bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact of obesity on time to recurrence in ovarian cancer: A retrospective study.
Authors: Hew Karina E , Bakhru Arvind , Harrison Evan , Turan Mehmet Ozhan , Rosenshein Neil B.
Published: March 2020

5055

Background: There has been conflicting data regarding the relationship between obesity and progression free survival in patients with ovarian cancer. There has been some evidence to suggest that obesity results in altered tumor biology and a poorer prognosis in these patients. The aim of this study was to examine whether obesity is a risk factor for time to recurrence in primary epithelial ovarian cancer. Methods: A multicenter retrospective chart review was performed at Mercy Medical Center and University of Michigan Medical Center. 591 patients were diagnosed with primary epithelial ovarian cancer between 2004-2009. However, 221 patients were excluded from the analysis because of persistent or progressive disease, treatment with neoadjuvant chemotherapy, presence of synchronous tumors or incomplete follow-up data. 370 patients were eligible for analysis. Data collected included: height and weight at the time of surgery, age, race, medical co-morbid illnesses, tumor stage, grade and histology. Treatment related data such as number of cycles of adjuvant chemotherapy; and optimal versus suboptimal tumor debulking was also collected. Body mass index (BMI) was defined according to WHO 2004 criteria. Women with a BMI greater than 30 were categorized as obese. The diagnosis of recurrence was made by positive radiological or pathological diagnosis of cancer recurrence after patient had surgery, received adjuvant chemotherapy and had no clinical, radiological or serological evidence of recurrence during this time. The time to recurrence was then quantified in terms of months from the initial surgery. Survival analyses were performed with the Kaplan-Meier method and compared using log-rank testing. Time to recurrence was analyzed using Mann-Whitney U and Wilcox W tests. Results: 130 (35%) obese patients were compared with 240 (65%) non obese patients. A recurrence was documented in 125 (47.9%) non obese patients and 49 (37.7%) obese patients. Time to recurrence between both BMI groups was found to be identical, at 15 months (p=1.0). The progression free survival was similar in both obese and non obese subjects (p=0.118). Conclusions: Obesity does not impact the time to recurrence in patients with primary ovarian cancer.
A phase Ib study of the combination of temsirolimus (T) and pegylated liposomal doxorubicin (PLD) in advanced or recurrent breast, endometrial, and ovarian cancer.
Authors: Boers-Sonderen Marye , Desar Ingrid , Van Der Graaf Winette T.A. , Ottevanger P. B. , Van Herpen Carla
Published: March 2020

5061

Background: PLD is active in metastatic breast, endometrial and ovarian cancer. Preclinical studies suggest that mTOR inhibitors (mTORi), such as T, have an additive therapeutic effect to chemotherapy and resistance to doxorubicin can be reversed by adding an mTORi. Therefore, the combination of T and PLD is highly promising. Methods: This phase I study assessed the maximum tolerated dose (MTD), safety and activity of the combination of T and PLD in advanced or recurrent breast, endometrial or ovarian cancer. Patients (pts) who were not previously treated with PLD or T, with adequate organ function were eligible. After a two week run in period with T iv once weekly, PLD iv once every four weeks was added. In case of clinical benefit, pts were treated for a maximum of 9 cycles combination therapy. T could be continued as monotherapy afterwards. The MTD was defined as the highest dose at which ≤ 1 dose limiting toxicity (DLT) had been observed among 6 pts. FDG PET scans were performed at baseline and after 2 and 6 wks to assess the effect on tumor metabolism. Pharmacokinetic (PK) sampling was performed during cycle 1. Results: 20 pts were enrolled. On the 4th dose level with 20 mg T and 40 mg/m2 PLD 2 DLTs occurred in 6 pts: a grade 3 thrombocytopenic bleeding and a grade 3 skin toxicity. Therefore, the MTD was assessed at 15 mg T and 40 mg/m2 PLD. Adverse events (all grades/grade 3-4 in %) occurring most frequently were fatigue (84/5), nausea (84/16), mucositis (79/21), vomiting (74/16) and anorexia (74/0) Furthermore, rash and hand foot syndrome occurred both in 53% of pts, with 11% and 21% grade 3 respectively. 3 pts had a confirmed PR and 9 had SD (> 3 months). The mean progression free survival (PFS) was 4.9 months with 2 pts still on treatment. Results of FDG PET and PK data are currently being analyzed and will be presented. Conclusions: The combination of T and PLD is safe and tolerable. The MTD was assessed at PLD 40 mg/m2 once every 4 weeks and T 15 mg weekly. The activity of this combination in breast, endometrial and ovarian cancer pts is promising and warrants further studies.
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.
A dendritic metagene that predicts prognosis and endocrine resistance in breast cancer.
Authors: Giampaolo Bianchini , Pusztai Lajos , Qi Yuan , Iwamoto Takayuki , Kelly Catherine M , Zambetti Milvia , Symmans William Fraser , Gianni Luca
Published: March 2020

545

Background: High expression of dendritic-associated genes in estrogen receptor-positive (ER+), highly proliferative breast cancer is associated with good prognosis in untreated patients (pts) and poor response to neoadjuvant endocrine therapy (Dunbier SABCS 2010). We examined the prognostic and predictive value of a dendritic metagene (DM) signature in subgroups defined by proliferation and estrogen-related genes (Bianchini SABCS 2011). Methods: We evaluated Affymetrix HGU133A-based gene expression profiles from ER+ untreated (n=511) and adjuvant tamoxifen (TAM)-treated pts (n=606). Three previously defined scores were assessed: MKS for proliferation (Bianchini, Cancer Res 2010); estrogen-related score (ERS) adopted from Oncotype DX; and DM (Bianchini JCO 2010). Median cut-off points were used. Outcome was assessed according to distant relapse. Results: DM was significantly predictive for early (within 5 years) relapse. In TAM-treated pts with low-MKS tumors, DM was not significantly prognostic. The table shows hazard ratios (HRs) for low vs. high-DM by ERS in untreated and TAM-treated pts with high-MKS. In low-DM, the 5-yrs distant-event free survival was 92.3% and 60.6% (HR 6.58 (2.55-17.0); p<0.001) and in high-DM it was 80.7% and 79.8% (HR 1.06 (0.48-2.32); p=0.88), respectively in high and low-ERS respectively. The interaction between DM and ERS was significant only in TAM-treated tumors (p=0.003). In high-MKS/low-ERS tumors, DM retained significance over the 10-year period in multivariate analysis adjusting for clinical variables (HR= 2.27 (1.13-4.58); p=0.02). Conclusions: For high-MKS, untreated and TAM-treated tumors with low-ESR, high-DM is associated with a low risk of relapse, and for untreated tumors with high-ERS. These data suggest that high infiltration of tumor by dendritic cells may be a novel mechanism of endocrine resistance. DM could refine risk in poor prognosis ER+ tumors and rationalize immuno-modulating strategies. [Table: see text]
Randomized phase II trial of cisplatin and radiotherapy with or without erlotinib in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN).
Authors: Martins Renato , Parvathaneni Upendra , Sharma Anand K. , Raez Luis E. , Papagikos Michael A. , Yunus Furhan , Bauman Julie E. , Eaton Keith D. , Liao Jay Justin , Mendez Eduardo , Futran Neal , Kurland Brenda F , Wang David X. , Xiaoyu Shawn , Wallace Sarah G. , Hayes David N.
Published: March 2020

5503

Background: The combination of cisplatin and radiotherapy is a standard treatment for patients with locally advanced SCCHN. Cetuximab-radiotherapy is superior to radiotherapy alone in this population, validating EGFR as a target. Erlotinib, a small molecule inhibitor of EGFR, has activity in recurrent/metastatic disease. Adding EGFR inhibition to standard cisplatin-radiotherapy may improve efficacy. Methods: Patients with locally advanced SCCHN were randomized to receive cisplatin 100mg/m2 on days 1,22 and 43 combined with 70Gy of radiotherapy (arm A) or the same chemoradiotherapy combined with erlotinib 150mg/day, starting one week prior to radiotherapy and continued to its completion (arm B). Randomizing 204 patients had 80% power to compare a 60% complete response rate (CRR) to a 40% null rate. Available tumors were tested for p16, ERCC1 and EGFR FISH. Results: Between June 2006 and October 2011, 204 patients were randomized. Results presented are based on intention to treat. There were more females on arm A however no other differences in patient characteristics, including p16 positivity. Patients on arm B had more rash and gastrointestinal adverse events, but treatment arms did not differ for rates of other grade III/IV toxicities or serious adverse events (SAEs). Arm A had a CRR of 61% and arm B had a CRR of 68% (p=0.3). With a median follow-up of 23 months, there were only 29 events in the overall survival analysis and 46 in the progression-free survival (PFS) analysis. The 2 and 3 year PFS were 71% and 63% for arm A and 78% and 73% for arm B (p=0.61). Conclusions: The addition of erlotinib did not increase the rate of SAEs but failed to significantly increase CRR. As seen in other recent trials, our results in both arms are superior to historical comparisons. Updated PFS data will be presented. Supported by a grant from the investigator-initiated trial program of Genentech/OSI.
Five years' results of the German ARO 04-01 trial of concurrent 72 Gy hyperfractionated accelerated radiation therapy (HART) plus once weekly cisplatinum/5-FU versus mitomycin C/5-FU in stage IV head and neck cancer.
Authors: Budach Volker , Cho Chie-Hee , Sedlmaier Benedikt , Wittlinger Michael , Iro Heinrich , Engenhart-Cabillic Rita , Hautmann Matthias , Strutz Juergen , Flentje Michael , Hueltenschmidt Beatrix , Moser Lutz , Bleif Martin , Budach Wilfried , Staar Susanne , Becker Gerd , Tribius Silke , Feyer Petra C. , Wernecke Klaus Dieter , Werner Jochen
Published: March 2020

5512

Background: Are 6 cycles of once weekly DDP plus one cycle of 5-FU with concurrent HART superior to 2 cycles of MMC plus one cycle of 5-FU in terms of overall survival (OS) and metastases-free survival (MFS)? Methods: Eligibility: Stage IV SCC of oro(OP)- and hypopharynx(HP), KFS of ≥80% stratified for sites, N-status, grading, hemoglobin and center. The HART schedule was reported elsewhere (V.Budach, JCO 23;2005). HART was applied concurrently with DDP/5-FU at 30mg/m² days 1,8,15,22,29,36 or MMC/5-FU at 10mg/m2 day 1+36 and for both arms with 600mg/m² 5-FU days 1-5 as 120 hrs. c.i. TVD dose prescription was 72 Gy using 3D-conformal or IMRT-TP. 364 patients were analysed using an ITT principle for OS, MFS, progression-free survival (PFS) and loco-regional control (LRC). Hazard ratio (HR) calculations were adjusted for competing risk factors. Results: Median follow-up was 48 mos. for both arms. Mean age was 55.4 years, 83/17% were male/female and 100% stage IV patients (UICC 2002). 58.5%/41.5% of all patients suffered from OP- or HP cancer, respectively. The OS and MFS at 4 years for the DDP- versus MMC-arm was 42.1% vs. 38.8% (n.s.) and 67.3% vs. 56.6% (p=.05), respectively. The LRC and PFS for the DDP versus MMC-arm was 58.6% vs. 57.2% (n.s.) and 46.4% vs. 38.7% (n.s.). Seven items recorded for acute toxicity and 9 for late morbidity showed no significant differences between the treatment arms except for creatinine for the DDP-arm (p < 0.001) using nonparametric analyses of variances for repeated measurements. The overall compliance rates for RTX were 96%, DDP: 72%, 5-FU: 97%, MMC: 86%, respectively. Conclusions: This phase III trial first establishes level IB-evidence for a once weekly DDP chemoradiation regimen. For MFS at 4 yrs., DDP/5 FU-HART is superior to MMC/5 FU HART at equal levels of acute and late radiation sequelae for both treatment arms. No significant differences were seen yet for OS, PFS or LRC. Chemoradiation with weekly DDP/5-FU or MMC/5-FU shows excellent compliance rates and can easily compete with other concurrent chemo- or bio-radiation schedules including induction TPF followed by radiation.
Safety, molecular, and imaging responses to cetuximab administered in a window pre-operative study in squamous cell carcinoma of the head and neck (SCCHN).
Authors: Schmitz Sandra , Hamoir Marc , Reychler Herve , Magremanne Michele , Weynand Birgit , Lhommel Renaud , Hanin Francois-Xavier , Lonneux Max , Rommel Denis , Michoux Nicolas , Duprez Thierry , Machiels Jean-Pascal H.
Published: March 2020

5519

Background: Only a minority of SCCHN pts benefits from anti-EGFR mAbs. Trials with pre- and post-therapy tumor biopsies are crucial to better characterize the molecular pathways involved in treatment response or resistance. Targeted agents (TA) are often investigated in unselected end-stage cancer pts, making difficult optimal translational research. One way to resolve this issue is to perform “window” studies where a TA is given during the incompressible period between the diagnosis and surgery. Methods: We conducted a phase I/II study: cetuximab (C) was given pre-operatively to treatment-naïve SCCHN pts selected for primary curative surgery. C (400mg/m2 first wk followed by 250mg/m2/wk) was given during 2 wks (day -15 until day -1, 3 infusions) before surgery (day 0). Tumour biopsies, FDG/PET, and CT were performed at diagnosis and surgery. In the phase I, we investigated the safety of preoperative C by progressively reducing the delay between the last dose of C and surgery (minimum delay : 24 hrs ; 3+3 phase 1 design). The aims of the phase II were (i) safety, (ii) C activity by FDG-PET (Po=0.10, P1=0.35, a=0.05 and b= 0.10). As controls, 5 additional pts were included without C treatment but with the same requirements regarding biopsies and imaging. Results: The phase 1 study (n=18) demonstrated that C infusion given 24 hrs before surgery was safe. Safety was confirmed in the phase II (n=20). 90 % had a FDG-PET partial response (PR) (EORTC guideline) in the C group and 0% in the controls. 52% had a ΔSUVmax decrease of >50%. 2 pts evaluable by CT/MRI had a PR (RECIST). Then, we compared the pre-and post treatment biopsies by immunochemistry. For the whole group, C did not reduce Ki67 (p=0.1) and did not seem to induce apoptosis (caspase). However, for pts with ΔSUVmax decrease > 25% or > 50%, Ki67 was decreased (p=0.04 and 0.006). C induced downregulation of pEGFR (p=0.0004) and pERK (p=0.007) but not pAKT/AKT (Histoscore). Conclusions: Pre-operative study with C is safe. Our findings suggest that the main downstream molecular pathway blocked by C in SCCHN is the RAS/RAF/ERK. Further analyses are ongoing to better characterize molecular response and escape mechanisms.
The influence of institutional head and neck cancer (HNC) clinical trial accrual on overall survival (OS): An analysis of RTOG 0129.
Authors: Wuthrick Evan John , Zhang Qiang , Machtay Mitchell , Ang K. Kian , Rosenthal David Ira , Nguyen-Tan Felix , Fortin Andre , Silverman Craig I. , Raben Adam , Kim Harold , Horwitz Eric M. , Read Nancy E , Harris Jonathan , Wu Qian , Gillison Maura L. ,   Radiation Therapy Oncology Group
Published: March 2020

5530

Background: NCCN recommends HNC patients (pts) be treated by providers with experience in HNC management. Whether treatment by experienced providers (measured by no. of pts treated) is associated with HNC survival outcome is unknown. Methods: Analysis included 471 pts in RTOG 0129 with stage III-IVa HNC with known tumor HPV and smoking status randomized to cisplatin concurrent with standard or accelerated fractionation radiotherapy (RT). Participating centers were stratified into pt accrual tertiles (ATs) to 21 RTOG HNC trials from 1997-2002. As a surrogate for experience, we investigated the independent effect of AT on OS and progression-free survival (PFS) in multivariable cox proportional hazards models. Results: Median follow up was 4.8 yrs (range 1.1 - 6.5). In Kaplan-Meier analysis, OS and PFS for pts at centers in the two lower AT (low accruing centers [LAC]) were similar and compared to the upper AT (high accruing centers [HAC]). Median accrual in LAC vs HAC was 11 vs 82 pts. Pts treated at LAC and HAC had similar age, HPV status, pack-years, N stage, comorbidities and study arm assignment (SAA), but pts at LAC had better performance status (PS)(Zubrod 0; 62% vs 52%; p=0.04), fewer T4 tumors (27% vs. 35%; p=0.05) and were more likely uninsured (12% vs 4%; p=0.009). Compared to HAC, LAC pts had significantly worse OS, (5 yr 51.0% vs 69.1%; p = 0.002), and PFS (5 yr 42.7% vs 61.8%; p = 0.001) and more locoregional failure (5 yr 36.4% vs 20.8%; p <0.001). Treatment at LAC was associated with ~90% increase in risk of death (OS HR 1.91, 95%CI 1.37-2.65) and progression (PFS HR 1.89, 95%CI 1.39-2.56) when compared to pts treated at HAC, after adjustment for age, PS, pack-years, T and N stage, SAA and HPV status. Acute and chronic toxicities, RT dose, fractions, and treatment duration did not differ for pts at LAC vs HAC. RT at LAC was more likely than HAC to differ from protocol (18% [16.8% acceptable variation {AV}, 1.2% unacceptable deviation {UD}] vs 6% [4.7% AV, 1.3% UD]; p<0.001). Conclusions: Pts with HNC treated at LAC in RTOG trials were associated with significantly worse survival outcomes compared to pts treated at HAC.
Prevalence, trends, and survival impact of human papillomavirus on oropharyngeal cancer in Indian population.
Authors: Bahl Ankur , Dar Lalit , Mohanti BK , Kumar Pankaj , Thakar Alok , Karthikeyan Venkat , Sharma Atul
Published: March 2020

5540

Background: Among oropharyngeal squamous cell carcinoma (OSCC), the true prevalence of HPV remains variable and studies have estimated that up to 60% may be HPV positive. Patients with HPV positive tumor are usuallyyounger in age, less likely to have history of tobacco or alcohol consumption and associated with a better prognosis but this information for Indian patients is largely unknown. Methods: 105 newly diagnosed patients of OSCC were enrolled. HPV genotyping was done on the biopsy specimen by consensus polymerase chain reaction and reverse line-blot hybridization assay. HPV prevalence was studied according to gender, age, tobacco and alcohol use and high risk sexual behavior. Results: Overall HPV prevalence was 22.8%. HPV positive patients were younger by 8 years as compared to negative patients (P=0.003). No significant correlation between tobacco consumption, alcoholic habits, and HPV status was observed. The mean number of life time sexual partners in HPV positive patients was 1.66 while, it was 1.33 in HPV negative patients (P=0.049). Incidence of high risk sexual behaviors was more in HPV positive patients (P<0.001). There were no significant associations between the two groups with respect to tumor size, nodal stage and the overall stage of the tumor. 16% of the base of tongue cancers and 40% of tonsillar carcinoma were positive (P = 0.02). Among positive samples, HPV 16 was the commonest (79%) followed by HPV 18 (12%). 96% of patients received treatment. At 18.8 months there was no significant difference in OS, EFS between HPV positive and negative OSCC (P = 0.97 and P= 0.51 respectively). Conclusions: The current study reconfirms that HPV positive OSCC patients are younger with high risk sexual behavior. Impact of smoking and alcohol consumption on HPV status was not found in this study. HPV positive rates were significantly higher for tonsillar cancer. Contrary to literature, we did not find any differences in OS or EFS between two groups. Small numbers of patients in the study group, short follow up period and significant tobacco smoking in HPV group may be the one of the reason for this.
Phase II study of temsirolimus and erlotinib in patients (pts) with recurrent/metastatic (R/M), platinum-refractory head and neck squamous cell carcinoma (HNSCC).
Authors: Bauman Julie E. , Arias-Pulido Hugo , Lee Sang-Joon , Considine Michael , Fekrazad M Houman , Howard Jason , Bishop Justin A. , Olson Garth T , Jones Dennie V. , Fertig Elana J. , Chung Christine H.
Published: March 2020

5549

Background: The Epidermal Growth Factor Receptor (EGFR) is a validated target in HNSCC. In R/M disease, primary or acquired resistance to anti-EGFR therapy inevitably occurs. Downstream activation of the PI3K/Akt/mTOR pathway is an established resistance mechanism. We hypothesized that concurrent mTOR blockade may improve efficacy of anti-EGFR therapy and conducted this phase II study. Methods: We evaluated the combination of erlotinib 150 mg po daily and temsirolimus 15 mg IV weekly in pts with platinum-refractory R/M HNSCC and ECOG PS 0-2. The exact, single-stage phase II design had 80% power (5% significance level) to detect improvement in progression-free survival (PFS) from 2.3 to 4.4 mos with 35 evaluable pts. Correlatives included determination of PIK3CA mutation (mut) status; p16, EGFR and PTEN expression; and immunomodulatory cytokine levels. Results: From Dec 2009 – Mar 2011, 12 pts enrolled. Six pts withdrew prior to first planned response assessment, due to toxicity (5) or death (1), prompting referral to the Data Safety and Monitoring Committee and early closure. Grade ≥ 3 toxicities included fatigue (5), diarrhea (2), GI infection/peritonitis (2), dyspnea (2), HN edema (2), and neutropenia (1). Among 8 progression-evaluable pt, median PFS was 1.9 mos. Median OS was 4.1 mos. 4/12 tumors were p16(+); 4/10 were EGFR(+); 11/11 showed no PTEN expression. PIK3CA mut was present in 1/11; the mut(+) pt withdrew after 3 wk for diarrhea/peritonitis with minor response. There were no associations between tumor p16, EGFR or PTEN status and oncologic outcomes. Five of 6 toxicity-related withdrawals occurred in p16(-) pts. Immunomodulatory cytokine levels in pre- and post-temsirolimus plasma did not significantly differ or associate with toxicity. Two pts with ≥ 4.4 mos PFS were p16(-) and PIK3CA mut(-). Conclusions: The combination of erlotinib and temsirolimus was poorly tolerated in this population, with toxicities predominant in p16(-) pts. Although the sample size was small, this R/M cohort demonstrated lack of PTEN expression and 9% PIK3CA mut, justifying further investigation of PI3K/Akt/mTOR pathway inhibitors in selected HNSCC pts.