from 48 615 AE. The overall 5-year IR was 4.11 per 1000 AEs (3.57-4.72 95% confidence intervals). Skill players sustained the highest IR in the preseason (IR, 7.56) compared with line (IR, 4.26) and other (IR, 4.10) position groups. In addition, skill players demonstrated a significantly higher IRR compared with the line (IRR, 1.75, P < 0.05) and other (IRR, 1.85, P < 0.05) position groups. Conclusions: Skill players sustained most of their injuries in the preseason, whereas the linemen and other position groups suffered most of their injuries in the first half of the regular season. Skill players demonstrated a significantly higher IR in preseason, noncontact mechanism injuries, and injuries to the upper leg and thigh compared with line and other position groups. Efforts to reduce soft-tissue muscle strains in skill players targeting the preseason may provide one of the best opportunities to significantly decrease current football IRs, whereas efforts to reduce contact exposures may have the greatest effect on concussions and contact mechanism injuries for the other position group. There were no significant differences in IRs between position groups and type of exposure.

ObjectiveCurrently, there are no reliable biomarkers for predicting therapeutic response in patients with rheumatoid arthritis (RA). The synovium may unlock critical information for determining efficacy, since a reduction in the numbers of sublining synovial macrophages remains the most reproducible biomarker. Thus, a clinically actionable method for the collection of synovial tissue, which can be analyzed using high‐throughput strategies, must become a reality. This study was undertaken to assess the feasibility of utilizing synovial biopsies as a precision medicine‐based approach for patients with RA.MethodsRheumatologists at 6 US academic sites were trained in minimally invasive ultrasound‐guided synovial tissue biopsy. Biopsy specimens obtained from patients with RA and synovial tissue from patients with osteoarthritis (OA) were subjected to histologic analysis, fluorescence‐activated cell sorting, and RNA sequencing (RNA‐seq). An optimized protocol for digesting synovial tissue was developed to generate high‐quality RNA‐seq libraries from isolated macrophage populations. Associations were determined between macrophage transcriptional profiles and clinical parameters in RA patients.ResultsPatients with RA reported minimal adverse effects in response to synovial biopsy. Comparable RNA quality was observed from synovial tissue and isolated macrophages between patients with RA and patients with OA. Whole tissue samples from patients with RA demonstrated a high degree of transcriptional heterogeneity. In contrast, the transcriptional profile of isolated RA synovial macrophages highlighted different subpopulations of patients and identified 6 novel transcriptional modules that were associated with disease activity and therapy.ConclusionPerformance of synovial tissue biopsies by rheumatologists in the US is feasible and generates high‐quality samples for research. Through the use of cutting‐edge technologies to analyze synovial biopsy specimens in conjunction with corresponding clinical information, a precision medicine–based approach for patients with RA is attainable.

Abstract Purpose: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive ovarian cancer in young women that is universally driven by loss of the SWI/SNF ATPase subunits SMARCA4 and SMARCA2. A great need exists for effective targeted therapies for SCCOHT. Experimental Design: To identify underlying therapeutic vulnerabilities in SCCOHT, we conducted high-throughput siRNA and drug screens. Complementary proteomics approaches profiled kinases inhibited by ponatinib. Ponatinib was tested for efficacy in two patient-derived xenograft (PDX) models and one cell-line xenograft model of SCCOHT. Results: The receptor tyrosine kinase (RTK) family was enriched in siRNA screen hits, with FGFRs and PDGFRs being overlapping hits between drug and siRNA screens. Of multiple potent drug classes in SCCOHT cell lines, RTK inhibitors were only one of two classes with selectivity in SCCOHT relative to three SWI/SNF wild-type ovarian cancer cell lines. We further identified ponatinib as the most effective clinically approved RTK inhibitor. Reexpression of SMARCA4 was shown to confer a 1.7-fold increase in resistance to ponatinib. Subsequent proteomic assessment of ponatinib target modulation in SCCOHT cell models confirmed inhibition of nine known ponatinib target kinases alongside 77 noncanonical ponatinib targets in SCCOHT. Finally, ponatinib delayed tumor doubling time 4-fold in SCCOHT-1 xenografts while reducing final tumor volumes in SCCOHT PDX models by 58.6% and 42.5%. Conclusions: Ponatinib is an effective agent for SMARCA4-mutant SCCOHT in both in vitro and in vivo preclinical models through its inhibition of multiple kinases. Clinical investigation of this FDA-approved oncology drug in SCCOHT is warranted. Clin Cancer Res; 24(8); 1932–43. ©2018 AACR.

Clinical history, questionnaire data and response to antisecretory therapy are insufficient to make a conclusive diagnosis of GERD in isolation, but are of value in determining need for further investigation. Conclusive evidence for reflux on oesophageal testing include advanced grade erosive oesophagitis (LA grades C and D), long-segment Barrett’s mucosa or peptic strictures on endoscopy or distal oesophageal acid exposure time (AET) >6% on ambulatory pH or pH-impedance monitoring. A normal endoscopy does not exclude GERD, but provides supportive evidence refuting GERD in conjunction with distal AET <4% and <40 reflux episodes on pH-impedance monitoring off proton pump inhibitors. Reflux-symptom association on ambulatory reflux monitoring provides supportive evidence for reflux triggered symptoms, and may predict a better treatment outcome when present. When endoscopy and pH or pH-impedance monitoring are inconclusive, adjunctive evidence from biopsy findings (histopathology scores, dilated intercellular spaces), motor evaluation (hypotensive lower oesophageal sphincter, hiatus hernia and oesophageal body hypomotility on high-resolution manometry) and novel impedance metrics (baseline impedance, postreflux swallow-induced peristaltic wave index) can add confidence for a GERD diagnosis; however, diagnosis cannot be based on these findings alone. An assessment of anatomy, motor function, reflux burden and symptomatic phenotype will therefore help direct management. Future GERD management strategies should focus on defining individual patient phenotypes based on the level of refluxate exposure, mechanism of reflux, efficacy of clearance, underlying anatomy of the oesophagogastric junction and psychometrics defining symptomatic presentations.