bluuebunny/crossref_metadata_2025 huggingface dataset:
Non-adherence behaviors among young women on adjuvant endocrine therapy for breast cancer.
Authors: Wassermann Johanna , Gelber Shari I. , Rosenberg Shoshana M. , Ruddy Kathryn Jean , Tamimi Rulla M. , Schapira Lidia , Borges Virginia F. , Come Steven E. , Partridge Ann H.
Published: September 2018

526

Background: Young age at diagnosis (dx) is a predictor of worse prognosis in patients (pts) with luminal breast cancer (BC). Poorer adherence to endocrine therapy (ET) among younger women may contribute to this disparity. Aim: To assess non-adherent behaviors and associated factors among young women with stage 1-3 hormone receptor (HR)+ BC taking ET. Methods: This study is a part of a multi-center, prospective cohort of pts with dx of BC at or under age 40. On a survey 30 months after dx, among pts reporting taking ET, adherence was measured using a 3-item Likert-type scale (Do you ever forget to take your ET? If you feel worse when you take your ET, do you stop taking it? Did you take your ET exactly as directed by your doctor?). Pts reporting any non-adherent behavior during the last 3 months were classified as non-adherers. Variables with a p-value <0.20 were included in a multivariate logistic model. Results: Among361 pts eligible for this analysis, 174 (48%) reported some non-adherent behaviors in the last 3 months; 56 (16%) moderate or greater non-adherent behaviors. None of the studied variables was associated with non-adherent behaviors (table). Conclusions: Non-adherent behaviors to ET are present in almost half of the young women with HR+ BC. Further analyses of explanatory factors and impact of non-adherence are required to understand and potentially improve this problem. [Table: see text]
Endocrine therapy non-persistence in young women with early-stage breast cancer.
Authors: Rosenberg Shoshana M. , Gelber Shari I. , Ruddy Kathryn Jean , Tamimi Rulla , Wasserman Johanna , Schapira Lidia , Borges Virginia F. , Come Steven E. , Meyer Meghan E , Partridge Ann H.
Published: September 2018

531

Background: The greatest age disparity in early stage breast cancer (BC) outcomes is in young women with hormone receptor positive (HR+) BC. While differences in biology may play a role, understanding the role of non-persistence (early discontinuation) with endocrine therapy (ET) is critical given the demonstrated efficacy of ET in this population. Methods: As part of a prospective cohort that enrolled women with BC diagnosed (dx) at age ≤40 between 2006-2016, we identified women with HR+, Stage I-III BC. Socio-demographic and treatment information, fertility concerns and confidence with the ET treatment decision were assessed by survey within 1 yr of dx. Medical record review was used to ascertain stage and HR status. Women who initiated ET but did not report taking tamoxifen or an aromatase inhibitor at 3 yrs post-diagnosis (or last follow-up if <3 yrs) were classified as non-persistent. Chi-square tests were used to compare categorical variables between persisters and non-persisters and stepwise multivariable regression to evaluate predictors of non-persistence. Results: In 538 women who initiated ET, median age at dx was 36; 10% were non-persistent. Discontinuation of ET was more likely in those who were less confident with their ET decision compared to those who were more confident (25/179, 14% vs 18/263, 7%, p=0.01). A greater proportion of women concerned about fertility discontinued vs. women not concerned (29/213,14% vs 25/319, 8%, p=0.03), and fertility concerns were associated with non-persistence in multi-variable analyses (OR: 1.85, 95% CI 1.05-3.26, p=0.03). Age at dx, race, education, employment, financial comfort, marital status, parity, stage, chemotherapy and local therapy were not associated with non-persistence. Conclusions: A significant minority of women with HR+ BC discontinued ET within 3 yrs. The association between fertility concerns expressed soon after dx and non-persistence underscores a need to address psychosocial issues that can impact treatment decisions in young women. Strategies to reduce decisional conflict and increasing confidence with the choice to take ET, may influence persistence. Future work will evaluate the contribution of other factors (eg symptom burden) to non-persistence.
The performance of the 21-gene assay standard cutpoints of 18 and 31 in HR+, HER2- invasive breast cancer (BC), while waiting for TAILORx mid-range recurrence score results.
Authors: Miller Dave P. , Petkov Valentina I. , Shak Steven
Published: September 2018

537

Background: The Recurrence Score (RS) was shown in NSABP B-20 to predict chemotherapy (CT) benefit for RS ≥31 and no CT benefit for RS <18. The TAILORx results for RS <11 (NEJM 2015) reported excellent outcomes with no opportunity for CT to add additional benefit. As we await TAILORx results for RS 11-25, we characterized BC specific mortality (BCSM) for RS groups (cutoffs of 11, 18, 25, and 31) in the population-based SEER study of pts treated based on RS. Methods: RS results were provided to SEER registries per their methods (npj Breast Cancer 2016). Pts diagnosed (Jan 2004 - Dec 2012) with N0 HR+ HER2- negative BC, and no prior malignancy were eligible. BCSM estimates by CT use were computed using standard cutpoints of 18 and 31 and TAILORx cutpoints of 11 and 25. Results: Among 49,681 with a RS, 9,486 (19%) had RS <11, 17,988 (36%) had RS 11-17, 14,541 (29%) had RS 18-25, 3,805 (8%) had RS 26-30, and 3,861 (8%) had RS ≥31. Reported CT use and 5-y BCSM increased with increasing RS. For pts with both RS <11 and RS 11-17, CT use was uncommon and 5-y BCSM was low regardless of CT use. For pts with RS 18-25, CT use was more common and the 5-y BCSM was about 1% regardless of CT use. For pts with RS of 26-30 or ≥31, CT was common, and lower 5-y BCSM was observed with CT reported yes than with CT reported no or unknown. Conclusions: Pts in real-world clinical practice with RS <11, consistent with TAILORx, and pts with RS 11-17 have low 5-y BCSM with limited CT use, supporting hormonal therapy alone for pts with RS <18. The high end of the TAILORx mid-range (18-25) also showed good 5-y BCSM both with and without CT, highlighting the importance of the randomized results of TAILORx. [Table: see text]
Recent time trends in chemotherapy use and oncologists' chemotherapy recommendations for early-stage, hormone receptor-positive breast cancer.
Authors: Kurian Allison W. , Bondarenko Irina , Jagsi Reshma , McLeod Chandler , Hawley Sarah T. , Hamilton Ann S. , Ward Kevin C. , Katz Steven J.
Published: September 2018

541

Background: Advances in tumor genomic profiling enable increasingly precise estimates of the benefit of adjuvant chemotherapy in early-stage breast cancer. However, little is known about how chemotherapy use, medical oncologists’ (MO) perspectives and recommendations have changed in recent years, particularly in key clinical subgroups such as node-negative and node-positive. Methods: We surveyed 5,080 women (70% response rate), newly diagnosed with breast cancer in 2013-2015 and accrued through two population-based SEER registries (Georgia and Los Angeles), about their MOs’ chemotherapy recommendations and whether they received chemotherapy. Using patient report, we identified 470 attending MOs and surveyed them (n=310, 66% response) about approaches to chemotherapy recommendation, using node-negative and node-positive case scenarios. We evaluated factors associated with chemotherapy receipt over time using multi-level logistic regression. Results: The analytic sample was 2,926 patients with stages I-II, estrogen receptor-positive, HER2-negative breast cancer. Chemotherapy use declined to 21% from 34% during the study period (2013-2015, p<.001). For node-positive patients, chemotherapy use declined to 64% from 81% and for node-negative/micrometastasis patients to 14% from 27%. Based on patient report, MOs’ recommendations for chemotherapy declined during the study period to 32% from 45% (p<.001). Recommendations reported by MOs were generally guideline-concordant. MOs were much more likely to order tumor genomic profiling when patient preferences were discordant with recommendations [67%, standard error (SE) 3% versus 18% (SE 2%) without discordance], and they adjusted chemotherapy recommendations based on patient preferences and genomic profiling results. Conclusions: For both node-negative/micrometastasis and node-positive patients, chemotherapy receipt and oncologists’ recommendations for chemotherapy declined markedly in recent years. The results of ongoing clinical trials of genomic profiling will be essential to confirm the quality of this approach to breast cancer care. Funded by NCI P01CA163233.
Is the mesenchymal transition subtype more responsive to dose dense taxane chemotherapy combined with carboplatin (ddTC) than to conventional taxane and carboplatin chemotherapy (TC) in high grade serous ovarian carcinoma? A survey of Japanese Gynecology Oncology Group study (JGOG3016A1).
Authors: Murakami Ryusuke , Matsumura Noriomi , Tanabe Hiroshi , Michimae Hirofumi , Yunokawa Mayu , Iwase Haruko , Sasagawa Motoi , Nakamura Toshiaki , Tokuyama Osamu , Takano Masashi , Sugiyama Toru , Sawasaki Takashi , Isonishi Seiji , Takehara Kazuhiro , Nakai Hidekatsu , Okamoto Aikou , Mandai Masaki , Konishi Ikuo ,   JGOG
Published: September 2018

5510

Background: High-grade serous ovarian cancer (HSOC) was divided into four transcriptome subtypes (i.e. Mesenchymal, Immunoreactive, Proliferative, and Differentiated). We established a new pathological classification based on these transcriptome subtypes: Mesenchymal Transition (MT) type, Immune Reactive (IR) type, Solid and Proliferative (SP) type and Papillo-Glandular (PG) type (PMID: 26993207). The MT type has the worst prognosis. We discovered the Mesenchymal transcriptome subtype might be sensitive to taxane chemotherapy. Therefore, we hypothesized that the MT type, which represents the Mesenchymal transcriptome subtype, may respond better to dose dense taxane combined with carboplatin (ddTC) rather than to conventional taxane and carboplatin (TC). Methods: We collected 207 HSOC slides registered in the Japanese Gynecology Oncology Group 3016 (JGOG3016) study. Two of the authors, R.M. and I.K., classified the samples into the four pathological subtypes (n=201). We categorized the patients into two groups based on the treatment they received: ddTC (n=95) or TC (n=106). Progression free survival (PFS) was compared between the two groups for each pathological subtype. Results: Among the MT patients, the ddTC group had a significantly better PFS than the TC group (n= 30 vs 42, median survival: 1.8 vs 1.2 years, p=0.01). Among the SP patients, the ddTC group had better PFS than the TC group, even though the difference was not statistically significant (n=22 vs 27, median survival: 3.2 vs 1.4 years, p=0.08). In contrast, among the IR patients, the two groups showed no significant difference in PFS (n=16 vs 16, median survival: 5.2 vs 5.8 years, p=0.64). The PG patients also showed no significant difference in PFS between the two groups (n=27 vs 21, median survival: 1.5 and 1.7 years, p=0.64). Conclusions: The HSOC of MT type is more responsive to ddTC than to TC. This new pathological classification reflecting HSOC transcriptome subtypes leads to individualization of chemotherapy treatments.
Functional and oncologic outcomes of radical trachelectomy in early-stage cervical cancer: A prospective multicentric cohort of 61 patients.
Authors: Balaya Vincent , Rossi Lea , Ngo Charlotte , Bats Anne-Sophie , Mathevet Patrice , Lecuru Fabrice ,   SENTICOL Group
Published: September 2018

5529

Background: The aim of this study was to assess the post-operative morbidity of patients who have undergone a radical trachelectomy for early-stage cervical cancer and the oncologic outcomes. Methods: We retrospectively analyzed the data of two prospective trials on sentinel node biopsy for cervical cancer (SENTICOL I & II). Patients underwent a radical trachelectomy for early-stage cervical cancer between January 2005 and March 2012 from 8 French oncologic centers. Results: A total of 61 patients have undergone a radical trachelectomy: 41 patients by laparoscopic-assisted vaginal way, 7 patients by total laparoscopic way, 11 patients by total vaginal way and 2 patients by laparotomy. The median age was 33 years (range = 22-68 years). 88.5 % of patients had a stage IB1 disease. There were 63.9% of epidermoid carcinoma and 34.4 % of adenocarcinoma. Eighteen patients (29.5%) had only a sentinel lymph node biopsy and 43 patients (70.5%) had an additional pelvic lymphadenectomy. The median follow-up was 46 months (range = 0-85 months). Twenty patients (32.8%) had a urinary complication. There were 12 cases of urinary infections (19.6%), 6 cases of dysuria (9.8%), 3 cases of urinary incontinence (4.9%), and one case of ureteral fistula (1.6%). Nine patients had a major neurologic complication (14.7%): the genito-femoral nerve was injured in 4 cases (6.5%) and the obturator nerve was injured in 5 cases (8.2%). Sixteen patients (26.2%) presented a lymphovascular complication. There were 12 cases of limb lymphedema (19.7%) and 5 cases of pelvic lymphocyst (8.2%). During the follow-up, 3 patients (4.9%) had a local recurrence and two patients died : one from a breast cancer and one from a liver metastasis. Conclusions: The radical trachelectomy is a feasible and safe alternative option for young patient with a early-stage cervical cancer in order to preserve their fertility. See table. [Table: see text]
Role of axillary node dissection after mastectomy with positive sentinel nodes.
Authors: Park Tristen Sinae , Thomas Samantha Marie , Greenup Rachel Adams , Hwang Eun-Sil Shelley
Published: September 2018

554

Background: The ACOSOG Z11 trial demonstrated that sentinel lymph node biopsy (SLNB) alone was safe for women with early stage node positive cancer undergoing breast conservation therapy with radiation. Little data exists regarding management of this population undergoing mastectomy. The purpose of our study is to determine the benefit of axillary lymph node dissection (ALND) or SLNB with adjuvant radiation in patients with 1-3 positive SLN after mastectomy. Methods: Using data from the National Cancer Database (2004-2014), we performed a retrospective review of patients who underwent mastectomy and were clinically node negative at presentation, but were found to have 1-3 positive nodes on pathology. Patients were categorized as undergoing SLNB alone (1-5 nodes examined) or ALND (≥8 nodes examined). Patients who received SLNB without ALND were further categorized by receipt of radiation treatment (RT). Patients with either neoadjuvant chemotherapy or stage IV disease were excluded. Results: Of 42,371 patients, 10.0% had SLNB+RT, 22.4% had SLNB alone, and 67.5% had ALND. Median age of the cohort was 58 years and median tumor size 2.3 cm. Median follow up was 4.1 years. After adjustment for covariates including age at diagnosis, tumor size, chemotherapy, endocrine therapy and receptor status, SLNB+RT had comparable overall survival to ALND (HR = 1.06, p = 0.52), but SLNB alone was found to be associated with a 25% increase in hazard of death compared to ALND (HR = 1.25, 95% CI 1.11-1.41, p < 0.001). Conclusions: In clinically node negative patients with 1-3 positive sentinel nodes treated with mastectomy, SLNB alone was associated with a significantly increased risk of all-cause mortality compared to ALND or SLNB+RT. These results suggests that ALND may be avoided in these patients in the setting of adjuvant radiation, possibly avoiding the morbidity associated with axillary lymphadenectomy.
CD8+ TILs in early stage epithelial ovarian cancer: A GEICO study.
Authors: Romero Ignacio , Leskella Susanna , Redondo Andres , Gutierrez-Pecharroman Ana , Santaballa Ana , Cristobal Lana Eva Maria , Calvo Elisa , Rosa-Rosa Juan Manuel , Oaknin Ana , Bover Isabel , Herrero Ana , Sanchez-Heras Ana Beatriz , Churruca Cristina Maria , De Juan Ana , Mendiola Cesar , Romeo Margarita , Ojeda Belen , Lopez-Guerrero Jose Antonio , Palacios José , Poveda Andres ,   GEICO Group
Published: September 2018

5543

Background: The extent of tumor infiltrating lymphocytes (TILs) has emerged as a potential clinical useful biomarker in epithelial ovarian cancer (OC); however differences in TILs among OC histological types have not been extensively analysed. Methods: From a prospective early stage (I-II) GEICO registry of 1151 cases, 573 were sent for central pathology review. Complete analysis for classification of OC correctly identified 488 cases. Histological typing was performed according to morphological features and the expression of WT1, p53, p16, estrogen receptor (ER), progesterone receptor, and napsin A. The expression of mismatch repair (MMR) proteins MLH1, PMS2, MSH2 and MSH6 was performed in all tumors. The absolute number of stromal and intraepithelial CD8+ TILs per 0.6 mm2 TMA core was quantified and correlated with pathological features. Results: The series included 127 high-grade serous carcinomas (HGSC) (26%), 22 low-grade serous carcinomas (LGSOC) (4.5%), 165 endometrioid carcinomas (EC) (33.8%), 124 clear cell carcinomas (CCC) (2.4%), and 50 mucinous carcinomas (MC) (10.2%). The mean of intraepithelial CD8+ TILs was higher in HGSG (48.7) than in all other histological types (LGSG: 16.3; EC: 27.1; MC: 7.0; and CCC 10.3; p<0.0001). In the stromal component, the mean of CD8+TILs was also higher in HGSG (31.1) than in EC, MC and CCC (15.8, 8.0 and 12.7, respectively; p<0.0001). The mean of intraepithelial CD8+ TILs was significantly higher in RE-positive (71.9) than in RE-negative (34.8) HGSC ( p=0.002). In the complete series, 33 (6.6%) OCs showed absent expression of at least 1 MMR protein, and the mean of intraepithelial CD8+ TILs was significantly higher in these OCs (57.0) than in those with preserved expression of all MMR proteins (23.6; p=0.0035). MMR protein deficiency was observed in 27 (16%) ECs, and these tumours had significantly higher mean of both intraepithelial (60.4 vs. 20.7 p=0.003) and stromal CD8+ TILs (26.6 vs. 13.8, p= 0.046). No significant differences in TILs were observed among EC of different histological grades. Conclusions: The extent of CD8+TILs significantly correlates with the histological type and MMR status in OCs, being HGSCs and EC with MMR deficiency those OCs with higher CD8+TILs.
BRCA-like classification in ovarian cancer: Results from the AGO-TR1-trial.
Authors: Richters Lisa Katharina , Schouten Philip C. , Kommoss Stefan , Hauke Jan , Burges Alexander , Dietrich Dimo , El-Balat Ahmed , Hilpert Felix , Kluin Roel , Heubner Martin Leonhard , Kast Karin , Heimbach André , Braicu Elena Ioana , Schmidt Sandra , Baumann Klaus H. , Jackisch Christian , Linn Sabine C. , Schmutzler Rita K. , Harter Philipp , Hahnen Eric
Published: September 2018

5546

Background: BRCA associated cancers show a distinct pattern of genomic gains and losses that is associated with impaired repair of DNA double-strand breaks via homologous recombination (HR). We investigated whether BRCA1- and BRCA2-like classifiers could predict BRCA1 and BRCA2 mutation status in ovarian cancer. In addition, we explored whether promoter hypermethylation or mutations in other genes involved in DNA repair associate with a BRCA-like profile in ovarian cancer. Methods: The AGO-TR1 cohort study (NCT02222883 ) enrolled 525 consecutive patients with primary (PR) and platinum sensitive relapsed (RE) ovarian cancer to perform paired mutational analysis of germline and tumor tissue. We performed mutation panel sequencing, BRCA1 promoter hypermethylation and low-coverage whole genome sequencing to classify samples as BRCA1-like or BRCA2-like in 298 ovarian cancer samples (PR: n = 159, RE: n = 139). Results: A BRCA-like profile was observed in 58.1% of the samples without germline or somatic mutation in BRCA1/2 (n = 179; BRCA1-like: n = 26, BRCA2-like: n = 23, BRCA1- and 2-like: n = 55). There was no significant difference between PR- and RE-cases (54.5% vs 61.3%). 64 of 70 BRCA1 germline mutation carriers could be identified by the BRCA1-like classifier (sensitivity: 0.91). The BRCA2-like classifier identified BRCA2 germline mutation carrier with a sensitivity of 0.71 (17 of 24). The complementary use of both classifiers led to the detection of 22 of 25 somatic mutations in BRCA1 (16/16) or - 2 (6/9). Remarkably, 12 of 13 tumor samples from germline RAD51C mutation carriers were recognized by the BRCA1-like classifier (sensitivity: 0.92). No correlation of PALB2 mutation status (n = 7) with BRCA-like profile was observed. Of 28 tumor samples with a BRCA1 promoter hypermethylation 26 had a BRCA1-like profile (sensitivity: 0.93). Conclusions: A high number of ovarian cancer cases display a BRCA-like profile. Mutations (germline and somatic) in BRCA1, BRCA2, RAD51C as well as BRCA1 hypermethylation strongly associate with a BRCA-like profile and can explain 146 of 212 cases. Future studies will investigate whether the classifiers identify patients who benefit from HR-deficiency directed approaches beyond the BRCA mutation status. Clinical trial information: NCT02222883.
Prognostic impact of neo-adjuvant vs adjuvant vs neo-adjuvant plus adjuvant chemotherapy in advanced ovarian cancer: Analysis of National Cancer Database.
Authors: Mukkamala Suresh , Saha Sukamal , Ramanathan Sabarina , Livert David , Oza Rajen , Salib Hayman S. , Bajaj Vinay , Lee Jeen , Wiese David , Arora Madan L.
Published: September 2018

5552

Background: Patients (Pts) with advanced ovarian cancer (OvCa) are usually treated with primary debulking (deb) surgery (Sx) followed by adjuvant (adj) chemotherapy (CRx). Recently neo-adjuvant (neo-adj) CRx is increasingly being used to reduce the bulk of the tumor. Hence, we analyzed for any prognostic impact of neo-adj vs adj vs neo-adj plus adj CRx along with deb Sx in the management of advanced OvCa. Methods: Only Stage III and IV Pts in National Cancer Data Base (NCDB) from 2006-2014, who underwent deb Sx without bowel resection (1), with bowel resection (2) and with bowel and bladder resection (3) were analyzed. Group (gp) A Pts had neo-adj CRx, gp B had adj CRx and gp C Pts had neo-adj plus adj CRx. The Pearson Chi square testing was used to evaluate the survival between gp A vs B vs C. Results: A total of 20910 Pts in stage III and 7483 Pts in stage 4 were included. Stage III Pts had a better 5 year (yr) survival in gp B compared to gp A and C, in all Pts who underwent Sx 1, 2 and 3 (Table 1). Stage IV Pts had a better 5 yr survival in gp C compared to gp A and B who underwent Sx 1 and 2, and gp B had a better 5 yr survival in Pts who underwent Sx 3 (Table 1). Overall survival was worse for all stages in Pts with neo-adj ( gp A) than gp Band C. Conclusions: Deb Sx followed by adj CRx had better survival than in gp A or C. This may be secondary to less bulkier disease in the beginning in gp B than those in gp A or C requiring neo-adj CRx for the later. Pts survival also improved after addition of adj CRx following deb Sx compared to no adj CRx. A prospective multicenter randomized trial between each group may further validate the true benefits of neo-adj CRx in advanced OvCa. [Table: see text]
Cell-free tumor DNA in peri-operative blood samples from advanced high-grade serous ovarian cancer patients with and without complete resection.
Authors: Heitz Florian , Lakis Sotirios , Harter Philipp , Sehouli Jalid , Talwar Jatin , Sprokmann Mareike , Bertrand Miriam , Ataseven Beyhan , Mariotti Erika , Schneider Stephanie , Müller Judith N , Menon Roopika , Prader Sonia , Leenders Frauke , Hengsbach Alexandra , Gloeckner Christian , Braicu Elena Ioana , Heukamp Lukas C. , Heuckmann Johannes , Du Bois Andreas
Published: September 2018

5555

Background: Surgical outcome is an important prognostic factor in advanced high-grade serous ovarian cancer (HGOC). Intra-operative determination of residual disease may be prone to subjective bias. Methods: We prospectively collected and analyzed tumor tissue and plasma from 21 pts with FIGO IIIC-IV HGOC. All tumor specimen showed loss of TP53 in immunohistochemistry. Tumor DNA from tissue and peri-operative cell-free DNA at baseline (BL) and at d(ays) 1, d4 and d10 were subjected to comprehensive hybrid-capture based next-generation sequencing (NEO New Oncology GmbH, Cologne, Germany). Results: The initial cohort comprised 10 pts without (TR>0) and 11 pts with complete resection TR0, with a total of 43 somatic genomic alterations. TP53 was mutated in 20/21 (95.2%) of tissue samples and in 15/21 (71.4%) corresponding plasma samples at BL. Therefore, TP53 mutations were used as a molecular marker of circulating tumor DNA levels post-surgery. In the remaining 5 BL cases the TP53 mutations were either not present in plasma (N= 3) or rested below the detection limit (N= 2). In d1, d4 and d10 post-surgical samples, the sample specific TP53 mutations were detected in 12 out of 15, 10 out of 14 and in 7 out of 13 cases, respectively. TP53variant allele frequency (VAF) did not differ among TR0 and TR>0 at BL (mean= 1.91 versus 1.73, Mann-Whitney test p = 0.86) whereas it was significantly lower for TR0 at d1 (mean= 0.06 versus 2,06; p value= 0.002), d4 (mean= 0.07 versus 1.8; p= 0.04) and d10 (mean VAF= 0 versus 1.04; p= 0.008). Five out of 9 TR>0 cases showed at least one increase in VAF between d0 and any additional time-point. In 8 out of 9 mutations remained detectable at d10 (VAF: 0.076 – 3.26). By contrast, TR0 cases showed consistent reduction in VAF throughout the follow-up period which maximized at d10. Conclusions: Liquid biopsycan efficiently detect somatic mutations in the cfDNA of pts with HGOC following debulking surgery. Variation of the TP53 VAF in sequential post-surgical samples appears to be restricted to TR>0 cases, whereas in TR0 pts VAF progressively decreases. Liquid biopsy may hold promise as a tool for the objective determination of residual disease after debulking surgery.
A re-analysis of the prostate, lung, colorectal, and ovarian (PLCO) cancer screening trial accounting for ovarian cancer (OVCA) heterogeneity.
Authors: Temkin Sarah Madhu , Miller Eric A , Samimi Goli , Berg Christine D , Pinsky Paul , Minasian Lori M.
Published: September 2018

5564

Background: A mortality benefit from screening for OVCA has not been demonstrated, but screening efficacy could differ for histologic subtypes. We re-analyzed PLCO evaluating whether OVCA detection and outcomes were affected by the heterogeneous biologic behavior of this disease. Methods: Type 2 tumors (moderately/poorly differentiated serous and adenocarcinoma) were compared to all other tumor (OT) types (low grade serous and endometrioid, clear cell, other, low malignancy potential) (LMP). We examined differences in the distribution of tumor types and stage by study arm and method of diagnosis [screen detected (SD) and interval detected (ID) (i.e. assigned to screening but diagnosed between screening tests)]. Stage distribution and survival were analyzed. Results: Among the entire PLCO population, 531 women were diagnosed with OVCA during the study; 282 (53%) in the screening arm and 249 (47%) in the usual care arm. Of the tumors able to be characterized (n=408; 77%), 74% (n=300) were Type 2 and 26% OT (n=108). In the screening arm, 70% of tumors diagnosed were Type 2 compared to 78% in usual care (p=0.07). Overall, survival was significantly better for OT tumors compared to Type 2 tumors (p<0.01) but there was no difference in survival by study arm for either tumor type separately (Type 2: p=0.50; OT: p=0.23). Within the screening arm, 30% of Type 2 tumors were SD compared to 54% of OT tumors (p=0.02) (see Table). Only 15% of Type 2 SD tumors were Stage I/II, compared to 82% of SD OT tumors (p<0.01). Stage at diagnosis was similar among Type 2 patients whether they were SD or ID (p=0.56) and there was no difference in survival (p=0.56). Conclusions: A significant difference in tumor types by study arm was not observed. However, within the screening arm, Type 2 tumors were less likely to be SD or Stage I/II compared to OT tumors. Survival for Type 2 tumors was similar regardless of method of diagnosis. [Table: see text]
Homologous recombination deficiency and platinum rechallenge in platinum-resistant ovarian cancer patients.
Authors: Da Costa Alexandre Andre B. A. , Salvadori Marcela Marinelli , Valadares Camila Vieira , Stecca Carlos , Brot Louise , do Canto Luisa Matos , Baiocchi Glauco , Rogatto Silvia Regina , Achatz Maria Isabel Waddington
Published: September 2018

5576

Background: Ovarian carcinomas show homologous recombination deficiency (HRD) in up to 50% of cases and in 15 to 20% of cases occur due to germline BRCA1 or BRCA2 mutations. BRCA mutated tumors are more sensitive to PARP inhibitors and platinum based chemotherapy. The objective of this study was to characterize a cohort of ovarian cancer patients regarding HRD and to evaluate the impact of these scores in prolonged platinum sensitivity. Methods: Thirty one ovarian cancer patients with platinum resistant recurrence reexposed to platinum based chemotherapy were selected. Paraffin embedded tumor samples from 14 patients were analyzed using ONCOSCAN assay (Affymetrix) to evaluate HRD scores. The association of the scores with response rate to platinum rechallenge, overall survival and clinical pathologic factors was evaluated. Results: From the cohort of 31 patients, 15 samples from 14 patients were analyzed for genomic alterations. Median scores were 19.5 for TAI, 12.5 for cnLOH+L, 26.0 for LST and 6.3 for HRD. High scores were found in 10 out of 14 (for cnLOH+L score) and 9 out of 14 (for LST score) patients. Seven of the 14 patients analyzed analyzed for genomic alterations had response, which suggested homologous recombination deficiency. No significant differences were observed between response rates for high versus low scores. Numerically, cnLOH+L, LST and HDR scores were higher in patients with response to treatment compared to those without response. Median overall survival was 13.4 months from the beginning of platinum rechallenge and no difference in survival according to scores was observed. Among the clinical pathologic factors, family history of breast or ovarian cancer or personal history of breast cancer was associated to higher response rate to platinum rechallenge. Conclusions: In conclusion,HRD scores showed to be potential markers of response to platinum rechallenge in the platinum resistant setting. Further studies are necessary to clarify the best cutoffs for each score, the impact of tumor heterogeneity and the analysis of tumor samples in the moment of treatment. Positive family history of cancer is a clinical factor predictvie of platinum rechallenge response.
Immunologic and genomic characterization of high grade serous ovarian cancer (HGSOC) in patients (pts) treated with pembrolizumab (Pembro) in the phase II INSPIRE trial.
Authors: Colombo Ilaria , Lien Scott , Yang Cindy , Clouthier Derek L. , Bonilla Luisa , Cyriac Sunu , Ethier Josee-Lyne , Lee Yeh Chen , Kanjanapan Yada , Mandilaras Victoria , Dhani Neesha C. , Butler Marcus O. , Oza Amit M. , Quintos Judy , Chow Helen , Pugh Trevor John , Ohashi Pamela S , Siu Lillian L. , Lheureux Stephanie
Published: September 2018

5581

Background: Checkpoint inhibitors have shown to be effective in different tumors and are under investigation in HGSOC. Methods: INSPIRE (NCT02644369) is a prospective multi-cohort study investigating tumor genomic and immune landscapes in pts treated with Pembro at 200 mg IV Q3W. Patients underwent tumor biopsy pre, on-treatment and at progression for DNA/RNA sequence, immune-profile, and PD-L1 expression by immunohistochemistry (IHC). Serial blood samples for immunophenotyping were collected. Correlative data are available for 6 pts: 3 with shrinkage in target lesion and 3 with progressive disease (PD). Results: At interim analysis as of January 2017, 18 pts with HGSOC have been enrolled and 16 have platinum-resistant disease, with median 3 prior lines of treatment (range 1-7). Of 14 evaluable pts, best response by RECIST 1.1 was stable disease (SD) in 5 (36%) and PD in 9 (64%). Mean Tumor Proportion Score of PD-L1 by IHC (Qualtek) was 6.4% (range 0-30%). Grade 3/4 adverse events possibly related to Pembro were observed in 4/18 (22%) pts; none was fatal and the most common were fatigue and hyponatremia. Preliminary correlative data showed no significant change in CD4, CD8 and myeloid-derived suppressor cells in peripheral blood after Pembro treatment. Mean PD-1 expression on CD4 and CD8 T cells on baseline tumor tissue (measured as product of PD-1+ cells and the per cell expression of PD-1 [% of mean fluorescence intensity]) was significantly higher in pts with tumor shrinkage compared to pts with PD (CD4: 2658 vs 678, p = .02; CD8: 1999 vs 451, p = .048). Genomic analysis of baseline tumor tissue was available for 3 pts with tumor shrinkage and 2 with PD. Mean mutation burden was higher for pts with tumor shrinkage (2.38 vs 1.0 mutations/Mb covered). The pt with the longest SD in our cohort (6 months) had the highest mutation burden (2.72), including somatic POLE (c.6331-6C > G) and germline BRCA2mutations. Conclusions: In HGSOC, pts with higher PD-1 level on tumor CD4 and CD8 T cells and higher mutation burden at baseline may have a better outcome following treatment with Pembro. POLE mutation is rare in HGSOC but may correlate with checkpoint inhibitor activity. Clinical trial information: NCT02644369.
Clinical activity of the selective DRD2 antagonist ONC201, an imipridone, in metastatic endometrial cancer (mEC).
Authors: Rodriguez-Rodriguez Lorna , Mehnert Janice M. , Silk Ann W. , Chan Nancy , Malhotra Jyoti , Aisner Joseph , Saunders Tracie , Yu Bangning , Dickerson Siobhan , Tarapore Rohinton , Allen Joshua E. , Stogniew Martin , Oster Wolfgang , Kaufman Howard , Haffty Bruce George , Bertino Joseph R. , Stein Mark N.
Published: September 2018

5592

Background: mEC is a generally incurable, with limited therapeutic options. ONC201 is the founding member of the new class of compounds called imipridones that are orally active small molecules. ONC201 a specific antagonist of the G protein-coupled receptor DRD2 exerts antitumor activity via a series of established signaling pathways (dual inhibition ERK/AKT, integrated stress response). DRD2 expression is elevated in malignant versus normal endometrial tissue. Furthermore ONC201 has shown anti-cancer activity in preclinical models of EC. Methods: In a Phase I trial that included an expansion cohort, a total of 28 evaluable patients (pts) were treated with ONC201 at doses from 125mg every 3 weeks to 625 weekly. Five of these patients had advanced mEC. Results: The median age for the mEC patients was 60 years (56-72), the median number of prior treatments was 5 (3-6), 3 patients had prior radiation and all patients had prior surgery. One patient received 375mg ONC201 while the other 4 patients received 625mg ONC201, orally every 3 weeks. The median number of doses was 3 (2-14). Two of 5 patients exhibited regressions in individual metastatic lesions, however they did not qualify as overall objective responses by RECIST criteria. One of these two patients experienced stable disease for 42 weeks. There were no reported SAEs and no Grade > 1 AEs attributed to study drug. Conclusions: ONC201 is clinically active and well tolerated with oral administration in refractory mEC patients. Clinical trial information: NCT02250781. [Table: see text]
Spectroscopy of blood samples for the diagnosis of endometrial cancer and classification of its different subtypes.
Authors: Paraskevaidi Maria , Morais Camilo L. M. , Raglan Olivia , Lima Kassio M. G. , Martin-Hirsch Pierre L. , Paraskevaidis Evangelos , Kyrgiou Maria , Martin Francis L.
Published: September 2018

5596

Background: Symptoms of endometrial cancer often appear in early stages, thus a diagnosis, based on microscopic histological examination of endometrial tissue, can be given relatively on time. However, this procedure interferes subjective interpretation allowing human error, while screening of the asymptomatic population is not widely performed because of the high cost of the available tests (e.g. transvaginal ultrasound) and the relative invasiveness [biopsy or dilation and curettage (D+C)]. Consequently, there is a widespread need to develop inexpensive, non-invasive techniques that would accurately diagnose endometrial cancer, as well as classify the different subtypes. Spectrochemical methods generate a signature fingerprint of biological material in the form of spectra. Unlike immunological methods, which detect only one molecule at a time, the spectra obtained from a clinical sample represent all the molecular constituents within that sample, including proteins, lipids and carbohydrates; this provides a holistic picture of the sample. Previous studies have confirmed spectroscopy’s ability to diagnose gynecologic cancers in blood. Methods: Attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy was used to analyse blood plasma and serum from 71 women with endometrial cancer and 18 age-matched healthy controls; classification algorithms were then applied to extract the underlying biological information. Results: Principal component analysis followed by support vector machine (PCA-SVM) diagnosed endometrial cancer with 100% accuracy in plasma and 95% in serum. Discrimination between the different subtypes [endometrioid adenocarcinoma (n = 43) vs carcinosarcoma (n = 14)] was achieved with 98.33% accuracy in both plasma and serum. The spectral regions responsible for discrimination were attributed to protein and lipid alterations. Conclusions: Our preliminary results suggest an accurate and objective diagnostic tool for endometrial cancer with blood testing, allowing therefore thoughts for a potential screening test in high risk populations. Future work will include higher number of normal cases and different subtypes and grades.
Safety of MEDI4736 (anti-PD-L1 antibody) administered concomitant with weekly nab-paclitaxel and dose dense doxorubicin/cyclophosphamide (ddAC) as neoadjuvant chemotherapy for stage I-III triple negative breast cancer (TNBC): A Phase I/II trial.
Authors: Pusztai Lajos , Silber Andrea , Hofstatter Erin Wysong , Chung Gina G. , Horowitz Nina Ruth , Lannin Donald R. , Killelea Brigid K. , Chagpar Anees B. , Szekely Borbala , Frederick Courtney , Rispoli Lawrence , DiGiovanna Michael
Published: September 2018

572

Background: Pathologic complete response (pCR) rates to neoadjuvant chemotherapy in TNBC plateaued at 40% with existing regimens, the co-administration of an immune checkpoint inhibitor might increase pCR rate. The objective of the Phase I portion of this trial was to assess the safety of administering MEDI4736 concomitant with sequential taxane and anthracycline chemotherapy. Methods: The Phase I part followed the 3+3 design exploring two dose levels of MEDI4736 (3 and 10 mg/kg iv q2wk) in combination with weekly nab-paclitaxel (100 mg/m2) x 12 followed by ddAC x 4. Dose limiting toxicities (DLT) were evaluated during the entire 20 weeks of therapy and were defined as (1) gr 4 immune related adverse event (irAE), (2) gr 3 irAE that did not resolve to gr 2 within 3 days or to ≤ gr 1 within 14 days, (3) > gr 3 colitis or pneumonitis, (4) ≥ gr 3 non-irAE causally related to MEDI4736. Results: 3 patients completed therapy at the 3 mg/kg dose without any DLT, 1 additional patient refused further study medication because of recurrent gr 2 fatigue after 7 weeks of therapy. At the 10 mg/kg dose level, all 3 patients completed the nab-paclitaxel+MEDI4736 treatment without any DLT and 2 patients also completed 3 of the 4 planned treatments with ddAC without DLT. Among all 7 patients who started therapy, 1 at the 3 mg/kg group experienced gr 3 dehydration and dyspnea without chest X ray abnormalities which resolved within 48 hours with hydration. There were no other gr 3 AEs. Among the 3 patients who have completed therapy as per protocol (not including the patient who withdraw consent), 1 achieved pCR, 1 had minimal, and 1 had extensive residual cancer. No surgical AE were seen. All patients at the 10 mg/kg dose level will complete surgery by March 2017 and final Phase I toxicity and efficacy results will be presented. Conclusions: Concomitant administration of MEDI4736 10 mg/kg with weekly nab-paclitaxel and subsequently with ddAC neoadjuvant chemotherapy appears safe. The Phase II portion of the trial is open and will accrue a maximum of 50 patients to assess the efficacy of the combination. Clinical trial information: NCT02489448.
Association of molecular subtype, proliferation, and immune genes with efficacy of carboplatin versus gemcitabine addition to taxane-based, anthracycline-free neoadjuvant chemotherapy in early triple-negative breast cancer (TNBC): Results of the randomized WSG ADAPT-TN trial.
Authors: Gluz Oleg , Liedtke Cornelia , Prat Aleix , Christgen Matthias , Gebauer Daniel , Kates Ronald E. , Grischke Eva-Maria , Forstbauer Helmut , Braun Michael Wilhelm , Warm Mathias , Hackmann John , Uleer Christoph , Aktas Bahriye , Schumacher Claudia , Kummel Sherko , Wuerstlein Rachel , Pelz Enrico , Nitz Ulrike , Kreipe Hans Heinrich , Harbeck Nadia ,   West German Study Group
Published: September 2018

573

Background: In the ADAPT-TN neoadjuvant trial, 12-week nab-paclitaxel (nab- pac)+carboplatin (carbo) was highly effective and superior to nab-pac+gemcitabine (gem). However, within TNBC, reliable predictive markers for carbo use have yet to be identified. Methods: Patients with early TNBC (centrally confirmed) were treated by nab-pac 125 mg/m2 with either carbo AUC2 or gem 1000 mg/m2 d 1,8 q21 given for 4 cycles. Genomic data (80 genes) and Prosigna (PAM-50) scores were available in 306 pre-therapeutic samples of 331 treated patients. Fisher’s exact test was performed for pCR differences; associations of continuous measurements or scores with pCR were analyzed by the Mann-Whitney statistic. Results: pCR was 44.5% to 28.4% (p=.004) in favor of nab-pac - carbo. Specifically within the carbo- containing arm, immunological (CD8, PD1, PFDL1) genes and proliferation markers (proliferation score and ROR scores, MKI67, CDC20, NUF2, KIF2C, CENPF, EMP3, TYMS) were positively associated with pCR (p<.05 for all). Specifically within the gem-arm, angiogenesis genes were negatively associated with pCR (ANGPTL4: p=.05; FGFR4: p=.02; VEGFA: p=.03). In the whole collective, basal-like (83.3%) was favorable for pCR (38% vs. 20%, p=.015) compared to other subtypes (HER: 6.4%; luminal-A: 1.7%; normal: 8.7%), as was lower HER-2 score (p<.001). Proliferation was positively associated with pCR: i.e., Pam50 proliferation score, ROR scores (all p<.004), and higher Ki67 by central IHC (p<.001) -- though not MKI67 RNA expression, despite their moderate correlation. Conclusions: In early TNBC, basal-like subtype, higher Ki67 (by IHC), and lower HER-2 score were associated with chemo-sensitivity for both neoadjuvant arms. Chemo-resistance pathways differed between the two taxane-based combinations (low proliferation and immune marker gene expression for carbo, high angiogenesis for gem). The positive predictive impact of immunological genes in the nab-pac - carbo arm could influence optimal patient selection for immune-modulative therapy. Clinical trial information: NCT01815242.
Effect of TCHL-based therapy on immune cell content in on-treatment, neoadjuvant-treated HER2-positive breast cancer patients.
Authors: Keegan Niamh M. , Toomey Sinead , Fay Joanna , Madden Stephen F. , Moran Bruce , Milewska Malgorzata , Das Sudipto , O'Connor Darran , Kennedy M. John , Power Colm , Hill Arnold D. , Egan Keith , Teiserskiene Ausra , Kay Elaine , Crown John , Eustace Alex J , Hennessy Bryan
Published: September 2018

583

Background: In the TCHL trial (NCT01485926) 78 women with HER2-positive breast cancer (BC) underwent neo-adjuvant treatment with either TCH (Docetaxel, Carboplatin, Trastuzumab) or TCHL (TCH + Lapatinib) therapy. Of the 78 patients, 24 consented to an optional on-treatment biopsy 20 days after 1 cycle of therapy. We analysed the impact of tumour infiltrating lymphocytes (TILs) on pathological complete response (pCR) and also determined the impact of TCH/TCHL therapy on immune cell modulation after 20 days of treatment. Methods: We assessed TIL and stromal lymphocytes (SL) counts using immunohistochemical staining with Haemotoxalyin+Eosin, AE1/AE3 and CD45 in formalin fixed paraffin embedded (FFPE) baseline biopsy samples and in fresh frozen (FF) biopsies taken 20-days post cycle 1 (Day-20) of TCH/TCHL. RNA libraries were generated, using the Truseq mRNA library prep kit on the Neoprep platform and sequenced on the NextSeq 500. We measured the transcriptomic profile of 8 pre and on-treatment sample pairs and then used the Microenvironment Cell Populations (MCP)-counter method to measure the abundance of 10 immune cell populations (T cells, CD8 T cells, cytotoxic lymphocytes, NK cells, B lineage, myeloid dendritic cells, neutrophils, endothelial cells and fibroblasts). Results: We found that higher baseline levels of TILs (p = 0.045) but not SL were associated with an increased likelihood of a patient achieving a pCR to TCH/L based therapy. We found in day 20 on-treatment biopsies of women that subsequently went onto have a pCR that levels of SLs but not TILs were significantly higher (p = 0.049) than in those women who did not have a pCR. Finally we found significant increases in the level of monocytes (p = 0.05) and fibroblasts (p = 0.01), but not other immune cell populations, in the day 20 on-treatment biopsies in comparison with the mutated pre-treatment biopsies. Conclusions: In our study baseline TILs but not SLs have a predictive role in the likelihood of a patient achieving a pCR. We also found that TCHL based therapy significantly altered both monocytes and fibroblasts, indicating a possible role for these immune subtypes in response to TCHL therapy.
A phase 1b/2 study of amcasertib, a first-in-class cancer stemness kinase inhibitor in advanced head and neck cancer.
Authors: Cote Gregory Michael , Chau Nicole Grace , Spira Alexander I. , Edenfield William Jeffery , Laurie Scott Andrew , Richards Donald A. , Richey Stephen Lane , Gao Yuan , Li Youzhi , Li Wei , Hitron Matthew , Li Chiang
Published: September 2018

6032

Background: Amcasertib (BBI-503) is an oral first-in-class cancer stemness kinase inhibitor. By targeting multiple serine-threonine stemness kinases, amcasertib inhibits Nanog and other cancer stemness pathways. A phase I clinical trial of amcasertib showed safety and signs of anti-cancer activity in patients (pts) with advanced solid tumors during dose-escalation and RP2D expansion, including pts with advanced head & neck cancer. Methods: Pts with advanced, pre-treated head & neck cancers were enrolled. Amcasertib was administered orally, once or twice daily, in continuous 28-day cycles at a starting dose of 10 mg to 300 mg total daily. Adverse events were categorized according to CTCAE v4.03 and tumor imaging was evaluated per RECIST 1.1 guidelines every 8 weeks. Results: A total of 21 pts were enrolled, 15 with HNSCC and 6 with salivary or parotid gland cancers. Prior treatments included radiation in 90% (19/21), surgery in 71% (15/21) and prior systemic therapy in 90% (19/21, average 3 prior lines, range 1 to 6). Amcasertib was well tolerated with 43% of pts treated at 300 mg daily (n = 9), 33% at 150 mg BID (n = 7), 19% at 200 mg daily (n = 4), and 5% at 10 mg daily (n = 1). Grade 3 AE included diarrhea (n = 4) and nausea (n = 1). Among all patients who received an evaluation per RECIST (n = 16), the objective responses rate (ORR, proportion with partial response [PR] or complete response [CR] per RECIST) was 13% and the disease control rate (DCR, proportion with stable disease [SD] at 8 weeks, PR or CR) was 50%. At 12 months, in the intent-to-treat population (n = 21) 38% of pts were alive. Median overall survival (mOS) of 7.2 months. Conclusions: Clinical safety and encouraging signs of anti-cancer activity were observed in pts with advanced head and neck cancers who have received treatment with amcasertib. Objective response, prolonged disease control, and extended survival have been observed in this pre-treated population with a poor prognosis. Further clinical evaluation of amcasertib in patients with head and neck cancers is warranted. Clinical trial information: NCT01781455.