bluuebunny/crossref_metadata_2025 huggingface dataset:
Circulating tumor cells (CTCs) with small-cell like pathology are prevalent in metastatic castration-resistant prostate cancer (mCRPC) and show selective pharmacodynamic reductions in patients treated with platinum but not ARSI or taxane.
Authors: Scher Howard I. , Jendrisak Adam , Gill Audrey , Barnett Ethan , Gopalan Anuradha , Zaidi Samir , Benoliel Hannah , Carbone Emily , Byun Jiyun , Schonhoft Joseph , Wenstrup Rick
Published: May 2020

5572

Background: The increasing availability and earlier use of life prolonging drugs targeting the androgen receptor signaling axis (ARSI) has resulted in an increase in the frequency of late state tumors with “small cell/neuroendocrine (NESC) phenotypes” similar to small-cell lung cancer (SCLC). Definitive pathologic criteria to diagnose the “entity” are lacking, and the eligibility criteria across trials are inconsistent, limiting the ability to relate outcomes between studies. We hypothesized that an analytically valid assay for a rigorously defined “small-cell CTC” phenotype might serve as a unifying biomarker for the presence of NESC-like tumors in an individual for use in clinical trials. Methods: Using the WHO guidelines for small-cell diagnosis in tissue as reference, we defined an equivalent set of single-cell CTC criteria for defining a CTC with small-cell histology: a small and circular CD45-, CK+ cell with high N/C ratio lacking detectable nucleoli. Small-cell subtype pharmacodynamic changes were studied in 233 patients with progressing mCRPC about to start an AR signaling inhibitor ARSi (N=111), taxane (N=89), or platinum (N=33). Results: CTCs with small-cell morphology had lower AR protein expression compared with non-small-cell CTCs (P<0.0001) and increased with therapy line. The small-cell CTC subtype decreased in number from baseline to on-therapy in patients treated with platinum but not in those treated with ARSi or taxane (Table). Conclusions: Digital pathology analysis of CTCs defined a CTC subtype consistent with that of small-cell carcinoma that were only reduced in number with platinum-based therapy. The tracking of CTC subtypes after treatment with different drug classes may help assess drug activity in heavily treated patients that often have heterogeneous disease that of which may not be captured using standard measures of response. [Table: see text]
Clinical outcomes and markers of treatment response in a randomized phase II study of androgen deprivation therapy with or without palbociclib in RB-intact metastatic hormone-sensitive prostate cancer (mHSPC).
Authors: Palmbos Phillip Lee , Tomlins Scott A. , Daignault Stephanie , Agarwal Neeraj , Twardowski Przemyslaw , Morgans Alicia K. , Kelly William Kevin , Arora Vivek , Antonarakis Emmanuel S. , Siddiqui Javed , Robinson Dan , Knudsen Karen E. , Chinnaiyan Arul , Hussain Maha H. A.
Published: May 2020

5573

Background: Targeted therapies based on tumor molecular markers are not currently used in mHSPC. Palbociclib, a CDK4/6 inhibitor, blocked proliferation and promoted G1 arrest in a Rb-and Cyclin D-dependent manner in preclinical models of HSPC. We hypothesized that co-targeting AR (ADT) and cell cycle (palbociclib) would improve outcomes in mHSPC pts. Methods: mHSPC pts with Rb intact tumors based on IHC of metastatic tumor biopsy were stratified and randomized (1:2) to Arm A: ADT or Arm B: ADT+ palbociclib (125mg 3 weeks on, 1 week off). Primary endpoint was confirmed PSA RR (≤ 4 ng/mL) after 28 weeks of therapy. Secondary endpoints included safety/tolerability, PFS, PSA and radiographic RR. Metastatic biopsy and primary tumors were subjected to whole exome and transcriptomic sequencing where available. CTC’s were enumerated at various time points. Results: 72 eligible pts (median age 67 years, PSA 73ng/mL) with newly diagnosed mHSPC were registered and underwent biopsy. 97% retained RB expression (IHC). 62 pts were stratified by disease extent and early initiation of ADT, and randomized. 60 pts initiated therapy (Arm A: 20; Arm B: 40). Adverse events were reported previously. 80% of pts (Arm A: 16/20, Arm B: 32/40; p = 0.87) on both arms met primary PSA endpoint (≤4ng/mL at 28 weeks). PSA undetectable rate at 28 weeks was Arm A: 50% (10/20) and Arm B: 43% (17/40; p = 0.5). Measurable disease RR: Arm A: 89% and Arm B: 89%. 12-month biochemical PFS was Arm A 69% (95%CI: 44-85%), Arm B 74% (95%CI: 57-85%). 41 patients on trial underwent sequencing of metastatic biopsy and 10 patients had matched primary prostate tumor sequencing results. CCND1 amp, 8q gain, PTEN and KMT2C mutations were each observed in metastatic, but not paired prostate primary tumors. TP53, PIK3 pathway (PIK3CA, AKT1, PTEN) mutations and 8q gains were associated with reduced PSA PFS [HR (95%CI): 3.0 (1.2-7.2), p = 0.018; 3.2(1.03-10),p = 0.044; 4.96 (1.8-12), p = 0.001, respectively]. Pretreatment CTCs were associated with lower PSA CR (p = 0.04) and shorter PFS (12-month PFS: 58% vs. 86%, p = 0.031). Conclusions: A tissue based biomarker preselected trial is feasible in mHSPC. ADT + palbociclib did not impact outcomes. Pretreatment CTC counts, TP53 and PIK3 pathway mutations, and 8q gain may offer prognostic value in mHSPC. Support: Movember-PCF Challenge Award, Pfizer. Clinical trial information: NCT02059213 .
A blood-based multi-mRNA liquid biopsy with >90% accuracy for diagnosis and assessment of prostate cancers.
Authors: Rahbar Kambiz , Kidd Mark S. , Drozdov Ignat A. , Kitz Alexandra , Malczewska Anna , Rajwa Pawel , Boegemann Martin , Bernemann Christof , Bodei Lisa , Modlin Irvin Mark
Published: May 2020

5574

Background: There are a paucity of blood-based biomarkers with clinical utility for prostate cancer (PCa). We developed a circulating mRNA (27-gene) prostate cancer signature to diagnose and manage PCa. Methods: Gene identification: Publicly available PCa transcriptome sets ( n= 1,159 samples) were evaluated and compared with normal blood-based transcriptomes using gene co-expression network enrichment, differential expression and functional enrichment analyses to identify candidate markers. Gene expression evaluation: Seven PCA cell lines and two normal prostate epithelial lines were used to assess candidate genes. Marker genes were determined in PCa tumor tissue ( n= 50) and validated in the TCGA-PRAD ( n= 500) dataset. Blood gene expression: Set #I: PCA: n= 132, BPH: n= 44, controls n= 55. Set #II: n= 50 (biochemical recurrence [BCR]). We constructed an artificial intelligence PCa model using classification algorithm analyses. Scoring: normalized algorithmically analyzed gene expression (0 to 100), positive score >20. PSA: BPH ( n= 44) and PCa ( n= 132). Clinical score assessment: Surgical cohort: ( n= 47), samples: pre-surgical and post: 1 week - 14 months. Statistics: Kruskal-Wallis, Pearson-correlation, Fisher’s and AUROC analyses (Mean±SEM). Results: Transcriptomic analysis identified 27 candidates. Cell lines/tissue: Expression levels were significantly elevated ( p< 0.001, 2.1-35.8-fold) in cell lines and PCa surgical samples. All 27 markers were confirmed in TCGA-PRAD samples (average TPM: 58 to 10,366). Blood: In Set#I, levels in PCa were 47±2 ( p< 0.0001) compared to BPH (19±1) and controls (18±0.5); AUROC: 0.92 (BPH) and 0.94 (controls), with an accuracy of 85-88%, a sensitivity of 86% and specificities 82 and 93%. For PSA, the AUROC (PCa vs. BPH) was 0.51 ( p= 0.88). PSA was positive in 86% of BPH and was > 10ng/ml in 30%. PSA was positive in 83% of PCa and > 10ng/ml in 40% (Fisher’s p= 0.28). PSA accuracy ( > 10ng/ml) was 48%. Levels in Set#II (BCR) were 44±3. ProstaTest-was positive in 48 (96%). Surgical cohort ( n= 47): Prostatest accuracy 100% pre-surgery. Resection decreased levels (KW-statistic: 57.4, p< 0.0001) from 52±1 to 23.5±2. Conclusions: A 27-gene blood signature was developed for PCa that exhibited a diagnostic accuracy of 92%; significantly better than PSA (48%, p< 0.0001). Surgical resection significantly ( p< 0.0001) decreased levels. Biochemical recurrence was accurately detected (96%). A multi-gene prostate cancer liquid biopsy is likely to have clinical utility in both diagnosis and monitoring of PCa.
Osteonecrosis of the jaw (ONJ) in radium 223 (Ra223)-treated metastatic castration-resistant prostate cancer (mCRPC) patients (pts) with exposure to zoledronic acid and/or denosumab.
Authors: Cao Yen Thi Kim Hong , Trieu Janson , Rojas Vanessa , Elias Michael , Anderson Michael J. , Vogelzang Nicholas J.
Published: May 2020

5575

Background: Bone health agents (BHA) including denosumab, a monoclonal antibody, and Zoledronic acid (ZA), a bisphosphonate, are recommended for men with CRPC and bone metastases to prevent skeletal-related complications. ONJ occurs in about 5% of patients (pts) on BHA. The incidence of ONJ in pts treated with Ra223 and BHA remains unknown, particularly in those who receive sequential treatment of BHAs. Here we describe the rate of ONJ in a real-world setting in mCRPC pts treated with Ra223 in 3 groups: 1) denosumab alone, 2) ZA alone, and 3) sequential ZA /denosumab or vice versa. Methods: A retrospective analysis of a cohort of mCRPC pts with bone metastases who received Ra223. Follow-up was until date of death or last data entry. Chart inclusion criteria included patients who received Ra223 between November 2010 to August 2018 with documentations of data points. Results: A total of 177 pts received Ra223 between 11/2010 and 8/2018. Median age 73 at 1st Ra223 (range 40-93); Median PSA 15.8- at 1st Ra223 (range 0.1-1952); Demographics-AA-10, C-130, Asian-9, unspecified-28; Median Alk Phos 95 at 1st Ra233 (range 25-1515). 93 % (164/177) received BHA. Of the 164 who received BHA, 45% (73/164) received denosumab only, 37% (61/164) received ZA only, and 18% (30/164) received sequential treatment. ONJ developed in 9.7% (16/164) of all patients on BHA. Denosumab alone caused ONJ in 7 of 73 pts (9.6%). ZA alone caused ONJ in 6 of 61 pts (9.8%). ONJ occurred in 3 of 30 pts (10%) in the sequential group. The median number of doses of BHA before development of ONJ was 10 with denosumab, 20 with ZA, and 19.5 (denosumab) and 22 (ZA) in the sequential group. Conclusions: In patients treated with Ra223 and a BHA, the rate of ONJ is 9.7%. The rate of ONJ was similar in groups treated with denosumab alone, ZA alone, and sequential treatment of ZA and denosumab However, ONJ developed more quickly in patients on denosumab. We conclude that the risk of ONJ is increased in patients treated with Ra223 and BHA. ZA or sequential therapy appears to delay time to onset of ONJ compared to denosumab. Clinicians should be mindful of the toxic synergy between Ra223 and BHA. ZA may be the preferred BHA partner with Ra223.
Radiographic paradoxical response in patients with metastatic castrate-resistant prostate cancer (mCRPC) undergoing treatment with second-generation hormone therapy (second-HT).
Authors: Alamiri Jamal , Ahmed Mohamed E. , Andrews Jack R. , Dundar Ayca , Motterle Giovanni , Karnes Jeffrey , Kwon Eugene D. , Bryce Alan Haruo , Kendi Ayse T. , Bold Michael S.
Published: May 2020

5577

Background: Prostate specific antigen (PSA) has well-recognized limitations as a marker for treatment response and disease progression. A post hoc analysis of the PREVAIL trial reported 24.5% of chemotherapy naïve mCRPC patients on enzalutamide had radiographic progression on conventional imaging with non-rising PSA. In this study, we sought to retrospectively compare PSA levels with C-11 choline positron emission tomography/ computed tomography (PET/CT) images in patients with m-CRPC on 2nd-HT with prior use of chemotherapy. Methods: We identified 123 patients with mCRPC on 2nd-HT following prior use of docetaxel chemotherapy (Abiraterone, n = 106; Enzalutamide, n = 17). Patients underwent serial PSA testing and C-11 choline PET/ CTs every 3–6 months. Disease progression was defined by the increase in blood pool corrected maximum standardized uptake value (SUVmax) of the index lesion on C-11 choline PET/CT scan. Suspicious lesions were confirmed by biopsy and/or conventional imaging. Results: Approximately 43% (n = 53) of patients had radiographic disease progression while on 2nd-HT. At time of radiographic progression, 60.4% of patients showed a parallel rise in PSA (Group-A), while 39.6% showed a paradoxical response; defined as radiographic progression with stable or down-trending PSA (Group-B). Median PSA at time of progression was 3.1 ng/ml for Group-A, and 1.3 ng/ml for Group-B (p-value = 0.0176). Median SUVmax was the same (4.9 Group-A, 4.6 Group-B; p-value = 0.6072). Bone-predominance progression was more significant in Group-B (90%) versus Group-A (65%) (p-value = 0.0309). The median time for radiographic progression was 9.5 months versus 3.9 months for Group-A and Group-B, respectively (Log-Rank = 0.0063). Conclusions: Metabolic imaging is a useful tool that should complement PSA in the evaluation of treatment response and disease progression in mCRPC patients on 2nd-HT, especially considering the paradoxical response observed in our data.
Treatment patterns and outcomes of patients with penile squamous-cell carcinoma (PSCC) undergoing inguinal lymph node dissection (ILND): An analysis of a multicenter contemporary database.
Authors: Bandini Marco , Zhu Yao , Ye Dingwei , Ornellas Antonio Augusto , Watkin Nick , Ager Michael , Hakenberg Oliver W. , Heidenreich Axel , Raggi Daniele , Haidl Friederike , Marandino Laura , Pederzoli Filippo , Briganti Alberto , Montorsi Francesco , Chipollini Juan , Azizi Mounsif , Albersen Maarten , Spiess Philippe E. , Necchi Andrea
Published: May 2020

5585

Background: PSCC is a rare tumor and the administration of guidelines-based therapies is still problematic in real-world practice. Survival outcomes remain suboptimal in patients (pts) with ILN involvement. Multinational analyses of real-world patterns are needed. Methods: Within an international, multicenter database of 965 PSCC pts who received ILND from 1980-2019, 630 had complete information for the variables of interest, from USA (N=81), Europe (EU, N=355), South America (SA, N=90), and China (Ch, N=104). Descriptive analyses according to geographical and ethnicity/race distribution were made. Comparisons of outcomes were made with Kaplan-Meier analyses and corresponding logrank tests. Results: Median age at diagnosis was 59 yrs, with no differences worldwide and according to ethnicity/race. Pts from SA presented with more advanced cT-stage (cT3-4: 26.7% vs. 17.3% USA vs. 7.6% EU) while EU pts presented with more advanced cN-stage (cN3: 14.9% vs. 11% USA vs. 7.8% SA vs. 5.8% Ch) as well as pathological (p)N-stage: pN3 pts were 53% in EU, 33.3% in USA, 20% in SA, and 18.3% in Ch. Perioperative chemotherapy (pCT) was more frequently administered in EU (53.8%) vs. USA (34.6%) SA (5.6%) Ch (7.7%). cT-stage was more frequently advanced in black pts (cT3-4: 33.3% vs. 12% Caucasian, 6.2% Hispanic/latino, 0% Asian) and the same was for cN-stage (cN3: 25% in black, 13% in Caucasian, 6.2% in Hispanic/latino, 6% in Asian). Conversely, pN3 pts were more frequently Caucasian (45.6%) vs. black (25%), Hispanic/latino (19%), and Asian (18%). pCT was more frequently administered in Caucasian pts (45%) vs. black (8.3%), Hispanic/latino (0), and Asian (8%). No significant differences in overall survival (OS) were observed according to geographical region or ethnicity/race, in the total pts and in the subgroups according to cT, cN, pN-stages and pCT. Median OS after pCT and ILND was 95 months. Bilateral ILN involvement was equally observed regardless of geographical region and ethnicity/race. In the total population, pCT significantly prolonged OS in pts with bilateral ILN (p=0.04), but not in pts with pelvic LN. Conclusions: Treatment patterns for PSCC undergoing ILND remain heterogeneous worldwide, and adherence to guidelines is seemingly poor. However, long-term outcomes with pCT remain uniformly suboptimal with <50% pts alive at 10 yrs. Further collaborative efforts are needed in this orphan disease to harmonize the therapeutic paradigm.
Clinical utility of 18F-FDG-PET/CT in staging localized breast cancer prior to initiating preoperative systemic therapy.
Authors: Ko Heidi , Baghdadi Yaser , Love Charito , Sparano Joseph A.
Published: May 2020

563

Background: 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET/CT) is recommended as an optional study in current National Comprehensive Cancer Network (NCCN) guidelines after computerized tomography and bone scan (CTBS) in patients with stage IIA-IIIC breast cancer. We evaluated our experience with use of PET/CT in this setting prior to beginning primary systemic therapy (PST) before planned surgery. Methods: We performed medical record abstractions to identify all adult female patients with clinical stage IIA to IIIC breast cancer diagnosed at Montefiore Medical Center from January 1, 2014 to January 1, 2019 who underwent PET/CT. We calculated the proportion of patients upstaged after PET/CT, stratified by their initial clinical stages and use of PST, and examined the cost and radiation exposure associated with PET/CT compared with CTBS. Results: 227 patients with 230 breast cancers (bilateral disease in 3) met the study inclusion criteria. PET/CT was the only staging done in 195 patients (86%); 32 patients had PET/CT based on suspicious findings from prior CTBS. Among these 195 patients with 196 breast cancers (bilateral disease in 1) that had PET/CT as the only staging done, the overall upstaging rate for regional nodal and/or distant metastasis was 37% (73/196), including 24% for stage IIA (9/38), 39% for IIB (31/79), 54% for IIIA (22/41), 27% for IIIB (8/30), and 37% for IIIC (3/8). The overall upstaging rate to stage IV was 14% (27/196), including 0% for stage IIA, 13% for IIB (10/79), 22% for IIIA (9/41), 17% for IIIB (5/30), and 37% for IIIC (3/8). The sensitivity and specificity of PET/CT in detecting distant metastasis was 100% and 94%, respectively. Our institution's total Medicare reimbursement rate of PET/CT is $1604.37 whereas CTBS is $1679.94. Radiation dose for PET/CT is 14 mSv whereas CTBS is 21 mSv. Conclusions: Approximately 37% of patients with clinical stage IIA-IIIC breast cancer who underwent PET/CT prior to PST showed more extensive disease, including 23% with more extensive regional nodal metastases and 14% with distant metastasis. Given the high detection rate, comparable cost, lower radiation dose and greater convenience, PET/CT should be considered as an alternative to CTBS rather than “optional” after CTBS, especially in patients who require an efficient and expeditious work up prior to initiating PST.
Artificial intelligence to accurately identify breast cancer patients with a pathologic complete response for omission of surgery after neoadjuvant systemic therapy: An international multicenter analysis.
Authors: Pfob André , Sidey-Gibbons Chris , Tasoulis Marios Konstantinos , Lee Han-Byoel , Koelbel Vivian , Kuerer Henry Mark , Heil Joerg
Published: May 2020

565

Background: Neoadjuvant systemic treatment elicits a pathologic complete response (pCR) in up to 80% of women with breast cancer. In such cases, breast surgery, the gold standard for confirming pCR in the breast, may be considered overtreatment. So far, no approach alone – e.g. imaging, vacuum-assisted biopsy (VAB) – has accurately detected and excluded residual disease without surgery in multicenter prospective trials. We evaluated the ability of Artificial Intelligence algorithms to securely identify patients with residual tumor in the breast to safely select patients who might be spared from surgery. Methods: We collected multicenter, international data from 570 women who were included in prospective trials with initial stage I-III breast cancer of all biological subtypes and at least partial response on imaging, undergoing VAB before guideline-adherent surgery. We trained an ensemble of algorithms (including Regularized Regression, Support Vector Machines, and Neural Network) using 27 patient, tumor and VAB variables. Data were randomly partitioned into training and test sample with a 3:1 ratio and developed with 10-fold cross-validation. Primary endpoint was the sensitivity to diagnose residual disease by algorithm compared to surgery. Diagnostic performance of the algorithm was further evaluated on an external, independent dataset. Results: The algorithm was able to reliably identify women with residual disease before surgery (see table): Sensitivity for the internal test set was 96.9% (94 of 97; 95%CI 91.2-99.4%) and for the external, independent dataset 96.2% (26 of 27; 95%CI 80.4-99.9%). Most informative predictor of residual disease were tumor cells diagnosed in the VAB specimen, DCIS in the initial diagnostic biopsy, grading, and largest diameter on imaging after neoadjuvant treatment. Conclusions: Safely selected patients without residual disease as assessed by our algorithm may be spared by breast surgery in future trials. [Table: see text]
Impact of axillary lymph node dissection (ALND) on survival in patients with ypN1 breast cancer that receive regional nodal irradiation (RNI): A national cancer database (NCDB) analysis.
Authors: Kharouta Michael , Damico Nicholas , Harris Eleanor Elizabeth , Lyons Janice A.
Published: May 2020

572

Background: The innovation of sentinel lymph node biopsy (SLNB) has allowed many patients with invasive breast cancer to forego ALND. However, the benefit of ALND is unclear in patients with pathologic N1 disease detected on SLNB following neoadjuvant chemotherapy, particularly in patients who receive adjuvant regional nodal irradiation. Methods: The National Cancer Database (NCDB) was queried for women ages 18-75 with cT1-3N1, and ypT0-T3N1M0 invasive breast cancer who underwent definitive surgical resection with axillary staging and also received adjuvant RNI. Patients treated from 2012 – 2015 were included to allow for appropriate coding of extent of axillary surgery. Overall survival (OS) was estimated using the Kaplan-Meier method and compared between patients who received SLNB alone and ALND with or without SLNB utilizing log rank testing. Propensity matching was performed to reduce the impact of potential confounders and balance sample bias. Cox proportional hazards regression was used to identify predictors of overall survival. Results: A total of 1411 women were identified who met inclusion criteria. The median age was 52 (23-75) years. 206 (15%) women had SLNB alone and 1205 (85%) had ALND with or without SLNB. Five year OS was 73% in patients who underwent ALND compared to 76% in those who had SLNB alone (p =0.39). Following propensity matching by age, race, Charlson Deyo Comorbid Condition score, pT stage, grade, ER status, and HER2 status, 5 year OS was 79% in patients who underwent SLNB alone vs. 69% in patients who had ALND performed (p = 0.33). On Cox regression analysis, none of the variables predicted for 5 year OS. Conclusions: ALND in addition to RNI did not improve survival in patients with cT1-3N1M0 and ypT0-3N1M0 breast cancer compared to SLNB and RNI. We await results of the Alliance 011202 randomized trial for prospective validation of ALND omission in a similar subset of patients. [Table: see text]
Inhibiting fatty acid synthase in operable triple negative breast cancer.
Authors: Sardesai Sagar D. , Thomas Alexandra , Gallagher Christopher , Lynce Filipa , Ottaviano Yvonne Lynn , Ballinger Tarah Jean , Schneider Bryan P. , Storniolo Anna Maria , Bauchle Amber , Althouse Sandra K. , Perkins Susan , Zhang Jian-Ting , Miller Kathy
Published: May 2020

584

Background: Fatty acid synthase (FASN) is overexpressed in 70% of newly diagnosed triple negative breast cancer (TNBC) and is associated with poor prognosis. In vitro, FASN overexpression induces drug resistance to DNA damaging agents. Proton pump inhibitors (PPI) selectively inhibit FASN activity and induce apoptosis in breast cancer cell lines with minimal effect on non-malignant cells. We report the results of a single arm phase II study of high dose omeprazole (OMP) in combination with anthracycline- taxane (AC-T) based neoadjuvant chemotherapy. Methods: Patients (pts) with operable TNBC independent of baseline FASN expression; and no prior PPI use within 12 months were enrolled. Pts began OMP 80 mg PO BID for 4-7 days prior to AC-T; carboplatin was allowed per physician discretion. OMP was continued until surgery. Paired biopsy samples were obtained before and after OMP monotherapy. The primary endpoint was pathologic complete response (pCR), defined as no residual invasive disease in breast or axilla, in pts with baseline FASN expression (FASN+) assessed using immunohistochemistry. Relevant secondary endpoints included pCR in the intent to treat population, change in FASN expression, enzyme activity and downstream target gene expression after OMP monotherapy; safety and limited OMP pharmacokinetics. We targeted a pCR rate of 60% in FASN+ pts (null pCR ~ 40%) with 80% power and alpha of 0.10. Results: A total of 42 pts were recruited from 5 US sites. Median age was 51y (28-72). Most pts had >cT2 (33, 79%) and ≥N1 (22, 52%) disease. 14 (33%) were African American. FASN expression prior to AC-T was identified in 28 (85%) samples available for analysis. The pCR rate was 71.4% (95% CI 51.3 to 86.8) in FASN+ pts and 71.8 %( 95% CI 55.1 to 85.0) in all enrolled pts. Fifteen pts (36%) received carboplatin with AC-T; pCR in this subset was 73%. Peak OMP concentration was significantly higher than IC50 observed during preclinical testing; FASN positivity significantly decreased with OMP monotherapy from 0.53(SD 0.25) at baseline to 0.38(SD 0.30; p = 0.02). OMP was well tolerated with no known grade (G) 3 or 4 toxicities. Chemotherapy toxicity was similar to prior studies using AC-T with G3 or 4 neutropenia (19%), febrile neutropenia (7%) and peripheral neuropathy (7%) being the most common. Conclusions: Consistent with previous studies, FASN is frequently expressed in early stage TNBC. OMP can be safely administered in doses that inhibit FASN. The addition of high dose OMP to neoadjuvant AC-T yields a promising pCR rate without adding toxicity. Funded by the Breast Cancer Research Foundation. Clinical trial information: NCT02595372 .
Efficacy of neoadjuvant chemotherapy (NAC) in male breast cancer (MaBC) compared with female breast cancer (FBC): A National Cancer Database (NCDB) study.
Authors: Leone Jose Pablo , Freedman Rachel A. , Hassett Michael J. , Leone Julieta , Tolaney Sara M. , Vallejo Carlos Teodoro , Leone Bernardo Amadeo , Winer Eric P. , Lin Nancy U.
Published: May 2020

587

Background: NAC is frequently used in the treatment of FBC. The efficacy of NAC in MaBC is unclear. Few studies have compared outcomes for MaBC and FBC after similar treatment. The aim of this study was to compare proportions of pathologic complete response (pCR) between MaBC and FBC according to tumor subtype (TS). Secondary aims were clinical response and overall survival (OS). Methods: We evaluated men and women with breast cancer treated with NAC between 2010 and 2016 with known hormone receptor (HR) status and human epidermal growth factor receptor 2 (HER2) status at NCDB centers. The proportion with pCR (ypT0/Tis ypN0) was compared for MaBC and FBC for each TS by Fisher’s exact test. Logistic regression evaluated odds of pCR. OS was estimated by Kaplan-Meier and compared by log-rank test. Results: Of 7,721 MaBC and 859,096 FBC patients, 385 MaBC (5%) and 68,065 FBC (7.9%) underwent NAC and were included in this study. Median age for MaBC was 58 years (y) (range 23-88) and for FBC was 53 y (range 18-90). Within each TS, there were no significant differences in the distribution of tumor grade between MaBC and FBC. Clinical stage in MaBC and FBC were: Stage I: 8% v 11%, Stage II: 54% v 59%, Stage III: 38% v 30%; respectively. Median time from initiation of NAC to surgery was 143 days in MaBC and 148 days in FBC. Compared with FBC, MaBC had a lower proportion of complete clinical response (18% v 31%) and a higher proportion of no clinical response (14% v 7%); p < 0.001. Proportions and odds of pCR were numerically lower in MaBC compared with FBC for each TS and statistically significant for HR+/HER2- and HR+/HER2+ (table). pCR was associated with OS in both MaBC and FBC. Specifically, in MaBC who achieved pCR v not, 5 y OS was 90% v 64.7%; p = 0.02. In FBC who achieved pCR v not, 5 y OS was 91.9% v 75.3%; p < 0.01. Among pts receiving NAC, MaBC had worse OS at 5 y than FBC (67.1% v 79.0%; p = 0.02). Conclusions: Men receiving NAC achieved lower proportions of pCR than women and had significantly worse OS. However, pCR is prognostic in both MaBC and FBC. Limitations include small sample sizes for HR-/HER2+ and triple-negative TS and lack of detailed regimen information. Nevertheless, our results suggest that, compared with FBC, MaBC may be intrinsically more resistant to NAC. [Table: see text]
Impact of body composition on toxicity and pathological complete response in locally advanced breast cancer (BC).
Authors: Munoz-Arcos Laura Sofia , Mayer Jessica , Haken Orli , Goldman Jessica , Sparano Joseph A. , Anampa Mesias Jesus Del Santo
Published: May 2020

593

Background: Obesity, defined as body mass index (BMI) > 30 kg/m2, has been associated with inferior outcomes in localized breast cancer (BC), including lower pathological complete response (pCR) to neoadjuvant chemotherapy (NAC). High BMI is usually associated with excess adipose tissue (AT), but also reflects skeletal muscle (SM) mass. Low SM mass (sarcopenia) has also been associated with inferior outcomes and more chemotherapy-associated toxicity. We aimed to evaluate the association of BMI, AT and SM tissue with pCR and toxicity after NAC for stage II-III breast cancer (BC). Methods: 191 patients with stage II-III BC received NAC, had information regarding baseline BMI, toxicity and pCR to NAC at surgery, and, had abdominal computerized tomography (CT) prior to NAC. Total AT (TAT), visceral AT (VAT), subcutaneous AT (SAT), SM area (SMA) and SM density (SMD) were measured by CT at the L3 level using the TOMOVISION software. SM index (SMI) was calculated (SMA/height) to assess for sarcopenia (SMI < 40). Association linking BMI, SAT, VAT, SMA and SMD to pCR and severe toxicity (ST ≥ grade 3) was evaluated using logistic regression models. Results: Patients were predominantly black (51%) with a median age of 54 years (interquartile range = 45-63). pCR was achieved in 31% (60/191) of patients. Of those, 47% (n = 28/60), 40% (n = 24/60) and 13% (n = 8/60) corresponded to HER2(+), triple negative, and hormone receptor-HR(+)/HER2(-) tumors, respectively. ST occurred in 38% (n = 73/191) of patients. Obesity and sarcopenia were present in 52% (n = 100/191) and 14% (n = 27/191) of patients, respectively. There was a statistically significant association between VAT and pCR (median VAT 95.3 cm2 vs. 121.8 cm2 in the pCR vs. no-pCR groups, respectively, p = 0.03). This association remained after adjusting for age, race, tumor grade, stage, BMI, SMD, HR and HER2 status (p = 0.04). There was a statistically significant association between SMA and ST (mean SMA 123 cm2 vs. 130 cm2 in the ST vs. no-ST groups, respectively, p = 0.03). This association disappeared after adjusting for age, race, BMI, VAT, SAT, and SMD (p = 0.21). Conclusions: This study provides evidence that in patients with stage II-III BC receiving NAC, excess VAT is associated with significantly lower pCR rates, and low SMA is associated with ST. Additional research is needed to elucidate the pathophysiologic mechanisms contributing to these associations.
Prediction of response to neoadjuvant hormonal therapy (NAHT) using upfront oncotype Dx recurrence score (RS): Results from the SAFIA phase III trial.
Authors: Al-Saleh Khalid A , Bounedjar Adda , Oukkal Mohammed , Mahfouf Hasen , Bouzid Kamel , Bensalem Assia , Fillali Prof Taha , Larbaoui Blaha , Kandil Alaa , Alfoheidi Meteb , Errihani Hassan , Ghosn Marwan , Abdulaziz Nashwa A , Dabouz Farida , Bahadoor Mohun Ranvir K. , El Zawahry Heba Mohamed , Kullab Sherif A , Nabholtz Jean-Marc A.
Published: May 2020

594

Background: While hormonal therapy (HT) is a fundamental treatment in breast cancer therapy, neoadjuvant NAHT is not considered standard. The SAFIA trial is a prospective international neoadjuvant Phase III investigating the potential role of the addition of palbociclib (P) in patients (pts) sensitive to HT. We report the results of induction Faslodex (+/- zoladex) in pts initially selected by RS < 31, in order to assess their individual HT sensitivity before double-blind randomization HT vs HT + P followed by surgery. Materials and Methods: A total of 308 pts (stages II and IIIA Luminal A/B HER2 negative) in 24 centers and 6 countries (Middle-East/Maghreb) underwent upfront RS to select pts for induction HT. Pts with RS < 31 received induction neoadjuvant fulvestrant (500 mg i.m Day 1, 14, 28 then q.4 weeks) + goseriline (3.6 mg s.c q.4 w for pre and peri-menopausal pts) for 4 months, followed by clinical and radiological assessment of the disease response before randomization. Response was defined as no progression: Complete Response-CR/ Partial Response-PR: > 50% and Minor Response-MR: < 50% to > 0%/ No Response-NR: progression > 0%. Results: A total of 70 pts (22%) with RS > 31 were excluded, leaving 238 eligible pts for NAHT, age (25-84); pre-peri/ post menopause: 135 (57%)/103 (43%); Luminal A/B: 112 (49%)/114 (51%); Stage II/IIIA: 196 (87%) / 29 (13%). One hundred and seventy-seven pts (177) have validated responses to induction NAHT: CR: 9 pts (5%) / MR: 105 pts (59%) for major response rate: 64% / MR: 56 pts (32%) / NR: 7 pts (4%); available RS 0-10: 23 pts (16%) / RS 11-18: 67 pts (47%) / RS 19-25: 34 pts (24%) / RS 26-30: 18 pts (13%). Correlations between Response to NAHT and RS are shown in the table below (not statistically significant). Conclusions: In our population, upfront Oncotype DX RS < 31 allowed to select pts for induction NAHT without loss of chances with a no-progression rate (CR+PR = MR) of 96%. No significant correlation was found between RS and response to NAHT. Upfront RS > 31 (22%) is selecting pts candidates for neoadjuvant chemotherapy with a potential high risk of endocrine resistance. Clinical trial information: ICRG1201 .
A phase II trial of the Wee1 inhibitor adavosertib (AZD1775) in recurrent uterine serous carcinoma.
Authors: Liu Joyce F. , Xiong Niya , Campos Susana M. , Wright Alexi A. , Krasner Carolyn N. , Schumer Susan T. , Horowitz Neil S. , Veneris Jennifer Taylor , Tayob Nabihah , Morrissey Stephanie , West Gabriela , Quinn Roxanne , Matulonis Ursula A. , Konstantinopoulos Panagiotis A.
Published: May 2020

6009

Background: Uterine serous carcinoma (USC) is an aggressive subtype of endometrial carcinoma characterized by TP53 mutations ( > 90%), often concomitantly with oncogenic mutations or amplifications that can increase replication stress. As such, USC may therefore be uniquely sensitive to further interference of cell cycle regulation by Wee1 inhibition. This two-stage single arm Phase 2 study was conducted to assess the activity of the Wee1 inhibitor adavosertib as monotherapy in recurrent USC. Methods: Women with recurrent USC (defined as non-carcinosarcoma uterine cancers with any serous component) were eligible. Patients (pts) were required to have had at least one prior platinum-based chemotherapy regimen; those with known MSI-H/MMRd disease were required to have received prior PD1/PDL1 therapy or to be ineligible for such therapy. There was no upper limit on the number of prior lines pts could have received. All pts were required to have RECIST measurable disease. Pts received adavosertib 300mg daily on days 1 through 5 and 8 through 12 of a 21-day cycle. Coprimary endpoints were objective response and progression-free survival at 6 months (PFS6). Results: Between OCT-11-2018 and SEP-30-2019, 35 pts enrolled on study. Median follow-up is 4.6 months. The median number of prior lines was 3 (range 1-8). 34 pts were considered evaluable for response. In these pts, 9 confirmed and 1 unconfirmed responses were observed, for an ORR of 29.4% (95% CI 15.1-47.5%). The PFS at 6 months was 58.7% (95% CI: 39.5-73.7%). The median PFS is 6.1 months and the median duration of response is 9.0 months. Frequently observed Grade 3 or higher related adverse events included neutropenia (32.3%), anemia (20.6%), and fatigue (23.5%). Immunohistochemistry and targeted next-generation sequencing were performed to investigate potential biomarkers of response. Conclusions: Adavosertib monotherapy demonstrates promising clinical activity in women with USC. The observed monotherapy activity is higher than in other diseases, and additional exploration of the biology of Wee1 inhibition in USC is needed. Further studies of adavosertib in this patient population are planned. Clinical trial information: NCT03668340.
Impact of chemotherapy alone or in combination with an anti-angiogenic on the immune tumor microenvironment (TME) of ovarian cancer: Data from the randomized CHIVA trial (a GINECO –GINEGEPS study).
Authors: Yaniz Elisa , Genestie Catherine , Klein Christophe , Salviat Flore , Ray-Coquard Isabelle Laure , Joly Florence , Ferron Gwenael , Pujade-Lauraine Eric , Pautier Patricia , Leary Alexandra
Published: May 2020

6011

Background: The neoadjuvant setting is an excellent opportunity to study ‘ in vivo’ the biological impact of treatment on tumor cells and the immune TME. Both chemotherapy and anti-angiogenics may have immunomodulatory properties which could prime the TME and increase effectiveness of immunotherapeutic agents. We performed comprehensive multiplexed immune biomarker analyses on paired tumor samples at diagnosis and after 3 cycles of neoadjuvant carboplatin+paclitaxel (CP) +/- the anti-angiogenic tyrosine kinase inhibitor nintedanib (N) in the randomized CHIVA trial. Methods: Patients were randomized 2:1 to CP + N or placebo for 3 cycles prior to interval debulking, samples were evaluable for immune profiling for 124 pts at diagnosis and 107 at surgery from the CHIVA trial. For 86 patients matched paired samples were available. Multiplexed IF or IHC panels were performed for CD4, CD3, CD8, CK, Granzyme B, FOXP3, CD68, CD163 and DC-Lamp. Wilcoxon tests were used to compare measurements. Results: At diagnosis the most abundant cells were CD8+ and CD4+ cells (median=118 and 119cells/mm2, respectively) compared to Foxp3+ TRegs (median=30/mm2). Among the myeloid lineage, the proportion of CD68+ (M1) and CD163+ (M2) macrophages was balanced, while mature dentritic cells (DC) represented <5% of myeloid cells. In the whole population, regardless of arm, neoadjuvant platinum-based treatment significantly increased CD4+ (p=0.03) and CD8+ infiltration (p=0.009), decreased FOXP3+ cells (p=0.01), and these differences pre- and post-treatment remained significant when analysis was restricted to pts with paired samples. Mature DC also increased significantly with neoadjuvant treatment (p=0.0003), there was no significant modification in CD68+ or CD163+ macrophages. Changes in immune parameters did not differ significantly between the CP+B vs CP+placebo arms. Conclusions: Neoadjuvant treatment has a profound impact on the immune cell composition of the TME in advanced OC. However this change seems to be mainly mediated by platinum+paclitaxel chemotherapy rather than the anti-angiogenic tyrosine kinase inhibitor nintedanib.
A Big Ten Cancer Research Consortium phase II trial of pembrolizumab with carboplatin and paclitaxel for advanced or recurrent endometrial cancer.
Authors: Pineda Mario Javier , Schilder Jeanne , Hill Emily K. , Teoh Deanna Gek Koon , Barber Emma Longley , Robertson Sharon E. , Strohl Anna Everett , Xu Jiahui , Kocherginsky Masha , Matei Daniela
Published: May 2020

6022

Background: There are limited chemotherapeutic options for patients (pts) with advanced or recurrent endometrial cancer (EC). Reported objective response rates (ORR) for first-line doxorubicin/cisplatin/ paclitaxel combination therapy was 57%; with a median progression-free survival (PFS) of 8.3 months. The goal of this phase II study was to assess the efficacy and safety of pembrolizumab in combination with standard carboplatin/paclitaxel in pts with measurable advanced or recurrent EC. Methods: This was a single-arm, open-label, multi-center phase II study for pts with RECIST measurable advanced or recurrent EC coordinated by the Big Ten Cancer Research Consortium. Patients may have had received 1 prior platinum-based regimen, with a platinum free interval > 6 months, < one non-platinum chemotherapy, or prior hormonal therapy. Pts received carboplatin AUC 6, paclitaxel 175mg/m2 (CT) and pembrolizumab 200mg IV every 3 weeks for up to 6 cycles; with dose reduced for prior radiation. The primary endpoint was ORR per immune-related RECIST. Planned sample size of 46 subjects provided 77% power to detect 15% ORR improvement compared to historical controls, with one-tailed test and 10% type I error rate. Results: 46 pts were enrolled. Median age was 67 (range: 43-86). 32 pts had recurrent and 14 had primary metastatic EC. Histological types were: 26 endometrioid, 11 serous, 3 clear cell, 6 other. 19 patients had received prior carboplatin/paclitaxel, 23 pelvic EBRT, 14 brachytherapy, 1 adriamycin and 1 hormonal therapy. Grade 3-4 adverse events (AEs) included: laboratory abnormalities (20), hematological (8), metabolism (6), nervous system (4), gastrointestinal (2), and others (6). There were 15 grade 3-4 SAEs occurring in 7 pts: vomiting (1), anaphylaxis (3), fever (2), dehydration (1), syncope (2), vascular (2), fatigue (1), neurological (2), thrombocytopenia (1), and no grade 5 SAEs. 36 patients were evaluable for response at the time of abstract submission. ORR was 77.8% (28/36) and median PFS was 10.55 months. Conclusions: The addition of pembrolizumab to standard of care CT chemotherapy for advanced or recurrent EC induced a clinically significant improvement in ORR compared to historical outcomes and toxicity did not exceed anticipated toxicity with standard treatment, supporting further testing in a phase III trial. Clinical trial information: NCT02549209.
Genome-wide association analysis in host genetic characteristics of progression to high-grade cervical intraepithelial neoplasia or higher for women with human papillomavirus infection and normal cytology.
Authors: Lai Chyong-Huey , Chang Su-Wei , Yang Lan-Yan , Hung Shuen-Iu , Lin Chiao-Yun , Chao Angel , Lee Yun-Shien , Huang Huei-Jean , Wu Ren-Chin , Chang Ting-Chang , Chang Chee-Jen , Fann Cathy S. J.
Published: May 2020

6033

Background: Human papillomavirus (HPV) testing is widely used for cervical cancer screening. The hazard ratio of developing cervical intraepithelial neoplasia grade 2 or higher (CIN2+) in HPV-positive/ normal cytology women is 20–34 fold as compared to those with HPV-negative/normal cytology. HPV-positivity would cause substantial anxiety. Apart from viral factors such as high-risk (hr) types, it is important to identify host characteristics for predicting outcome. Methods: An initial genome-wide association study (GWAS) of single nucleotide polymorphisms (SNPs) by Affymetrix Axiom™ Genome-Wide Human Arrays was conducted on 505 cases with histological diagnosis of CIN2+ (group D1) versus 920 female controls. An additional set of 2315 female controls from the Taiwan Biobank genotype array were added in the discovery stage. The identified 29 CIN2+ -associated SNPs from GWAS (p < 5 x 10−6) were verified in an independent cohort (group D2 [n = 306] versus group N [n = 600]). Group N were HPV-negative/normal cytology women from a population-based cervical cytology and HPV co-test study. A cohort with HPV-positive/normal cytology (group P, n = 755) underwent follow-up and was served as the prediction set. The predictive validity was analyzed by logistic regression and receiver operating characteristic (ROC) curve analysis. Results: Thirty-three individuals of the group P progressed to CIN2+ (median follow-up: 23.7 months, range 4.0–122.1). A risk-predictive panel of 8 SNPs rs3097662, rs35979982, rs7763822, rs4282438, rs3128927, rs7759943, rs213194, rs17835649 which were significant in the replication (p < 0.05) was used to train models for disease risk prediction using the combination of GWAS and verification sets. Two prediction models were finalized and determined using 7 SNPs for hr- and low-risk (lr) HPV groups respectively (sensitivity 0.72 and 0.75, specificity 0.651 and 0.884, area under the ROC curve 0.703 and 0.701). Among group P with hr-HPV, those carried < 6 risk-alleles had significantly decreased hazard (log-rank p < 0·001) of progression to CIN2+ than those with ≧6 risk-alleles, while among group P with lr-HPV, those with predictive probability of ≥ 0·095 had a cumulative risk of progression of 10% at 3 years. Conclusions: Two risk-predictive SNP panels including 7 SNPs with hr- or lr-HPV groups can assist risk stratification among HPV-positive/ normal cytology women. These panels could be further tested in other ethnic populations.
Low rates of BRCA1 and BRCA2 testing for patients with ovarian cancer in ASCO's CancerLinQ, a real-world database.
Authors: Dewdney Summer , Potter Danielle , Larsen Haidle Joy , Hulick Peter J , Riffon Mark , Monzon Federico A. , Keole Sameer R. , Miller Robert S.
Published: May 2020

6041

Background: Ovarian cancer is the deadliest gynecological cancer and has limited screening options for early stage diagnosis. Genetic mutations in genes such as BRCA1 and BRCA2 increase the risk of ovarian cancer, and if identified, patients can undergo risk-reducing surgery. It is recommended and well accepted to test any new ovarian cancer patient for genetic mutations, particulary BRCA1 and BRCA2. If a BRCA1/2 mutation is found in a patient (somatic or germ line), this information can be used to guide therapy. We sought to analyze the characteristics of genetic testing in a real-world database, ASCO’s CancerLinQ. Methods: We performed a retrospective cohort study using the CancerLinQ Discovery database. Women with ovarian, fallopian tube, or primary peritoneal cancer were identified using ICD9 and ICD10 codes. We included patients diagnosed between 1/1/11 to 12/31/18 and age >18. We included all epithelial histologies including carcinosarcomas and excluded patients without a known histology. Results: Of the 2654 patients meeting inclusion criteria, 600 had been tested for a BRCA1/2 mutation (22.6%). Of those tested, 63% were stage III/IV, 14% stage I/II, and 21.8% an unknown stage. The majority of the histologies were serous (76%), followed by undifferentiated (21.2%). The majority of patients tested were white (69.9%), with 18.8% unknown, and 9.9% black. The rate of a positive BRCA1 or BRCA2 mutation in this population was 17.2%. Of the patients with a BRCA1/2 mutation, the majority had serous histology (87%), followed by 18.5% undifferentiated, and 3.9% transitional cell. The majority of the patients found to have a BRCA1/2 mutation were age >50 (57.3%). Conclusions: Since 2008 evidence-based guidelines have recommended that all ovarian cancer patients be tested for BRCA1 and BRCA2 mutations, but in this real-world database only 22.6% have a recorded test. Of those tested, we found a BRCA1 or BRCA2 mutation rate of 17.2%. Our data is limited by what is recorded in the database and may not represent the true number of patients tested because of data missing from the EHR; however, these percentages appear similar to previous studies. Not only is testing important for cancer prevention for family members of patients, it now impacts the type of treatments for which these patients are eligible. Since genetic testing remains low at only 22.6% in this population, significant opportunities exist to impact cancer prevention and treatment.