bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proliferation pathway aberration frequencies in BRCA1- and BRCA2-mutated ovarian cancers.
Authors: Zajchowski Deborah A. , Salamon Hugh , Yamaguchi Ken D. 
Published: March 2020

5074 Background: Large-scale genomic analyses of high-grade, advanced-stage serous ovarian cancers by The Cancer Genome Atlas (TCGA) project revealed aberrations in genes comprising key proliferation and survival pathways (RB-E2F, RAS, PI3K) in the majority of tumors. Patients with germline BRCA1/2-mutations have more favorable prognoses than non-BRCA carriers, and recent work suggests that BRCA2 carriers do better than BRCA1. We hypothesized that concurrent proliferation pathway aberrations and BRCA1/2 mutations in tumors might play a role in patient outcome. Methods: Mutation, copy number, and clinical data for 309 TCGA-profiled serous ovarian tumors were downloaded from the MSKCC cBIO web portal. Each tumor was scored as aberrant for a pathway if any gene (RB: RB1, CDKN2A, CCND1, CCND2, E2F3, CCNE1; PI3K: PIK3CA, PTEN, AKT1, AKT2; RAS: KRAS, BRAF, NF1) in that pathway was mutated, amplified, or deleted. Results: 205 of 309 tumors had an aberration in at least one of these pathways. The frequency of pathway alteration differed significantly in BRCA1 (82%, 28/34), BRCA2 (52%, 17/33) and BRCA1/2 WT (66%, 160/242) tumors (BRCA1 vs. BRCA2: Fisher’s p= 0.0096). BRCA1 tumors more frequently contained alterations in multiple pathways than BRCA2 or WT tumors (41% vs. 24% or 25%, respectively). RB-E2F pathway alteration frequency was significantly different (BRCA1: 56%, BRCA2: 18%, WT: 43%, p=0.0043), but no significant differences in PI3K and RAS pathway aberration frequencies (BRCA1%: 41, 38; BRCA2%: 36, 27; WT% 28, 27), respectively, were observed. In agreement with the previous report, BRCA2 patients had significantly better overall survival (OS) than either BRCA1 or WT patients (median OS months for BRCA1: 35.9, BRCA2 45.4, BRCA1/2 WT 27.8; p=0.001). Presence of pathway alterations was not significantly associated with OS in BRCA1, BRCA2, or WT patients in this cohort. Conclusions: These results show a negative association between BRCA2 mutations and aberrations in key proliferation and survival pathways. Beyond BRCA1 and BRCA2 genetic mutations, the elevated frequency of pathway alteration in BRCA1 vs. BRCA2 tumors highlights differences that may be important for patient prognosis as well as therapy responses.
Concurrent chemoradiotherapy with paclitaxel and cisplatin for adenocarcinoma of the cervix.
Authors: Nagai Yutaka , Toita Takafumi , Inamine Morihiko , Kudaka Wataru , Nakamoto Tomoko , Wakayama Akihiko , Ooyama Takuma , Tokura Akemi , Aoki Yoichi 
Published: March 2020

5086 Background: Adenocarcinoma of the cervix has a worse prognosis than its squamous counterpart, particularly when cancer cells spread beyond the uterine cervix. This is derived from the observation that adenocarcinoma is less sensitive to radiotherapy (RT) and chemotherapy It is unclear whether cisplatin-based concurrent chemoradiotherapy (CCRT) has the same effect on adenocarcinoma as on squamous cell carcinoma. Methods: We retrospectively analyzed 32 patients with stage IIB–IVA cervical adenocarcinoma who were treated with RT or CCRT. Fourteen patients were treated with RT from 1983–1996, 8 with CCRT using cisplatin alone (CCRT-P) from 1997–2002, and 10 with CCRT using cisplatin+paclitaxel (CCRT-TP) after 2003. The patients were treated with external beam radiotherapy, and low-dose or high-dose rate intracavitary brachytherapy. For CCRT-P, the patients received 20 mg/m2 cisplatin for 5 days every 3 weeks, and for CCRT-TP, the patients received 50 mg/m2 cisplatin every 3 weeks and 50 mg/ m2 paclitaxel weekly. Results: A complete response was achieved in 7/14 patients in the RT, 4/8 patients in the CCRT-P, and 9/10 patients in the CCRT-TP group. Ten of the 14 patients in the RT, 7/8 patients in the CCRT-P, and 2/10 patients in the CCRT-TP group experienced locoregional recurrence. The 5-year overall survival rate in the RT, CCRT-P, and CCRT-TP groups was 7.1%, 25.0%, and 74.1%, respectively (p = 0.0094), and their central disease-free survival rate was 21.4%, 12.5%, and 78.8%, respectively (p=0.0119). The acute toxicities associated with CCRT-TP are manageable. Regarding late toxicity of CCRT-TP, no grade 3/4 adverse effect was observed. Conclusions: The present study demonstrated that CCRT-TP achieved much better local control for adenocarcinoma of the cervix, leading to a decrease in locoregional recurrence. Prospective trials in larger series of patients are urgently needed.
A phase II study of dose-dense neoadjuvant chemotherapy with weekly paclitaxel and carboplatin followed by chemoradiation in locally advanced cervical carcinoma.
Authors: Singh Rajkumar Bikramjit , Kumar Lalit , Chandra Subhash , Mohanti B. K , Pathy Sushmita , Kumar K. Sunesh , Bhatla Neerja , Thulkar Sanjay , Vishnubhatla Sreenivas 
Published: March 2020

5104 Background: We prospectively studied dose dense neoadjuvant chemotherapy (NACT) designed for an enhanced cell kill, better local control and eradication of micrometastases prior to standard concurrent chemoradiation (CRT) in locally advanced cervical cancer. Methods: Between June 2010 and December 2011, 21 patients (median age - 51 years, range 35 - 67) of cervical cancer with locally advanced disease received NACT using paclitaxel (60mg/m2) and carboplatin (AUC-2) weekly for 6 doses. Patients (pts) then received concurrent CRT (external and brachytherapy) with weekly cisplatin (40mg/m2 for 6 doses) at a mean interval of 15 days (range 7–20 days). The primary end-point was response rate i.e. complete response (CR) and partial response (PR) 12 weeks post CRT. Results: Baseline stages were: stage 2A - 19%, 3B - 71.4%, 4A - 9.5%. Squamous cell carcinoma and adenocarcinoma constituted 95.2% and 4.7% pts respectively. Following NACT, 66.6% pts responded (CR -9.5% %; PR – 57.1 %), 23.8% had stable disease (SD) and 4.7% had progressive disease (PD). A total of 18 pts completed NACT and CRT of which 17 were in CR and 1 in PR. One patient with stage 4A disease developed vesicovaginal fistula at end of NACT for which she underwent pelvic exenteration and was in pathological CR. After NACT, one patient developed choroid metastases and was taken off study protocol while another patient was lost to follow up. At a mean follow up 5.8 months (range 1 - 14), 90% pts were in CR, 5% in PR and 5% had PD. During NACT, Grade 3/4 neutropenia, thrombocytopenia and anemia were seen in 33.3%, 4.7% & 9.5% of pts, respectively and grade 3/4 non-hematological toxicities in 9.5% pts. Following CRT, Grade 3/4 neutropenia, thrombocytopenia and anemia were seen in 25%, 5% and 10% of pts, respectively while 20% pts had grade 3/4 non-hematological toxicities. G-CSF was used in 30% pts during NACT and 25% pts during CRT, respectively. Conclusions: NACT with weekly paclitaxel and carboplatin followed by radical CRT is feasible and is associated with a high response rate in locally advanced cervical cancer. This approach needs to be studied in a phase III trial.
Effects of everolimus (EVE) on disease progression in bone and bone markers (BM) in patients (pts) with bone metastases (mets).
Authors: Gnant Michael , Baselga José , Rugo Hope S. , Noguchi Shinzaburo , Pritchard Kathleen I. , Burris Howard A. , Piccart-Gebhart Martine J. , Hart Lowell L. , Eakle Janice F. , Mukai Hirofumi , Iwata Hiroji , El-Hashimy Mona , Rao Shantha , Taran Tanya , Sahmoud Tarek , Lebwohl David Edward , Hortobagyi Gabriel N. 
Published: March 2020

512 Background: BOLERO-2, a multinational, double-blind, placebo-controlled, phase III study in postmenopausal women with estrogen-receptor–positive breast cancer (BC) refractory to non-steroidal aromatase inhibitors (NSAIs), showed significant clinical benefits with the addition of EVE to exemestane (EXE) (Baselga J, et al. NEJM. 2011 Epub). As bone resorption is an important factor in BC mets, it is interesting to study bone-related effects of EVE. In preclinical studies, mTOR inhibition was associated with decreased osteoclast survival and activity. Exploratory analyses in BOLERO-2 evaluated the effect of EVE vs placebo (PBO) on BM levels and BC progression in bone in pts with bone mets at baseline. Methods: Eligible pts were treated with EXE (25 mg once daily) and randomized (2:1) to EVE (10 mg once daily) or PBO. Bone turnover markers were exploratory endpoints analyzed at 6 and 12 wks after treatment initiation, and included bone-specific alkaline phosphatase, amino-terminal propeptide of type I collagen, and C-terminal cross-linking telopeptide of type I collagen. Progressive disease in bone (PDB) was defined as worsening of a pre-existing bone lesion or a new bone lesion. Results: Baseline disease characteristics, including bone mets at baseline (n = 370, 76% EVE vs n = 184, 77% PBO), were well balanced between arms (N = 724), and baseline bisphosphonate use was not (44% EVE vs 55% PBO). At 12.5 mo median follow-up, progression-free survival (primary endpoint), overall response rate, and clinical benefit rate (P < .0001, all) were significantly higher with EVE (n = 485) vs PBO (n = 239). BM levels at 6 and 12 wks increased vs baseline with PBO, but decreased with EVE. The cumulative incidence rate of BC PBD was lower for EVE vs PBO at day 60 (3.03% vs 6.16%, respectively) and this trend was sustained beyond 6 months. Updated results will be presented. All bone-related adverse events reported were grade1/2 and occurred with similar frequency in EVE- (2.9%) and PBO- (3.8%) treated patients. Conclusions: Exploratory analyses from BOLERO-2 suggest that adding EVE has beneficial effects on bone turnover and BC progression in bone in pts receiving EXE therapy for NSAI-refractory BC.
Adjuvant zoledronic acid (ZOL) in postmenopausal women with breast cancer and those rendered postmenopausal: Results of a meta-analysis.
Authors: Gregory Walter , Marshall Helen , Bell Richard , Cameron David A. , Coleman Robert Edward 
Published: March 2020

513 Background: A number of groups have now reported results of randomised trials of adjuvant zoledronic acid (ZOL) for women with early stage breast cancer. Following an interaction effect observed in the AZURE trial, where postmenopausal women appeared to benefit from ZOL, we performed a meta-analysis, from both publications and presented data, of the most recent results from these trials. We also looked at recently reported large studies of clodronate and ibandronate in older or postmenopausal women to further examine this hypothesis. Methods: DFS data from 8735 women in 7 trials (AZURE, ABCSG-12, ZO-FAST, Z-FAST, EZO-FAST, NSABP-B34, GAIN) that included a randomization to ZOL vs. control or clodronate/ibandronate vs. control were examined. Median follow-up was 5 years. 14% of women experienced a DFS event. The ABCSG-12 study was included since, although it included only premenopausal women, they were all treated with goserelin, effectively rendering them postmenopausal, prior to and during treatment with ZOL. We analysed the subgroup of women aged ≥50 in the NSABP-B34 study in the absence of information on menopausal status, and included only postmenopausal women from the AZURE and GAIN trials. Sensitivity analyses confirmed that exclusion of some older, small, clodronate studies that lacked DFS data, or failed to report by age or menopausal status would be unlikely to alter these findings. Results: For the 5 ZOL studies alone, there was a very substantial and highly significant DFS benefit for ZOL, 2P=.0006, with a hazard ratio of 0.76, and therefore a DFS risk reduction of 24% (95% CI 11%-35%). The results were, in the main, extremely consistent, with the exception of the very small E-ZO-FAST study, which had only 30 events. The risk reduction lessened to 18% (95% CI 8%-26%) when adding in the clodronate and ibandronate studies, but the result remained highly significant (2P=.00075). Conclusions: These meta-analysis results, including more than 8000 women in a range of studies, now provide strong evidence that ZOL is an effective adjuvant treatment for postmenopausal women with early stage breast cancer, and that the treatment benefits are substantial.
Vasomotor (VM) and musculoskeletal (MSK) symptoms and association with outcomes on extended adjuvant letrozole therapy: Analyses from NCIC CTG MA.17.
Authors: Liedke Pedro Emanuel Rubini , Chavarri-Guerra Yanin , Shepherd Lois E. , Tu Dongsheng , Pritchard Kathleen I. , Goss Paul Edward 
Published: March 2020

524 Background: Surrogate markers of clinical outcomes can potentially guide cancer therapy. New onset MSK symptoms and VM symptoms on aromatase inhibitors (AI) for hormone receptor positive (HR+) early breast cancer (EBC) have been investigated as markers of clinical outcomes, but results have been conflicting. MA.17 showed improved disease free survival (DFS) with letrozole (L) as extended adjuvant therapy after 5 years of tamoxifen (T). We performed this exploratory analysis of new onset symptoms and their association with clinical outcomes in the MA.17 trial. Methods: Patients (pts) with HR+ EBC were randomized to receive L or placebo (P) for 5 years after 5 years of T. Symptoms were collected according to CTC v. 2.0 at baseline, 1 month (mo), 6 mos, and every 12 mos thereafter. Analyses included pts with new symptoms of any grade who received therapy and excluded pts with baseline symptoms, EBC not HR+, and deaths/ relapses prior to each time point. Symptoms were categorized as VM - hot flashes/flushes, flushing, or sweating; and MSK - arthritis, arthralgia, myalgia, bone pain, or MSK other. Multivariate Cox Models adjusting for age, nodal status, duration of T and prior chemotherapy were used for analysis of DFS, distant DFS (DDFS), and overall survival (OS) assessed before unblinding. Hazard Ratios [HR] and 95% confidence intervals (CI) for patients with either VM or MSK symptoms are presented below for L using pts with no symptoms as controls. Results: Emergent VM symptoms were associated with improved DFS and DDFS on L (Table). No association was found for MSK symptoms at any time point. No association between either MSK or VM and OS was found at any time point. Conclusions: New VM symptoms initiating with extended letrozole were associated with improved outcomes. Similar findings have been seen with up-front AI therapy. Our results should be confirmed as they are of potential significance in guiding therapy. [Table: see text]
Common polymorphisms in the estrogen receptor-1 may determine risk of hot flashes in early breast cancer patients using tamoxifen.
Authors: Dezentje Vincent O. , Guchelaar Henk-jan , van Schaik Ron H. N. , Vletter - Bogaartz Judith M. , van der Straaten Tahar , Wessels Judith A.M. , Meershoek – Klein Kranenbarg Elma , Hille Elysee T.M. , Berns Els M. , Seynaeve Caroline M. , Putter Hein , Van De Velde Cornelis J. H. , Nortier J. W. R. , Gelderblom Hans 
Published: March 2020

526 Background: In breast cancer patients the occurrence of hot flashes as common side effect of tamoxifen therapy may be associated with effective estrogen receptor antagonism dependent on genetic variations of metabolic enzymes and the estrogen receptor. Methods: 742 early breast cancer patients who were randomized to receive tamoxifen, followed by exemestane after 2.5 to 3 years within the Tamoxifen Exemestane Adjuvant Multinational (TEAM) Trial were genotyped for 30 germ line genetic variants of 11 enzymes that are involved in the tamoxifen metabolism and the estrogen receptor 1 (ESR1). These genetic variants were related to the occurrence of hot flashes during the first year of tamoxifen use (primary aim) and during the complete tamoxifen treatment period (secondary aim). A multivariable logistic regression was used to adjust for age and adjuvant chemotherapy. Results: No genetic variant was associated with the occurrence of hot flashes during the first year. Higher age was related to a lower incidence of hot flashes in the first year (adjusted odds ratio 0.94, 95% CI 0.92-0.96; p<0.001). The ESR1 PvuII XbaI CG haplotype (CG/CG vs CG/other + other/other: adjusted odds ratio 0.44, 95% CI 0.21-0.92; p=0.03), ESR1 PvuII XbaI TA haplotype (TA/TA + TA/other vs other/other: adjusted odds ratio 1.86, 95% CI 1.09-3.14; p=0.02) and age (adjusted odds ratio 0.94, 95% CI 0.92-0.97; p<0.001) were associated with the occurrence of hot flashes during the total tamoxifen treatment period. No association was found between the CYP2D6 predicted phenotype and hot flashes. Conclusions: Common polymorphisms in the estrogen receptor-1 might help to predict the occurrence of hot flashes in breast cancer patients treated with adjuvant tamoxifen. If replicated, this may provide clinicians with a tool to offer more personalized hormonal therapy.
Activity of cabozantinib (XL184) in metastatic breast cancer (MBC): Results from a phase II randomized discontinuation trial (RDT).
Authors: Winer Eric P. , Tolaney Sara , Nechushtan Hovav , Berger Raanan , Kurzrock Razelle , Ron Ilan-Gil , Schoffski Patrick , Awada Ahmad , Yasenchak Christopher A. , Burris Howard A. , Ramies David A. , Rafferty Teresa , Shen Xiaodong 
Published: March 2020

535 Background: Dysregulation of MET and VEGF signaling has been implicated in breast cancer development and progression, including tumor invasion and dissemination. Cabozantinib (cabo) is an oral, potent inhibitor of MET and VEGFR2. A RDT evaluated activity and safety in 9 tumor types, including MBC. Methods: Eligible patients (pts) were required to have progressive measurable disease per RECIST. Pts received cabo at 100 mg qd over a 12 wk Lead-in stage. Tumor response (mRECIST) was assessed q6 wks. Treatment ≥ wk 12 was based on response: pts with PR continued open-label cabo, pts with SD were randomized to cabo vs placebo, and pts with PD discontinued. Primary endpoint in the randomized discontinuation phase was progression-free survival (PFS). Results: Enrollment to this cohort is complete (n = 45); all pts are unblinded. Baseline characteristics: median age 56; invasive ductal 86%, invasive lobular 7%; ER+ 93%, HER2+ 18%, triple- 5%; visceral disease 91%; bone metastases 73%; median prior lines of therapy 3 (range 1-8), including 71% with prior anthracyclines. Median follow-up was 2.9 mos (range 0.1 -16). 21 pts (47%) completed Lead-in stage with only 9 randomized to continue cabo (n = 5) or placebo (n = 4). Median PFS from Study Day 1 was 4.1 mos. At wk 12, objective response rate was 14% and disease control rate 48%. Tumor regression was observed in 25/39 pts (64%) with ≥1 post-baseline tumor assessment. 4/10 pts evaluable by bone scan had partial resolution of bone lesions. Of 12 pts receiving narcotics for bone pain, 5 pts reported improved pain and 2 pts had decreased narcotics use, per investigator. 4/14 evaluable pts (29%) with bone metastases experienced ≥50% decline in serum NTx. Most common Grade 3/4 AEs were palmar-plantar erythrodyesthesia (13%) and fatigue (11%). One related Grade 5 AE of respiratory compromise was reported during the Lead-in stage. Conclusions: Cabo demonstrated a 14% rate of objective tumor regression in heavily pretreated MBC pts. Observed effects on bone scan and pain are consistent with those seen in other malignancies. The safety profile of cabo was comparable to that seen with other VEGFR TKIs.
Statin use and the development of bone metastasis in breast cancer patients.
Authors: King Gentry T , Yun Jeong H , Chae Young K , Valsecchi Matias E 
Published: March 2020

536 Background: The Mevalonic Acid Pathway has been implicated in the promotion of a microenvironment suitable for establishment of bony metastasis from breast cancer. The statins, which act on this pathway, have been shown to have in-vitro anti-neoplastic activity against breast cancer. This study was designed to evaluate the association of statin use and development of bony metastasis in breast cancer patients. Methods: Medical records of patients treated for stage II-III breast cancer from 1999 to 2010 were retrospectively reviewed. Statin use was defined as medication use for at least 3 months in patients with no evidence of disease after initial diagnosis and treatment. The primary outcome was development of metastasis to bone. Secondary outcomes were overall survival, disease free survival and other sites of distant metastasis. Results: A total of 841 patients were included in the study of which 223 used statins. Both unadjusted and multivariate analysis adjusted for age, race, grade, stage , BRCA status, showed that patients on statins had a significantly lower incidence of metastasis to bone (OR 0.49, 95% CI 0.25-0.96, p=0.04). Adjusted analysis for other sites showed a trend towards decreased incidence of metastasis for statin users, but was not statistically significant (95% CI 0.39-1.08, p=0.10). Overall survival was increased in statin users with mean survival of 66.45 +/- 2.48 months versus non-users 58.78 +/ - 1.41 months (p=0.05). Statin users had significantly longer disease free survival with a mean of 63.65 +/- 2.49 months versus 53.96 +/- 1.42 months in non statin users (p=0.00). Conclusions: The use of statin drugs in patients with breast cancer was significantly associated with decreased incidence of metastasis to bone, but not to other distant sites. The role of statins in chemoprevention of bone metastasis should be further explored.
Randomized trials of adjuvant tamoxifen versus tamoxifen and octreotide LAR in early-stage breast cancer: NCIC CTG MA.14 and NSABP B-29.
Authors: Chapman Judy-Anne W. , Costantino Joseph P. , Dong Bin , Margolese Richard G. , Pritchard Kathleen I. , Shepherd Lois E. , Gelmon Karen A. , Wolmark Norman , Pollak Michael N. 
Published: March 2020

538 Background: MA.14 and B-29 examined whether the addition of Octreotide (SMS 201-995 pa LAR; OCT) to 5 years adjuvant tamoxifen (TAM) prolonged disease-free survival (DFS). Excessive gallbladder (GB) toxicity in B-29 led to DMC recommended stopping of OCT and MA.14 shortening of OCT to 2 years. Data for the 2 trials were pooled. Methods: Median follow-up of the 667 MA.14 patients was 9.8 years, and of the 893 B-29 patients, 6.8 years for ITT analysis. The primary endpoint was DFS, defined as time from randomization to time of (local, regional or distant) breast cancer recurrence; any second primary cancer other than squamous or basal cell carcinoma of the skin, carcinoma in situ of the cervix, or lobular carcinoma in situ of the breast; or death. The primary test statistic was a pooled stratified log-rank test, with stratification within each trial by applicant stratification factors. Multivariate assessment was with Cox regression. Results: MA.14 patients were all postmenopausal with 97% ≥50 years of age while 62% of B-29 women were ≥50. 53% of MA.14 patients were lymph node negative (LN-), while all of B-29 patients were LN-. 33% of MA.14 patients received adjuvant chemotherapy, 2% concurrently, while 53% of B-29 received concurrent chemotherapy. 90% of MA.14 patients were hormone receptor positive while 100% of B-29 were positive. MA.14 patients experienced a 5 year DFS rate of 80% on TAM and 76% on TAM+OCT, while B-29 patients had a 5 year rate of 88% for both arms. The pooled 5 year rates were 85% and 83%. Pooled univariate stratified Cox HR of TAM+OCT to TAM was 0.99 (95% CI 0.81-1.20; p-value= 0.69). The HR for MA.14 was 0.93 (0.72-1.19; p= 0.50) and for B-29 was 1.09 (0.80-1.50; p=0.59). Multivariate pooled HR of TAM+OCT to TAM was 0.98 (0.81-1.20; p=0.84). Patients who were older (p=0.0006), and had higher T stage (p<0.0001) with LN+ (p=0.0008) had shorter DFS. Conclusions: OCT did not significantly improve DFS for women who were a broad spectrum of patients: pre- or post-menopausal, LN- or LN+, and received sequential, concurrent or no adjuvant chemotherapy. Neither study had the intended duration of OCT due to GB toxicity; thus, the results do not negate targeting the insulin - IGF-I receptor family.