bluuebunny/crossref_metadata_2025 huggingface dataset:
Outcome of primary tumor in patients with synchronous stage IV colorectal cancer receiving combination chemotherapy without surgery as initial treatment
Authors: Poultsides G. A. , Servais E. L. , Saltz L. B. , Patil S. , Kemeny N. E. , Guillem J. G. , Weiser M. , Temple L. K. , Wong W. , Paty P. B.
Published: February 2017

CRA4030

Background: In the absence of symptoms (bleeding, perforation, obstruction) or resectable metastatic disease, primary tumor resection in patients who present with synchronous metastatic colorectal cancer (CRC) is of uncertain benefit. The purpose of this study was to describe the frequency of intervention necessary to palliate the intact primary tumor in patients who present with synchronous stage IV CRC and receive up-front modern combination chemotherapy without prophylactic surgery. Methods: Using a prospective institutional database, we identified 233 consecutive patients from 2000 through 2006 with synchronous metastatic CRC and an unresected primary tumor who received oxaliplatin- or irinotecan-based, triple-drug chemotherapy (FOLFOX, IFL, or FOLFIRI) with or without bevacizumab as their initial treatment. The incidence of subsequent use of surgery, radiotherapy, and/or endoluminal stenting to manage primary tumor complications was recorded. Results: Of 233 patients, 217 (93%) never required surgical palliation of their primary tumor. Sixteen patients (7%) required emergent surgery for primary tumor obstruction or perforation, 10 patients (4%) required nonoperative intervention (stent or radiotherapy), whereas 213 (89%) never required any direct symptomatic management for their intact primary. Of those, 47 (20%) ultimately underwent elective colon resection at the time of metastasectomy and 8 (3%) during laparotomy for hepatic artery infusion pump placement. Neither use of bevacizumab, location of the primary tumor in the rectum, or metastatic disease burden were associated with increased intervention rate. In addition, when included as a time-varying covariate in a Cox regression model, the need for emergent intervention did not correlate with overall survival. Conclusions: Most patients with synchronous stage IV CRC who receive up-front modern combination chemotherapy never require palliative surgery for their intact primary. These data support the use of chemotherapy, without routine prophylactic resection, as the appropriate standard practice for patients with neither obstructed nor hemorrhaging primary colorectal tumors in the setting of metastatic disease.

[Table: see text]
Risk of breast cancer recurrence in women initiating tamoxifen with CYP2D6 inhibitors
Authors: Aubert R. E. , Stanek E. J. , Yao J. , Teagarden J. R. , Subar M. , Epstein R. S. , Skaar T. C. , Desta Z. , Flockhart D. A.
Published: February 2017

CRA508

Background: Tamoxifen (TAM) is metabolized to its active form, endoxifen, by hepatic cytochrome P450 (CYP) 2D6. Diminished CYP2D6 function, both by genetic variation or concurrent use of pharmacologic inhibitors, can significantly reduce endoxifen plasma concentrations and may lead to reduced TAM effectiveness. Methods: We interrogated an integrated research database comprised of de-identified medical and pharmacy claims (Rx) data for 10.7 million U.S. health plan members to identify women with breast cancer (BrCa) new to TAM therapy in a 30-month period from 2003 to 2005, and investigated the risk of recurrent BrCa as a function of concurrent use of potent and moderate inhibitors of CYP2D6. Inclusion criteria were: greater than or equal to 24 months of follow-up data and adherence to TAM (medication possession ratio > 70%) over 2 years (N = 1,298). Disease recurrence was defined by BrCa ICD-9 codes or CPT codes for mastectomy, lumpectomy, lymph node dissection, or radiation therapy occurring at least 6 months after the index TAM Rx. Two study groups were identified: TAM alone (N = 945) or TAM + a CYP2D6 inhibitor concomitantly (N = 353). BrCa recurrence rates were compared using Kaplan-Meier analysis with log-rank test, and univariate hazard ratios (HR) with 95% confidence intervals (CI) were estimated by Cox proportional hazards model. Results: The study groups were similar at baseline. Median age was 52 years (TAM) and 53 years (TAM + CYP2D6 inhibitor). Interventions performed in the TAM alone group included mastectomy in 54%, lumpectomy in 36%, and radiation therapy in 47%, and were 52%, 38%, 46%, respectively, in the TAM + CYP2D6 inhibitor group. Among women on a CYP2D6 inhibitor, the median duration of overlap with TAM was 255 days. Patients receiving TAM + a CYP2D6 inhibitor had a 2-year BrCa recurrence rate of 13.9% versus 7.5% in patients receiving TAM alone (HR 1.92, 95% CI 1.33–2.76, p < 0.001). Conclusions: Our findings support the presence of a clinically significant drug interaction between TAM and known CYP2D6 inhibitors. This resulted in a significant 1.9 fold higher BrCa recurrence within 2 years of initiating TAM therapy.

[Table: see text]
Cancer screening in adult survivors of childhood cancer: A report from the Childhood Cancer Survivor Study (CCSS)
Authors: Nathan P. C. , Ness K. K. , Hudson M. M. , Mahoney M. , Ford J. S. , Landier W. , Armstrong G. , Henderson T. , Robison L. L. , Oeffinger K. C.
Published: February 2017

CRA6501

Background: Childhood cancer survivors may develop a second malignant neoplasm (SMN) and require surveillance to detect new cancers. Methods: We surveyed survivors and siblings from the CCSS, a cohort study of patients who have survived ≥5 years after a diagnosis of childhood cancer from 1970–86. We assessed compliance with the American Cancer Society's (ACS) guidelines for surveillance mammography, colonoscopy and PAP smears, and compared them to a matched population comparison group drawn from the 2003 National Health Interview Survey. Further, we examined compliance with the Children's Oncology Group (COG) guidelines for more frequent colonoscopy, mammography and skin exams in survivors at high risk for cancers of the colon (≥30 Gy pelvic, abdominal or spinal radiation), breast (≥ 20 Gy breast radiation in females) or skin (any radiation). Proportions screened were compared between groups with adjusted generalized estimating equations or log-binomial regression models. Results: There were 8318 survivors (50.6% male, mean age at interview 31.2 ± 7.3 years), 2661 siblings and 8318 population controls. 141/829 (17.6%), 592/855 (70.4%) and 3362/3690 (92.6%) eligible survivors reported a colonoscopy, mammogram, or PAP smear per ACS guidelines. Survivors were less likely than siblings (odds ratio [OR] 0.30; 95% confidence interval [CI] 0.18–0.49) and population controls (OR 0.63; CI 0.50–0.80) to have a colonoscopy, and less likely than siblings to have a PAP smear (risk ratio [RR] 0.98; CI 0.97–0.99). However, they were more likely than siblings (RR 1.14; CI 1.03–1.27) and population controls (RR 1.05; CI 1.01–1.10) to have a mammogram. Among survivors at increased risk for a SMN, only 92/809 (11.4%) reported a colonoscopy within the COG recommended 5-year period, 164/537 (30.5%) reported a mammogram within a 1-year period and 1288/4833 (26.7%) reported a skin exam. Care at a cancer center was associated with mammography (RR 1.91; 95% CI 1.02–1.27) and skin exam (RR 1.55; 95% CI 1.22–196) in high-risk patients. Conclusions: Childhood cancer survivors are not screened adequately for SMNs. Surveillance is very poor amongst those at highest risk for colon, breast, or skin cancer. Survivors and their physicians need education about the importance of surveillance.

No significant financial relationships to disclose.
National survey of physicians practice patterns: Fertility preservation and cancer patients
Authors: Quinn G. , Vadaparampil S. T. , Jacobsen P. , Lee J. , Lancaster J. , Bepler G. , Keefe D. L. , Albrecht T. L.
Published: February 2017

CRA9508

Background: Addressing the impact of cancer treatment on fertility is a high priority in providing quality cancer care to patients of childbearing age. Evidence suggests less than 50% of patients receive adequate fertility information prior to cancer treatment. This study assessed the practice patterns of physicians and identified perceptions of barriers to communication about fertility. Methods: A 37 item survey was developed by a review of the literature and previous qualitative interviews. A random sample of physicians from the American Medical Association Masterfile was stratified by board specialty related to oncology. Three waves of surveys were distributed across the United States. The domains of the survey included demographics, knowledge, attitudes and practice behaviors related to FP with patients of childbearing age. Results: Of 1,979 physicians identified, a total of 613 physicians completed the survey, yielding a 33% response rate among oncologists. Oncologists with favorable attitudes towards FP were 4.9 times more likely to discuss the impact of cancer treatment on future fertility than those who have unfavorable attitudes. GYN or Medical/Hematological oncologists were 2.1 times more likely than other specialists to report feeling comfortable discussing FP with their patients. The majority of oncologists reported discussing FP with patients and indicated the primary barrier to discussion was a patient too ill to delay treatment. However, less than 25% of oncologists report referring patients for FP and only 38% report knowledge of the ASCO guidelines suggesting oncologists should discuss FP and refer all patients of childbearing age. Less than 25% of physicians surveyed reported distributing educational materials regarding FP. Conclusions: The majority of physicians in this survey report discussing FP; however they are not consulting specialists or providing educational materials to their patients. Future research will include the development of physician and nurse training curricula and interventions to facilitate discussion of FP between physicians and cancer patients.

No significant financial relationships to disclose.
A phase III trial comparing mFOLFOX6 to mFOLFOX6 plus bevacizumab in stage II or III carcinoma of the colon: Results of NSABP Protocol C-08
Authors: Wolmark N. , Yothers G. , O'Connell M. J. , Sharif S. , Atkins J. N. , Seay T. E. , Feherenbacher L. , O'Reilly S. , Allegra C. J.
Published: February 2017

LBA4

Background: The primary aim of this two-arm randomized prospective study was to determine whether mFOLFOX6 plus bevacizumab (mFF6+B) would prolong disease-free survival (DFS) compared to mFOLFOX6 (mFF6) alone. Methods: Between September 2004 and October 2006, 2,672 patients with follow-up (1,338 and 1,334 in respective arms) with stage II (24.9%) or III carcinoma of the colon were randomized to receive either mFF6 (oxaliplatin 85 mg/m2 IV d1, leucovorin 400 mg/m2 IV d1, 5-FU 400 mg/m2 IV bolus d1, and 5-FU 2400 mg/ m2 CI over 46 hrs (d1+2) q14d × 12 cycles) or mFF6+B (same mFF6 regimen + bevacizumab 5 mg/kg IV q 2 wks × 1 yr). The primary end point was DFS. Events were defined as first recurrence, second primary cancer, or death. Results: The median follow-up for patients still alive was 36 months. The hazard ratio (HR: FF6+B vs. mFF6) was 0.89; 95% CI (0.76=1.04); p=0.15. Data censored at intervals disclosed an initial benefit for bevacizumab that diminished over time: The smoothed estimate of the DFS HR over time indicated that bevacizumab significantly reduced the risk of a DFS event during the interval from 0.5 to 1.0 year. There was no evidence that patients receiving bevacizumab had a worse DFS compared to those receiving mFF6 alone following treatment. Conclusions: The addition of bevacizumab to mFF6 did not result in an overall statistically significant prolongation in DFS. There was a transient benefit in DFS during the one-year interval that bevacizumab was utilized. Consideration may be given to clinical trials assessing longer duration of bevacizumab administration. Supported by PHS grants U10CA-12027, -69974, -37377, and -69651 from the NCI and a grant from Genentech, Inc.

[Table: see text]

No significant financial relationships to disclose.
ESPAC-3(v2): A multicenter, international, open-label, randomized, controlled phase III trial of adjuvant 5-fluorouracil/folinic acid (5-FU/FA) versus gemcitabine (GEM) in patients with resected pancreatic ductal adenocarcinoma
Authors: Neoptolemos J. , Büchler M. , Stocken D. D. , Ghaneh P. , Smith D. , Bassi C. , Moore M. , Cunningham D. , Dervenis C. , Goldstein D.
Published: February 2017

LBA4505

Background: Adjuvant 5-FU/FA (ESPAC-1 trial) and GEM (CONKO-001 trial) provide improved survival for patients with resected pancreatic cancer compared to no chemotherapy. The aim of the ESPAC-3 (v2) trial was to compare 5FU/FA vs GEM to identify if either adjuvant chemotherapy was associated with a significantly better survival. Methods: Patients with an R0/R1 resection for pancreatic ductal adenocarcinoma were randomized (stratified for resection margin status and country) <8 weeks of surgery to receive either 5FU/FA (FA, 20 mg/m2, iv bolus injection followed by 5-FU, 425 mg/m2, iv bolus injection given 1–5d every 28 days) or GEM (1,000mg/m2 iv infusion 1d, 8d and 15d every 4 weeks) for 6 months. The primary outcome measure was overall survival; the secondary measures were toxicity, progression free survival and quality of life. 1,030 patients were needed to detect a 10% difference in 2-year survival rates with 90% power. Results: 1,088 patients from 16 countries were randomized from July 2000 to Jan 2007 (5FU/FA = 551, GEM = 537). Median (range) age was 63 (31–85) years; 598 (55%) were men. Median tumor size was 30 (20–350) mm; 384 (35%) were R1 resections; 777 (72%) were node positive; and 263 (25%) were poorly differentiated tumors. Final analysis was carried out on an intention to treat basis with a minimum of 2 years follow-up after 753 (69%) patients had died. Median (IQR) follow-up of 335 alive patients was 34.2 (27.1–43.4) months, equal across treatment groups. Median survival from resection of patients treated with 5FU/FA was 23.0 (95% CI: 21.1, 25.0) months and for patients treated with GEM this was 23.6 (95%CI: 21.4, 26.4) months. Log-rank analysis revealed no statistically significant difference in survival estimates between the treatment groups (c2LR=0.7, p=0.39, HRGEM=0.94 (95%CI: 0.81, 1.08)). There was no significant difference in the effect of treatment across subgroups according to R status (test of heterogeneity c21=0.3, p=0.56). Conclusions: This is the largest adjuvant trial ever conducted for pancreatic ductal adenocarcinoma and showed no significant difference in survival between adjuvant 5FU/FA and adjuvant GEM.

[Table: see text]
Breast cancer molecular profiles and tumor response of neoadjuvant doxorubicin and paclitaxel: The I-SPY TRIAL (CALGB 150007/150012, ACRIN 6657)
Authors: Esserman L. J. , Perou C. , Cheang M. , DeMichele A. , Carey L. , van 't Veer L. J. , Gray J. , Petricoin E. , Conway K. , Hylton N. , Berry D.
Published: February 2017

LBA515

Background: I-SPY is a multi-center trial designed to identify predictive markers of pathological complete response (pCR) and survival of women with locally advanced breast cancers (3cm or greater). Women received neoadjuvant doxorubicin and cyclophosphamide then paclitaxel. Methods: 237 women enrolled, 216 completed serial imaging and core biopsies. Pre-treatment assays include: Agilent expression arrays, MIP aCGH, p53 gene chip and sequencing, IHC and reverse phase protein arrays (RPMA). Response to therapy was measured by serial MRI, pCR and residual cancer burden (RCB). Associations among molecular markers, pCR, RCB and survival were evaluated using chi-square test, Kaplan-Meier curves and log-rank test. Results: Median tumor size was 6cm, % pCR and RCB 0/1 was 27% and 36% for the entire study; % pCR rate for the 144 Agilent arrays was 25%. Distribution, rates of pCR and RCB 0/1 are shown in the Table for molecular and IHC markers. DFS and OS will be presented. Several molecular subtypes, including NKI 70 gene low, luminal A, 21 gene set low and IHC HR+, define 15–28% of patients with 3–10% pCR, yet excellent early survival. Wound healing, most discriminatory for prognosis, is not predictive of chemotherapy response. By RPMA, patients with pCR had increased phosphorylation of 4EBP1, eNOS, cAbl, STAT5, EGFR, AKT (p<0.05). In ER+ patients with poor MR response, pIRS, pIGFR, p706S were activated (p<0.05). RCB is a more refined way to measure pCR and was more predictive of DFS and OS (p=0.01) than pCR alone with a mean follow up of 3.9 years. MR volume is highly predictive of pCR and RCB. For specific subtypes, e.g. basal, RCB is predictive of DFS (p<0.00001). Conclusions: LABC have aggressive biology. Response to therapy and outcome can be predicted by many biomarkers. The I-SPY data set provides a platform to compare, contrast and combine marker signatures to tailor therapy and demonstrates the power of the neoadjuvant setting. Support: ACRIN U01 CA079778 ; CALGB CA31964, CA33601; NCI SPORE CA58207.

[Table: see text]

[Table: see text]
Carboplatin plus paclitaxel (CP) versus carboplatin plus stealth liposomal doxorubicin (CLD) in patients with advanced ovarian cancer (AOC): Activity and safety results of the MITO-2 randomized multicenter trial
Authors: Pignata S. , Scambia G. , Savarese A. , Sorio R. , Breda E. , Ferrandina G. , Gebbia V. , Musso P. , Gallo C. , Perrone F.
Published: February 2017

LBA5508

Background: CP is standard first-line chemotherapy for AOC. MITO-2 (Multicentre Italian Trials in Ovarian Cancer) is an academic randomized phase III study testing whether CLD is more effective than CP. Methods: AOC patients (pts), stage IC-IV, aged≤75, ECOG PS≤2, were randomized to CP (C AUC5 + P 175 mg/m2,d1q21) or to CLD (C AUC5 + LD 30 mg/m2,d1q21), both for 6 cycles. Primary endpoint is progression-free survival (PFS). Secondary endpoints are overall survival, objective response rate (ORR), toxicity and quality of life. To have 80% power in detecting a 0.80 HR in PFS, with 2-sided α error 0.05, 632 events are needed and 820 pts were planned. Activity was evaluated according to RECIST, toxicity according to NCI-CTC. Activity analysis was not blinded and no confirmation of response was required. Results: From January 2003 to November 2007, 820 pts were randomized, 410 to each arm. Median age was 57 yrs (range 21–77). Stage III (60%) and IV (22%) were prevalent. As of March 30, 2009, with a median follow-up of 35 months, 530 events for PFS and 269 deaths have been recorded. Six cycles were received by 86% and 80% of pts, with CP and CLD respectively. With complete data for 97% of pts, 290 pts were eligible for activity analysis (≥1 target lesion). ORR was 59% with CP and 57% with CLD (p=0.70). In 182 pts with non-target lesions only, complete response was 33% with CP and 29% with CLD (p=0.64). In 168 pts with elevated CA-125 only, CA-125 normalization was obtained in 83% with CP and 86% with CLD (p=0.56). Toxicity data are complete for 97% of pts. Statistically significant differences in haematological toxicity (CP vs CLD) were: anemia all grades 59% vs 68%, grade (G) 3–4 4% vs 10%; thrombocytopenia all grades 19% vs 48%, G3–4 2% vs 16%. Statistically significant differences in non haematological toxicity were: hair loss 63% vs 14%; skin toxicity all grades 6% vs 20%, G3–4 0 vs 2%; diarrhea all grades 13% vs 6%; stomatitis all grades 9% vs 20%; neurotoxicity all grades 47% vs 15%, G3–4 3% vs 0.3%. Conclusions: CLD as first-line treatment of AOC produced a similar activity, with a different toxicity profile, compared to CP. Required events are awaited for final PFS analysis. Partially supported by Schering-Plough.

No significant financial relationships to disclose.
A phase II trial of proton radiotherapy for medulloblastoma: Preliminary results.
Authors: Yock T. I. , Yeap B. Y. , Ebb D. , MacDonald S. M. , Pulsifer M. B. , Marcus K. C. , Tarbell N.
Published: February 2017

CRA9507

Background: Pediatric medulloblastoma (MB) is commonly cured with surgery, chemotherapy and radiation. However, the late effects of radiotherapy can be disabling. Proton radiotherapy irradiates less normal tissue, which should result in fewer late side effects of treatment. The purpose of this study was to describe the clinical outcomes of proton radiotherapy.

Methods: All patients had surgery of the primary tumor followed by proton radiotherapy with or without concurrent chemotherapy and adjuvant platinum based chemotherapy. CSI doses ranged from 18-36 GyE, median dose 23.4 GyE. The tumor bed or posterior fossa was brought to 54 GyE. Concurrent enrollment in COG or other protocols was allowed. All pathology and imaging was reviewed at MGH to confirm the diagnosis.

Results: 60 patients with MB were prospectively enrolled from May 2003 to December 2009 and 59 were evaluable for this analysis. Median age 6.6 yrs, range 3.5 - 22 years; M/F ratio 1.3; standard risk (SR, 45) or high risk (HR, 14). The median follow-up is 16 months. Two-year overall survival (OS) and progression-free survival (PFS) for the entire group is 91% and 87%. Two-year OS for SR MB and HR MB is 92% and 87%. 54 pts have baseline (BL) neurocognitive testing and 19 pts (14 SR, 5 HR) have follow-up (FU) evaluations including FSIQ spanning at an average of 2 years. Mean FSIQ at BL and FU are 107 and 102 (paired t-test: 0.046). Endocrine late effects include 4 patients with growth hormone deficiency, 1 patient with central hypothyroidism and 2 other endocrinopathies. Audiology information will be presented.

Conclusions: Early results of this prospective trial are promising for improving clinical outcomes in patients with medulloblastoma.

[Table: see text]
Randomized phase III trial comparing adjuvant paclitaxel/gemcitabine/cisplatin (PGC) to observation in patients with resected invasive bladder cancer: Results of the Spanish Oncology Genitourinary Group (SOGUG) 99/01 study.
Authors: Paz-Ares L. G. , Solsona E. , Esteban E. , Saez A. , Gonzalez-Larriba J. , Anton A. , Hevia M. , de la Rosa F. , Guillem V. , Bellmunt J.
Published: February 2017

LBA4518

Background: Approximately half of patients with resected invasive bladder cancer will die within the first three years after surgery due to disease relapse, most of the recurrences being systemic. We have studied in a randomized phase III trial the role of 4 courses of the PGC triplet as compared to observation in this clinical setting.

Methods: Eligibility criteria included: (1) resected high-risk muscle invasive bladder carcinoma (pT3-4 and/or pN+), (2) ECOG PS 0-1, (3) adequate renal function (CrCl > 50 ml/min), (4) ≤ 8 weeks post-cystectomy, (5) no relevant co-morbidities, and (6) signed informed consent. Eligible patients were assigned to observation or 4 courses of PGC (P 80 mg/m2 d1 and 8, G 1000 mg/m2 d1 and 8 and C 70 mg/m2 d1) q21 days. The primary objective was overall survival (OS).

Results: The study was open in July 2000 and prematurely closed due to poor recruitment in July 2007, with 142 patients randomized (74 to observation and to 68 to PGC treatment). Baseline characteristics were well balanced among study arms. Median age was 63 yrs, pT3-4N0: 44%, anyTpN+:56%, PS 0: 59%, median time cystectomy-randomization: 48 days (14-91). In the PGC arm 76% of pts completed all 4 courses of therapy. Main Gr 3-4 toxicities were neutropenia 41%, febrile neutropenia 8%, thrombocytopenia 14%, anemia 5%, fatigue 14%, alopecia 10%, vomiting 8%, renal 5%. There was one toxic death (sepsis). At a median follow up of 30 months (range 1-95), 69 patients have died (45 in control arm and 24 in PGC arm). OS (ITT population) was significantly prolonged in the PCG arm (median NR; 5yr OS: 60%) compared to observation (median 26m; 5yr OS: 31%) (p<0.0009). DFS (p<0.0001), TTP (p<0.0001) and disease specific survival (p<0.0002) were also superior in the PGC arm.

Conclusions: The results of this study strongly suggest that adjuvant PGC improves OS and DFS following cystectomy in high risk invasive bladder cancer. As the study was prematurely closed, the power for firm conclusions is however limited.

[Table: see text]
Evaluation of circulating tumor cell (CTC) enumeration as an efficacy response biomarker of overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC): Planned final analysis (FA) of COU-AA-301, a randomized, double-blind, placebo-controlled, phase III study of abiraterone acetate (AA) plus low-dose prednisone (P) post docetaxel.
Authors: Scher H. I. , Heller G. , Molina A. , Kheoh T. S. , Attard G. , Moreira J. , Sandhu S. K. , Parker C. , Logothetis C. , McCormack R. T. , Fizazi K. , Anand A. , Danila D. C. , Fleisher M. , Olmos D. , Haqq C. M. , De Bono J. S.
Published: February 2017

LBA4517

Background: A preplanned interim analysis of COU-AA-301 showed that AA, a selective androgen biosynthesis (CYP17) inhibitor, significantly improves OS in mCRPC. This is the first phase III study to prospectively assess CTC as a surrogate biomarker as part of a regulatory qualification process, here using updated OS data. Methods: 1,195 patients (pts) with mCRPC post docetaxel were randomized 2:1 to AA (1 g QD) + P (5 mg BID) (n = 797) or placebo + P (n = 398). CTCs (screening and baseline [BL]; post BL at weeks 4, 8 and 12) were enumerated (cells/7.5 mL) at MSKCC and The ICR using CellSearch and analyzed with other prognostic covariates as dichotomous and continuous variables using updated OS data at 775 events (prior to crossover from placebo to AA). CTC (as part of a biomarker panel - LDH, PSA, Hg, AlkPhos) was examined as a surrogate for OS. Multivariate (Cox model) analyses were conducted. Results: At median follow up (FU) of 20.2 mo, the difference in median OS between the 2 groups improved from 3.9 to 4.6 mo (AA 15.8 mo vs placebo 11.2 mo; HR = 0.74; p < .0001). CTC counts were evaluated in 972 pts at screening and BL, 838 at 4 wks, 783 at 8 wks and 723 pts at 12 wks. High concordance between screening and BL values was observed (r = 0.83). CTC conversion using standard definition for unfavorable (CTC ≥ 5) and favorable (CTC < 5) counts was predictive of OS as early as 4 wks after treatment and its inclusion significantly reduced the treatment effect at all post-treatment time points (HR: from 0.74 to 0.97). A reduced model incorporating CTCs and LDH was developed. Conclusions: The magnitude of the treatment effect of AA on OS increased with longer FU. Using standard definition of CTC conversion, the biomarker panel demonstrated a level of surrogacy for OS by correlating well with survival and in a model-adjusted analysis dramatically attenuating the treatment effect. BL CTCs and CTC conversion, along with LDH, were key predictors of OS. Future trials will further evaluate the CTC-based surrogate developed from COU-AA-301.
Accuracy of stereotactic vacuum-assisted biopsies in a community population.
Authors: Edwards S. D. , Vossen J. A. , Pronovost M. , Reeser P.
Published: February 2017

106

Background: Stereotactic core biopsy in mammographically detected lesions permits histologic confirmation previous to surgery planning. We evaluated the use of stereotactic vacuum-assisted biopsy (VAB) for diagnosing suspicious, mammographically detected breast lesions in a community population. Furthermore, we determined the level of agreement between the pathology findings of VAB and the final surgical excisional biopsy.

Methods: We retrospectively evaluated the results of 128 consecutive stereotactic VAB with 9-gauge needles performed over a period of 1 year in our community population. The imaging histologic concordance was ascertained for each lesion. We also evaluated concordance between VAB results and surgical excision results.

Results: For the 128 patients included Breast Imaging Reporting and Data System (BI-RADS) staging showed BI-RADS 3: 4%; BI-RADS 4: 91%; and BI-RADS 5: 5%. VAB demonstrated 65 (51%) benign lesions, 31(24%) indeterminate lesions and 32 (25%) malignant lesions. The 31 indeterminate lesions included atypical ductal hyperplasia (n=13), lobular neoplasia (n=4), papillary lesions (n=12), radial sclerosing lesions (n=5), and flat epithelial atypia (n=13). Surgical excision was performed on 52 patients, and pathology demonstrated; 4 benign, 19 indeterminate, and 29 malignant lesions. There was one (3%) underestimation of an indeterminate lesion and there were 8 (25%) underestimations of malignant lesions after surgical excision. We did not observe any post-biopsy complications.

Conclusions: Stereotactic VAB with a 9-gauge needle is a reliable method for diagnosing mammographically detected breast lesions in a community population.
Patient characteristics associated with the decision to undergo bilateral prophylactic mastectomy for lobular carcinoma in situ.
Authors: Muhsen S. , Junqueira M. J. , Park A. , Sung J. S. , Patil S. , Oskar S. , Morrogh M. , Morrow M. , King T. A.
Published: February 2017

148

Background: Women at increased risk for breast cancer due to a diagnosis of lobular carcinoma in situ (LCIS) have three management options: high risk surveillance +/- chemoprevention (CP) or bilateral prophylactic mastectomy (BPM). Among a large cohort of women with LCIS, we previously reported there were no differences between women choosing CP compared to those choosing surveillance alone. The purpose of this study was to identify patient factors associated with the decision to pursue BPM for LCIS.

Methods: We reviewed our prospectively maintained LCIS database to identify women choosing BPM (1995-2009). Comparisons were made between patients who chose BPM versus those who chose high risk surveillance +/- CP.

Results: Among 995 pts with LCIS, 795 (80%) chose surveillance alone, 149 (15%) chose CP and 51 (5%) chose BPM. Compared to patients electing surveillance +/- CP patients who pursued BPM were younger at age of LCIS diagnosis (48 vs. 52 yrs, p < 0.001), more likely to have bilateral biopsies with LCIS (14% vs. 3%, p = 0.002) and more likely to be premenopausal (82% vs. 57%, p < 0.001). Patients choosing BPM were also more likely to have additional risk factors for breast cancer including: stronger family histories and extremely dense breasts (Table). Occult breast cancer was found in 4 (8%) BPM patients. At a median follow-up of 54 months (range 0-190 mos), 120/944 (13%) patients in the surveillance +/- CP group developed breast cancer.

Conclusions: High-risk surveillance alone is the preferred management option for women with LCIS at our institution. Patients electing BPM are younger and more likely to have other associated risk factors for developing breast cancer. Further research to define how the increased risk imparted by LCIS is augmented by these factors may allow for better risk stratification and more informed discussions with patients.

[Table: see text]
Number needed to treat and treatment cost per fracture avoided with denosumab compared with zoledronic acid in patients with breast cancer with bone metastases.
Authors: Wu E. Q. , Xie J. , Signorovitch J. , Diener M. , Sorg R. , Namjoshi M.
Published: February 2017

151

Background: Pathologic fractures (PF) are a common and expensive-to-treat skeletal-related event (SRE), which affect over two-thirds of metastatic breast cancer (MBC) patients, and cost $26,936 (2009 US dollars) per event on average for inpatient treatment. In a phase III trial ( NCT20050136 ), MBC patients randomized to denosumab (Dmab; n=1,026) demonstrated longer time to SRE, but comparable rates of survival and disease progression relative to those randomized to zoledronic acid (ZOL; n=1,020). We calculated the number needed to treat (NNT) to avoid one PF and the treatment cost per PF avoided with Dmab vs. ZOL in MBC patients.

Methods: Phase III trial results from the Dmab product label were used to determine the rate of PFs and SREs in MBC patients treated with Dmab vs. ZOL. Treatment cost included only the wholesale acquisition cost of Dmab and ZOL, and assumed 12 months of treatment. The NNT calculated the number of patients who would need to be treated with Dmab vs. ZOL to avoid one additional PF. Sensitivity analyses included expanding the treatment outcome from PFs to SREs and adding drug administration costs for Dmab and ZOL, and, renal monitoring costs only for ZOL.

Results: Based on the estimated differences in PF risk of 2.7%, 37.4 patients would need to be treated with Dmab vs. ZOL to avoid one additional PF, resulting in a treatment cost per PF avoided of $346,911. The lower 95% confidence limit for the cost per PF avoided with Dmab vs. ZOL was $148,114, which is significantly greater than the mean inpatient cost of treating a PF event. Including drug administration and renal monitoring costs led to a cost per PF avoided of $323,069. Expanding the treatment outcome from PFs to SREs showed that 17.3 patients would need to be treated with Dmab vs. ZOL to avoid one additional SRE (95% CI: 10.2 to 59.7; absolute risk reduction 5.8%), resulting in a treatment cost of $160,595 per SRE avoided.

Conclusions: PFs have a debilitating effect on patients, and treatment with Dmab compared to ZOL was associated with a treatment cost per PF avoided that exceeded 12 times the mean inpatient cost of a PF. Decision makers need to consider the high costs associated with Dmab prior to formulary inclusion.
Weight change associated with anastrozole and tamoxifen treatment in postmenopausal women with breast cancer or at high risk of developing it.
Authors: Sestak I. , Harvie M. , Howell A. , Forbes J. F. , Dowsett M. , Cuzick J. M.
Published: February 2017

165

Background: Weight gain is commonly reported by patients with breast cancer. Aromatase inhibitors are being tested in the preventive setting in high risk women and it is important to evaluate the association between treatment and weight change as this may effect the patient’s decision to continue to take the drug.

Methods: Weight change in postmenopausal women from three large clinical trials (ATAC, IBIS-I, IBIS-II) investigating endocrine treatment for the treatment and prevention of breast cancer have been analysed. The objective of this retrospective study was to assess the effects of anastrozole and tamoxifen on weight change in postmenopausal women.

Results: In the ATAC trial, a mean increase of 1.4 kg was observed after 12 months of follow-up and no statistically significant differences between treatment arms (anastrozole vs. tamoxifen) were found. The majority of women kept their weight stable and only 11.2% gained more than 5 kg within this time period. Significant baseline predictors for gaining more than 5 kg of weight after 12 months of follow-up were being younger than 60 years old at entry, smoking at entry, and mastectomy. Results for the two prevention studies IBIS-I and IBIS-II were quite similar. In the IBIS-II trial, the overall mean weight change after 12 months of follow-up was 0.5 kg. In the IBIS-I study women gained an average of 0.9 kg within the first 12 months of follow up. In both studies no differences between treatment and placebo (IBIS-I: tamoxifen vs. placebo; IBIS-II: anastrozole vs. placebo) were observed. Overall, women in the adjuvant setting gained more than 5 kg of weight (11.2%) after 12 months of follow up compared to those in the preventive setting (5.3% IBIS-I, 5.7% IBIS-II), but similar overall weight gain was seen after 60 months of follow up in both settings (5.7% IBIS-I vs. 6.1% ATAC).

Conclusions: All three trials have demonstrated that weight gain occurs primarily within the first 12 months of active treatment and are similar to those on placebo. Weight stabilises after 12 months of follow up and major weight gain was rare in all trials, and unrelated to treatment.
Change in patient-reported outomes over time from breast cancer diagnosis.
Authors: Hill-Kayser C. E. , Vachani C. , Hampshire M. K. , Di Lullo G. A. , Metz J. M.
Published: February 2017

210

Background: Breast cancer survivors may be at risk for significant late effects after treatment. Understanding the patterns of change over time of patient reported outcomes (PRO) is often very challenging.

Methods: Patient-reported data was gathered via a convenience sample frame from breast cancer survivors utilizing a publically available, free, Internet-based tool for creation of survivorship care plans. Available at www.livestrongcareplan.com and through the OncoLink website, the tool allows survivors to enter data regarding diagnosis, demographics, treatments received, and late effects experienced, and provides them with customized guidelines for future care. All data has been maintained anonymously with IRB approval.

Results: 1,145 breast cancer survivors were queried with regard to PRO. Median age at diagnosis (dx) was 49 yrs, and median current age 52 yrs. Of users, 98% reported having had surgery; of these 56% underwent mastectomy and 49% lumpectomy (5% both). Similarly, 59% underwent sentinel LN biopsy, and 47% axilary dissection. Of the same cohort, 88% received chemotherapy and/or hormonal treatment, and 70% radiation therapy. The median time from dx until use of the care plan tool was 2 years (range 0-33 years). Late effects reported by survivors ≤ 2 and > 2 years from diagnosis are shown (see table). Overall, survivors ≤ 2 years from dx were more likely to note changes in skin color or texture; those > 2 years from diagnosis were more likely to note osteopenia, lymphedema, and sexual changes. Patient reported cognitive changes, arm pain/numbness/tingling, and loss of shoulder flexibility did not differ between the two groups.

Conclusions: This anonymous tool uses a convenience sample frame to gather PRO after breast cancer diagnosis/ treatment. PRO varied significantly with time since dx, with more late effects reported > 2 years from dx. This information may be of use during patient counseling and survivorship care delivery.

[Table: see text]
Breast cancer molecular subtypes in Omani patients: Correlation with age, histology, stage distribution, and outcome—An anaylsis of 542 cases.
Authors: Mehdi I. , Abdulmasood A. a. , Al Bahrani B. J.
Published: February 2017

219

Background: Breast cancer is the commonest malignancy and major health issue globally. There is initial evidence and high possibility of molecular differences across the ethnic and geographic groups; responsible for variation in presentation, responses to treatment, and outcome.

Methods: Breast cancer data from 2006 to 2010 at National Cancer Center, The Royal Hospital Oman was retrospectively retrieved from electronic record system, and analyzed with respect to ER, PR, and HER2 status. The molecular subtypes were correlated with age, histology, and treatment out come. The results were compared with published international/regional data.

Results: Total 542 cases were available for evaluation (535 male and 7 male: 459 Omani and 83 Non-Omani). Right, left, and bilateral tumors were 42.6%, 51.4%, and 6%. IDC were 79.6%. G1 were 7.7%, while other grades were equally distributed. Luminal A, B, basal-like (TNBC), and HER2 positive were 35.9%, 15.8%, 25.5%, and 22.8% respectively. Their age (cut off 50 years) was a significant factor in basal-like (63.8% vs. 36.2%) and HER2 tumors (61% vs. 39%). High-grade tumors were highest (41%) in basal tumors and lowest in Luminal A (19%). Higher stage at presentation (stage 3 and 4) was highest in HER2 tumors (59%). Mortality was recorded higher 22.4% in basal-like/TN tumors. Table shows comparison with selected published data.

Conclusions: The molecular classification and subtyping have shown ethnic and geographic variation in taxonomy. These differences may have diagnostic, therapeutic, and prognostic implications. Large scale and multicenter studies may confirm these findings. They can be translated and incorporated to management strategies wherever applicable.

[Table: see text]
Re-establishing pluripotency in adult cells derived from breast stromal tissue.
Authors: Lim S. M. L. , Aksoy I. , Lim K. G. C. , Karuppasamy J. , Divakar U. , Ma F. J. , Lam F. L. , Remulla S. J. N. , Stanton L. W.
Published: February 2017

227

Background: Recent advances in pluripotent stem cell biology offer patient-specific disease models to investigate in vitro mechanisms of tumorigenesis. Induced pluripotent stem (iPS) cells were originally derived by reprogramming of human dermal fibroblasts through ectopic expression of pluripotency–associated transcription factors. A limitation to the use of dermal fibroblasts as the starting cell type for reprogramming is that it usually takes weeks to expand cells from a single biopsy, and the efficiency of the process is very low. In contrast, a large number of adipose-derived mesenchymal stromal cells (Ad-MSCs) can be easily obtained from the stroma of human breast tissue, without the time-consuming steps of cell expansion. Here we investigated the ability to induce pluripotency in committed, Ad-MSCs derived from the stroma of breast tissue.

Methods: The aim of this study is to investigate the potential of using Ad-MSCs derived from surgically discarded breast stromal tissue to generate human iPS. Discarded tissue during surgical procedures was processed in vitro and Ad-MSCs were derived. These Ad-MSCs were then used to generate iPS cells by ectopic expression of “Yamanaka’s cocktail” containing OCT4, SOX2, KLF4 and c-MYC.

Results: The success rate in generating iPS cells from human Ad-MSCs derived from breast stromal tissue is very high compared to the use of dermal fibroblasts. In our study, almost all human Ad-MSC cell lines can be reprogrammed into iPS cells, which share the same characteristics as skin fibroblast-derived iPS cells and human embryonic stem cells in their morphology, gene expression profile and differentiation capacities.

Conclusions: We are now optimizing this approach and making it more clinically relevant by adopting an integration-free method to deliver the reprogramming factors. The successful reprogramming of breast stromal-derived Ad-MSCs into iPS cells may provide a valuable source of patient-specific iPS cells to study the mechanism of tumorigenesis in patients with breast cancer.
The influence of iPS-inducing factors NANOG and KLF4 in the prognosis of patients with breast cancer.
Authors: Nagata T.
Published: February 2017

230

Background: iPS cell-inducing factors (Oct3/4, Sox2, Klf4, c-Myc, and Nanog) are reported that they appears not only in ES cells (embryonic stem cell), but also in normal cell or carcinoma cell, including breast carcinoma. We evaluated the expression of iPS inducing factors in the human breast cancer specimen with immunohistochemistry, and analyze the relativity of the relapse and the prognosis after the operation.

Methods: 66 cases of breast cancer that were performed the surgical operation in this department were examined. Expression of c-MYC, KLF4, NANOG, OCT4, and SOX2 were determined by immunohistochemistry of tissue microarray.

Results: The average of the patient’s age was 56.4 years old (36-87), and the advanced breast cancers in stage 2 or more were 44 cases (66%). About the hormone receptor and the HER2 appearance, hormone receptor-positive (HR+) types were 53 cases (80%), 6 cases (9%) were HER2-positive (HER2+) type, and 7 cases (11%) were triple-negative (TN) type. During the following period from operation, the relapse was found in 16 cases (24%), and six cases (9%) died. The average of survival time after the operation was 80.7 months (4-162). Patients with high expression group of NANOG had poor disease-free survival (p = 0.045) and overall survival (p < 0.0001) than those with low expression group. On the other hand, patients with high expression group of KLF4 had better disease-free survival (p = 0.028) than low expression group.

Conclusions: High expression of NANOG was prognostic factor, but KLF4 was inversely related to prognosis in breast cancer patients. It was suggested that NANOG increased the growth and metastatic activities of breast cancer cells, while KLF4 decreased these activities.
Contralateral risk-reducing (prophylactic) mastectomy (RRM) in patients (pts) with breast cancer (BC): Experience at Mastologica Lomas Breast Center in Mexico City.
Authors: Sanchez-Forgach E. R. , Sanchez Basurto C. , Zabalaga P.
Published: February 2017

236

Background: Contralateral RRM has increased in frequency due to patient (pt) and/or physician preference. We explore efficacy and satisfaction of procedure at our institution.

Methods: A retrospective review of RRM performed from 2002 to 2010. Age, stage, BC subtype, timing of procedure, RRM pathology, reconstruction technique, complications, delay in systemic therapy, satisfaction index, and pt status were compared to pts. who did not undergo RRM.

Results: 27 pts with BC had a contralateral RRM. Mean age was 34 (range 24-61). High-risk factors in 11 (40.75%) pts. Histology of BC breasts included 18 (66.66%) invasive ductal, 5 (18.52%) invasive lobular, 4 (14.81) in situ ductal carcinoma, and 1 (3.70%) tubular carcinoma. RRM was a synchronous contralateral procedure in 12 (44.44%) pts. Breast reconstruction technique for RRM: 22 (81.48%) subpectoralis implants, 2 (7.41%) tissue expanders and secondary implants, 1 (3.7%) latissimus dorsi flap with implant. RRM complications: seroma in 8 (29.63%) cases (2 required evacuation of implant), 5 (18.52%) diverse degrees of nipple-areola complex necrosis, total breast necrosis in one pt. These cases were performed earlier in the series, with a decrease in complications in the latter stages of the analysis. Pathology of RRM specimens: one (3.7%) case of ductal in situ BC in a stage IIa pt. and 4 (14.81%) atypical ductal hyperplasia. Surgical time increased a mean of 75 minutes; systemic therapy was delayed in only 2 (7.41%) pts. Recurrence presented in one pt in index breast after stage 0 BC at 13 months (7 mm invasive ductal), in reconstructed breast (3 mm invasive ductal), both treated with a total mastectomy and sentinel node biopsy. All pts are alive. Two have developed systemic metastases (brain, bone). Satisfaction results (medical and pt) were excellent or good in the RRM in 23 (85.19%), regular in 2 (7.41%), and bad in 2.

Conclusions: RRM after BC is increasing in frequency, specially in young age pts. Experience at our institution has made it a safe and commonplace procedure, specially in the younger aged pts. with high risk for a contralateral BC. Longer follow-up is needed to determine efficacy.