bluuebunny/crossref_metadata_2025 huggingface dataset:
Health-related quality of life (HRQoL) results from the AURELIA trial evaluating bevacizumab (BEV) plus chemotherapy (CT) for platinum-resistant recurrent ovarian cancer (OC).
Authors: Stockler Martin R. , Hilpert Felix , Friedlander Michael , King Madeleine , Wenzel Lari B. , Lee Chee , Joly Florence , De Gregorio Nikolaus , Arranz Arija Jose Angel , Mirza Mansoor Raza , Sorio Roberto , Freudensprung Ulrich , Sneller Vesna , Hales Gill , Pujade Lauraine Eric ,   AURELIA Investigators
Published: March 2020

5542

Background: Adding BEV to CT significantly improved PFS in platinum-resistant OC in the open-label phase III AURELIA trial. As symptom improvement is a major goal of treatment, determining effects on HRQoL was a key secondary aim of AURELIA. Methods: After investigator selection of single-agent CT (pegylated liposomal doxorubicin, topotecan, or weekly paclitaxel), patients (pts) with measurable/assessable platinum-resistant OC were randomized to CT ± BEV. HRQoL and symptoms were assessed at baseline and every 2 or 3 cycles (8/9 wks) until PD using the EORTC OC Module (OV28) and FOSI. The primary HRQoL endpoint was an absolute improvement of ≥15% (≥15 points) on the 100-point OV28 subscale for abdominal (abdo)/GI symptoms (items 1–6) at wk 8/9. Pts with missing questionnaires (Qs) were included and considered not to have improved. A sensitivity analysis excluded pts with Qs missing for reasons other than PD/death or switch from CT to BEV. Subgroup analyses of symptomatic pts included only those with a baseline score ≥15 (sufficient to show ≥15-point improvement). Mixed-model repeated measures (MMRM) analysis was used to compare Qs from all time points until PD/death, not just wk 8/9. The FOSI was analyzed similarly. Results: Baseline Qs were available from 89% of 361 randomized pts. At wk 8/9, 81% of BEV–CT vs 68% of CT pts who were alive and PD-free returned OV28 Qs. For the primary HRQoL endpoint, more BEV–CT than CT pts had a ≥15% improvement in the OV28 abdo/GI symptom subscale at wk 8/9 (21.9% vs 9.3%, 12.7% difference [95% CI 4.4–20.9]; p = 0.002). The sensitivity analysis described above showed a 13.3% difference [95% CI 4.5–22.1]. In the subgroup of 233 pts with a baseline score ≥15, there was a 16.9% difference (95% CI 6.1–27.6) favoring BEV–CT (29.6% vs 12.7%). MMRM analysis of OV28 abdo/GI symptom subscale scores also favored BEV–CT (6.4-point difference [95% CI 1.28–11.6]). More BEV–CT than CT pts had a ≥15% improvement in FOSI score at wk 8/9 (12.2% vs 3.1%, 9.0% difference [95% CI 2.9–15.2]). Conclusions: Adding BEV to CT resulted in more frequent ≥15% improvements in patient-reported abdo/GI symptoms in platinum-resistant OC. Clinical trial information: NCT00976911.
Efficacy and safety of front-line bevacizumab (BEV), weekly paclitaxel (wPAC), and q3w carboplatin (C) in elderly patients (pts) with ovarian cancer (OC): Subgroup analysis of OCTAVIA.
Authors: Gonzalez-Martin Antonio , Gladieff Laurence , Tholander Bengt , Stroyakovsky Daniel , Gore Martin Eric , Oosterkamp Hendrika M , Lisyanskaya Alla , Redondo Andrés , Teissier Eric , Rosenberg Per , Perez Ronco Julian , Freudensprung Ulrich , Pignata Sandro ,   OCTAVIA Investigators
Published: March 2020

5544

Background: Front-line BEV significantly improved PFS when combined with q3w paclitaxel and C in two randomized phase III OC trials. The single-arm OCTAVIA study combined two successful strategies, anti-angiogenic therapy and wPAC administration, demonstrating median PFS of 24 months at the primary analysis [IGCS 2012]. We report exploratory analyses of safety and efficacy in the subgroup of pts aged ≥65 y treated in OCTAVIA. Methods: Pts received 6–8 cycles of BEV (7.5 mg/kg, d1) + wPAC (80 mg/m2 d1, 8, 15) + C (AUC 6, d1) iv q3w, with BEV q3w continued alone for a total of up to 17 cycles (1 y) as front-line therapy for newly diagnosed OC (FIGO stage I–IIa [grade 3/clear cell] or stage IIb–IV [any grade]). The primary endpoint was PFS. Results: Of the189 treated pts, 37 (20%) were aged ≥65 y (11% 65–<70 y; 6% 70–<75 y; 3% ≥75 y). Compared with pts aged <65 y, the subgroup of pts aged ≥65 y included fewer pts with no residual disease after surgery (24% vs 34%) and more pts with grade 3 OC (62% vs 55%) or comorbidities at baseline (hypertension: 38% vs 17%; dyslipidemia: 14% vs 5%). Pts aged ≥65 y received a median of 6 chemotherapy cycles (range 1–8) and 17 BEV cycles (range 0–18). C or wPAC was given for ≥6 cycles to 86% and 68% of pts, respectively. AEs led to early discontinuation of C, wPAC, or BEV in 14%, 38%, and 14% of pts, respectively. After median follow-up of 26.5 months and events in 62%, median PFS was 20.5 mo (95% CI 17.8–29.1 mo) in the elderly subgroup. Seven pts (19%) had died, all from disease progression; the 1-y OS rate was 97.3%. The most common grade ≥3 AEs were hematologic (neutropenia 62%, thrombocytopenia 14%), with no major differences according to age. Overall, there was a numerically higher incidence of grade 3/4 AEs in pts aged ≥65 vs <65 y (86% vs 76%, respectively), driven by non-hematologic AEs. The incidences of grade ≥3 AEs of special interest were similar in older and younger pts, except for hypertension (11% in pts ≥65 y vs 3% in pts <65 y) and bleeding (3% vs 0%, respectively). Conclusions: BEV combined with wPAC and C is a feasible, well-tolerated, active front-line regimen, even in the small subgroup of pts aged ≥65 y, many of whom had comorbidities. Clinical trial information: NCT00937560.
Protein network mapping of platinum-resistant and poor-survival ovarian cancer.
Authors: Sereni Maria Isabella , Baldelli Elisa , Gambara Guido , Zanotti Laura , Bandiera Elisabetta , Bignotti Eliana , Meani Francesco , Ravaggi Antonella , Angioli Roberto , Liotta Lance A. , Pecorelli Sergio L. , Petricoin Emanuel , Pierobon Mariaelena
Published: March 2020

5560

Background: Epithelial ovarian carcinoma (EOC) is the fifth leading cause of tumor related death in the female population, with only 30% of patients alive at 5 years after diagnosis. Platinum resistance is a major cause of treatment failure. The aim of the study was to perform broad-scale drug target activation mapping of EOC to identify new druggable targets for personalized therapy. Methods: 72 ovarian primary lesions collected from chemo-naïve EOC patients were analyzed. Highly enriched tumor epithelial cells were isolated by laser capture microdissection, lysed and subjected to reverse phase protein microarray analysis for multiplexed protein pathway activation mapping. The activation/phosphorylation level of 156 key signaling proteins was analysed. Based on the disease-free interval to platinum therapy, 61 stage II-IV patients were segregated into platinum-resistant (<6 months), platinum-sensitive (6-12 months), and platinum-supersensitive disease (>12 months). One-way analysis of variance was used to detect significant differences among the three groups in the drug target activation profile. Results: Expression of the drug target PDGF Receptor β and activation of ErbB2/HER2 (Y1248) were significantly higher in patients with resistant disease compared to sensitive groups (respectively, p 0.0033 and p 0.0134), while the expression of Estrogen receptor α was greater in the supersensitive group (p 0.0295). Moreover, overall survival analysis including all stages revealed that the expression level of Cox2 is significantly higher in patients with shorter survival (HR: 2.48, p 0.0179). Conclusions: Functional drug target activation mapping revealed the unique signaling architecture of platinum-resistant EOC. If confirmed in independent study sets, these results suggest that the utilization of drugs targeting PDGF Receptor β and ErbB2/HER2 could be evaluated in platinum resistant EOC and/or in combination with platinum therapy in order to overcome acquired resistance. Finally, this study indicates that Cox2 may play an important role in aggressive EOC, and that the addition of Cox-inhibitors to standard of care could be rationally evaluated as a novel therapeutic regimen for ovarian cancer.
Benefits of neoadjuvant chemotherapy in ovarian, primary peritoneal, or fallopian tube carcinoma.
Authors: Brown Alaina J. , Huang Marilyn , Sun Charlotte C. , Zaid Tarrik M. , Balakrishnan Nyla , Mhadgut Hemendra , Lu Karen H. , Westin Shannon Neville , Bodurka Diane C.
Published: March 2020

5580

Background: NCCN guidelines recommend consideration of neoadjuvant chemotherapy (NACT) for poor surgical candidates with bulky stage III or IV ovarian, fallopian tube, or primary peritoneal cancer. However, new convincing evidence favoring NACT instead of primary tumor reductive surgery (PTRS) has resulted in shifting practices among gynecologic oncologists. This study compares operative and post-operative outcomes between patients receiving NACT and those undergoing PTRS. Methods: After IRB approval, patients who received NACT or PTRS were identified through the tumor registry and surgical database at a single institution from 2008-2012. Statistical analyses included Wilcoxon Mann-Whitney, Chi square and Fisher’s exact test. Results: Of 163 patients, 109 (67%) received NACT and 54 (33%) underwent PTRS. The majority in both groups was Caucasian (82%) and had ovarian cancer (85%). The median age of all patients was 62 years. There was no difference in median age between groups. High-grade serous histology was most common. In the PTRS group, 72% were stage IIIC. During cytoreductive surgery, NACT cases had significantly shorter total operative and anesthesia time compared to PTRS cases (p = 0.005). NACT patients had significantly less blood loss (p=0.002) than PTRS patients. Based on available data, there was no difference in intraoperative transfusion rate (p = 0.098). However, PTRS cases had a higher rate of postoperative transfusion compared to NACT cases (p = 0.043). There was no difference in the proportion of optimal surgical cytoreduction between groups (p = 0.422). Available data demonstrated that PTRS patients had significantly more complications and intensive care unit (ICU) admissions compared to those receiving NACT (p = 0.024, p = 0.002 respectively). Conclusions: NACT offers advantages regarding operative and anesthesia time, blood loss, postoperative complications, and ICU admissions. NACT may offer a valuable alternative to PTRS. Further studies are warranted to better define the role of NACT in the upfront treatment of advanced ovarian cancer.
Frequently deleted genes in ovarian cancer as indicators of platinum response.
Authors: Willis Scooter , Villalobos Victor Manuel , Young Brandon Michael , Sikic Branimir I. , Leyland-Jones Brian
Published: March 2020

5583

Background: Integrating chromosomal deletions/amplifications with sequencing alterations is increasingly important in the determination of key drivers of outcome in cancer (Leary 2008, Curtis 2012). We introduce a novel computational approach, Gene Set Outcome Analysis, to determine gene signatures constrained to regions with frequent deletion or amplification events in ovarian cancer identified by TCGA. Differential expressions of mRNA from these genes are used as a proxy for loss of function from deletions or amplifications. Methods: Gene signatures from each region were evaluated using log-rank test comparing high and low gene expression groups split by cohort mean. In total, 30,119,708 signatures constrained to 47 deleted and 36 amplified regions were tested for PFS for first line platinum treatment in a random 2/3 split of TCGA ovarian cohort (n=262) resulting in 26,271 gene signatures with p < .001. The remaining 1/3 cohort (n=135) and full cohort (n=397) were used as a replication study where 111 signatures have a p < .01 located in 2 deletion and 1 amplification region. The signature with the lowest p-value from each region that validated in the replication study, were evaluated in GSE9891 (n=179) (Tothill 2008) for PFS when treated with platinum and taxol resulting in gene signatures from 2 deletion regions with p<.05. Results: Greater than mean expression in this gene signature [OXTR, SATB1, WNT7A, SH3BP5, CRBN, ATG7, CRELD1, TMEM43] located at 3p23-p26.2 predicts poor response to platinum chemotherapy in TCGA full ovarian cohort (17.9 vs 14 months p = 1.4E-7) and validates in GSE9891 (19.6 vs 13.3 months p = .014). Using a separate, compact gene signature [CAAP1, LRRC19, IFNA8] located at 9p21.2, samples with lower than mean expression demonstrate increased platinum sensitivity in TCGA full ovarian cohort (12.2 vs 18.2 months p = 1.0E-6) and in GSE9891 (15.5 vs 18.6 p = .055). Conclusions: Response to platinum therapy is an important predictor of survival in high-risk ovarian cancer patients. These signatures arising from common deletion and amplification events in ovarian cancer can anticipate platinum sensitivity and merits further study for use in choosing optimal therapies studying platinum resistance mechanisms.
Pathologic distribution of disease at the time of interval debulking versus primary tumor reduction in women with primary peritoneal, ovarian, or Fallopian tube carcinoma.
Authors: Zaid Tarrik M. , Huang Marilyn , Brown Alaina J. , Balakrishnan Nyla , Mhadgut Hemendra , Pal Navdeep , Wei Caimiao , Broaddus Russell , Bodurka Diane C. , Lu Karen H. , Westin Shannon Neville
Published: March 2020

5584

Background: The surgical approach for interval debulking after neoadjuvant chemotherapy (NACT) for primary peritoneal, ovarian, or fallopian tube carcinoma has largely been extrapolated from experience with primary tumor reductive surgery (PTRS). It is unknown whether procedures considered mandatory in PTRS, such as hysterectomy, contribute to comparable removal of macroscopic disease in the NACT setting. Our study compared the difference in pathologic distribution of disease at interval debulking surgery versus primary tumor reduction. Methods: After IRB approval, patients who received NACT or PTRS were identified through the tumor registry and surgical database at a single institution from 2008-2012. Involvement of organs at the time of surgery was categorized as either macroscopic, microscopic and no tumor. Statistical analyses included Wilcoxon Mann-Whitney and Fisher’s exact tests. Results: Of the 163 patients identified, 111 (67%) received NACT and 54 (33%) underwent PTRS. Median age was 62 and the majority of patients had stage IIIC high-grade serous carcinoma (91%). Macroscopic ovarian involvement was more common at time of PTRS (92 % vs 63 %, p <0.001). Gross uterine involvement was significantly less in the NACT group compared to PTRS, with the majority of specimens in the NACT group free of disease (Macroscopic 11 % vs 42%, no tumor 62% vs 44 %, p <0.002). However, 27% of the NACT had microscopic uterine serosal disease. Macroscopic large bowel involvement was 50 % in the PTRS vs 26 % in NACT(p<0.005). There was no difference in disease involvement of the small bowel or omentum. Conclusions: The pathologic disease distribution at the time of interval tumor debulking is significantly different from that encountered during primary cytoreductive surgery.. NACT appears to reduce macroscopic large bowel and uterine tumor involvement and may negate the need for hysterectomy and/or large bowel resection at the time of interval debulking to achieve no gross residual.
Regional differences in therapy and clinical management of endometrial cancer: Findings of an international survey by the North-eastern German Society of Gynaecological Oncology (NOGGO).
Authors: Kraetschell Robert W. , Fotopoulou Christina , Dowdy Sean Christopher , Fujiwara Keiichi , Yaegashi Nobuo , Lorusso Domenica , Mahner Sven , Herzog Thomas J. , Casado Herraez Antonio , Vergote Ignace , Miller David S. , Marth Christian , Battista Marco Johannes , Lichtenegger Werner , Sehouli Jalid
Published: March 2020

5593

Background: We conducted an international survey to evaluate the differences in the systemic, radiotherapeutic and operative management of endometrial cancer (EC) in different regions of the world. Methods: In 2009 avalidated 15-item-questionnaire regarding surgical and adjuvant procedures of EC was sent to all German gynaecological clinics and in 2010 the English adapted questionnaire was set online as well as sent per post in most major gynaecological cancer societies. Results: 316 German institutions and 302 Institutions from 24 countries participated. We combined the different countries into regional groups: Central Europe (CE), southern Europe (SE), Asia and USA/UK. In Asian countries and in CE a lymph node dissection (LND) was performed routinely in 72.8% and in 55.6% of the cases, whereas in the USA/UK and in SE a LND was done mainly in selected cases when specific risk factors such as high-grade or non-endometrioid-histology applied (62.8% and 72.5%) than routinely (p < 0.001). A systematic pelvic and paraaortic LND was performed most frequently in CE 91.0%, in SE 76.9%, in Asia 70.9% and in USA/UK 68.6% (p < 0.001). A systematic LND with the intention of both adequate staging and for therapeutic value was performed in countries of central Europe to 74.6% and in Asia to 67.2%. In USA/UK the LND was seen merely as a staging instrument by 53.5% (p < 0.001). The LND was performed up to renal veins in CE in 86.8%, in Asia in 80.8%, in USA/UK in 51.2% and in SE in 45.1 %. A significant difference war found in the treatment for FIGO stage I (high risk factors (high grade, L1,V1)) and stage II disease between the countries: chemotherapy was applied in 84.8% of the participated centers in Asia,42.3% in SE, 21.2% in CE and only 13.6% in USK/UK (p<0.001).Vaginal brachytherapy was indicated as follows: USA/UK 84.1%, CE 78.8%, SE 78.8%, Asia 5.6% (p < 0.001). Conclusions: There is a large variety in the operative therapy and the clinical management of EC in different regions of the world. Future international prospective trials, will be necessary to improve and harmonize the evidence based treatment guidelines for EC- disease.
Early diagnosis program for cervical cancer in Tanzania: The “Vanda Project”.
Authors: Serra Patrizia , Amadori Dino , Nanni Oriana , Gennari Alessandra , Bravaccini Sara , Puccetti Maurizio , Tumino Rosario , Kahima Jackson , Masalu Nestory Andrew ,   African Italian Cooperative Oncology Group (AFRICOG)
Published: March 2020

5594

Background: In Sub-Saharan Africa cervical cancer represents 24% of all cancers and accounts for 23% of all cancer deaths in women. An early diagnosis program for breast and cervical cancer (Vanda Project) is ongoing in Mwanza and the surrounding lake area (12 districts with a population of 14,000,000). The aim of this project was to screen women aged 15-64 years living in the 12 districts. Methods: Women were invited to participate through local media and a mobile unit operating within the districts. A multidisciplinary team including medical oncologists was involved. Interventions consisted in Pap smear, clinical breast examination, breast self-examination training and training of district physicians to perform Pap smear and breast examination. Results: From May to December 2012, 2155 women from the districts of Shinyanga, Bukumbi, Kibara, Serengema and Musoma took part in the program: of these 91 (4%) had clinically evident cervical cancer. Age distribution classes were: < 18 years, 12% ; 18-35, 38%; 36-50, 41%; > 50, 9%. As expected a high stage distribution at diagnosis was observed: 30% stage III and 20% stage IV. Among the women with no clinical evidence of cancer, 408 samples were analyzed by cytology and 4% consisted of inadequate material. Of the remaining 392 samples, 85 (22%) were normal, 216 (55%) were infections (chiefly mycotic), 72 (18%) were precancerous lesions (50% H-SIL according to Bethesda classification) and 19 (5%) were positive for cancer (mainly stages III-IV). Precancerous lesions turned out to be cancer at histology in 44% of cases. 22% of precancerous lesions and 8% of clinically evident cancer were HIV-positive. Conclusions: This experience shows the high feasibility, good compliance and usefulness of a screening program for the early detection of cervical cancer in this high-risk population. [Table: see text]
Disseminated tumor cells in bone marrow of patients with endometrial and cervical cancer.
Authors: Taran Florin-Andrei , Wallwiener Markus , Hartkopf Andreas D. , Walter Christina , Brucker Sara , Rothmund Ralf , Kraemer Bernhard , Wallwiener Diethelm , Fehm Tanja N.
Published: March 2020

5598

Background: The presence of disseminated tumor cells (DTC) in the bone marrow (BM) of breast cancer patients is associated with poor prognosis. Several studies demonstrated that tumor cell dissemination may occur in gynecologic cancer and affect clinical outcome. The aim of our study was to evaluate the incidence of DTC and to assess their prognostic significance in patients with gynecologic malignancies. Methods: Bone marrow aspirates from 623 patients with primary endometrial (331), cervical (228), and vulvar cancer (64) undergoing surgery at the Department of Gynecology and Obstetrics, University Hospital, Tuebingen, Germany between November 2001 and May 2012, were included into the study. Disseminated tumor cells were identified by immunocytochemistry using the pancytokeratin antibody A45B/B3 and by cytomorphology. Results: Disseminated tumor cells were detected in 18% of BM aspirates from patients with gynecological malignancies. Incidences of DTC in endometrial, cervical, and vulvar cancer were 21%, 16% and 16%, respectively. The presence of DTC was associated with a lower tumor grade in endometrial cancer For patients with vulvar cancer, no correlation with established clinicopathological factors was observed. In case of cervical cancer, BM positivity was correlated with International Federation of Gynecology and Obstetrics stage, nodal involvement and the presence of lymphangiosis carcinomatosa. For all analyzed tumor entities, no association between BM status and clinical outcome could be observed. Conclusions: Disseminated tumor cells are a common phenomenon in solid tumors. However, only in cervical cancer DTC postivity was associated with advanced disease. The consequences for DTC positive patients have to be determined.
Conservative management of young women with endometrial adenocarcinoma with grade 2-3 and/or superficial myometrial invasion.
Authors: Park Jeong-Yeol , Kim Dae-Yeon , Kim Tae-Jin , Kim Jae Weon , Kim Jong-Hyeok , Kim Yong-Man , Kim Young-Tak , Bae Duk-Soo , Nam Joo-Hyun
Published: March 2020

5601

Background: To estimate the oncologic and pregnancy outcomes after progestin treatment of young women with endometrial adenocarcinoma with grade 2–3 and/or superficial myometrial invasion. Methods: Medical records of 48 young women with endometrioid adenocarcinoma of the uterus with grade 2–3 and/or superficial myometrial invasion who were conservatively managed with oral progestin were reviewed. Results: Fourteen patients (29.2%) received daily oral megestrol acetate (median dose, 160 mg/day; range, 40–240 mg/day) and 34 (70.8%) received daily oral medroxyprogesterone acetate (median dose, 500 mg/day; range, 80–1000 mg/day). The median treatment duration was 10 months (range, 3–20 months). Complete responses were observed in 37 patients (77.1%) and the median time to complete response was 17 weeks (range, 9–51 weeks). Complete response rates were 76.5%, 73.9%, and 87.5% for patients with grade 2–3 without myometrial invasion (n=17), patients with grade 1 and superficial myometrial invasion (n=23), and patients with grade 2-3 and superficial myometrial invasion (n=8), respectively (P = 0.731). Their recurrence rates after a median follow-up time of 48 months (range, 7–136 months) were 23.1%, 47.1%, and 71.4%, respectively (P = 0.104). None experienced disease progression or died of the disease. Nine patients gave birth to 10 healthy babies. Conclusions: Progestin treatment is safe for patients with grade 2–3 without myometrial invasion and patients with grade 1 and superficial myometrial invasion. However, it should be provided on an individual basis and must be applied cautiously in patients with grade 2–3 and superficial myometrial invasion.
Determination of the activated form of the progesterone receptor (PR) in endometrial cancer (EC).
Authors: Graham Dinny , Bosq Jacques , Caillaud Jean-Michel , Powell Matthew A. , Leblanc Eric , Fujiwara Keiichi , Herzog Thomas J. , Monk Bradley J. , Clarke Christine , Zukiwski Alexander A. , Gilles Erard M. , Coleman Robert L.
Published: March 2020

5602

Background: Endocrine treatments, in general have limited clinical efficacy in endometrial cancer. Upon ligand binding, PRs in normal tissue form discrete focal subnuclear distribution patterns (FDP), which are associated with DNA transcription. FDP are indicative of functionally activated PRs (APRs), and are observed in EC, independently of menopausal status. The feasibility of using an IHC technique to characterize the PR functional status has previously been reported in breast cancer and the APR phenotype in cell lines correlates with anti-progestin activity. The goal of this study is to determine if APR can be identified in EC and to determine if this IHC technique & APR phenotype could be developed as a companion diagnostic to predict anti-progestin efficacy in patients with EC. Methods: 72 archived primary EC specimens were processed with standard IHC for estrogen receptor (ER), PR & proliferation (Ki67). APR status was determined using commercially available antibodies specific to the A and B isoforms of the PR (PRA and PRB) with standard microscopy at 1000x magnification. Results: 56 (78%) tumors were of endometrioid histology. Endometrioid tumors were ER+ (68%) and PR+ (84%). Two PR nuclear distribution patterns were observed: an aggregated pattern (A) which is indicative of APR and a diffuse or finely granular pattern (D) indicative of an inactivated PR. This resulted in three tumor phenotypes: A cells only, D cells only, and a mix of A + D cells. APR was defined as any tumor with more than 5% A cells. An average of 49% of tumor cells were positive with PRA, 35% were positive for PRB. APR was present with PR A in 41% and with PR B in 47% of the PR+ endometrioid tumors. The APR status, for both PR A and PR B, was independent of PR positivity rate, PR staining intensity score and % Ki67 positive. APRpos phenotype was associated with a lower % ERposstaining. When observable, endometrial stromal and normal cells were PR positive (D pattern). Conclusions: APR can be identified using either PRA or PRB, in ~50 % of the EC samples; there was a pattern consistent with the presence of APR positive cells. The IHC technique to identify APR has the potential to be developed as companion diagnostic as a potential predictor of anti-progestin efficacy.
Comparing intensity modulated radiotherapy and conventional external beam radiotherapy in cervical cancer.
Authors: Gudipudi Deleep Kumar , Alluri Krishnam Raju , De Leon Maria B. , Cardenes Higinia Rosa , Del Priore Giuseppe
Published: March 2020

5610

Background: To compare Intensity-modulated radiation therapy (IMRT) with conventional external beam radiation therapy (CXRT) regarding morbidity, tumor response, and quality of life (QOL) in cervical cancer patients. Methods: Between 8/2009-2/2010, 50 patients (pts) with age range 20-85, with FIGO Stage IIA- IIIB were prospectively randomized 2:1 to CXRT and IMRT at Indo-American Cancer Institute. Both groups received concurrent chemotherapy (weekly cisplatin 30-40mg/m2) with external beam radiation (EBRT), 50Gy/25fractions followed by intracavitary brachytherapy at 21Gy/3fractions. Complications and QOL were evaluated during treatment and in follow-up with CTC 4.0 and EORTC QLQ-C30, and disease recurrence was based on pelvic exam. Analysis used Chi square(X2) at a significance level of 0.05. Results: Average time to completion was 49 and 48 days in CXRT and IMRT arms (p>.05). Four pts did not complete the treatment in the CXRT. Two months after completion 31/35 (89%) of CXRT and 15/15 (100%) of IMRT had complete response (p>.05). At 5 months, 30/35 (86%) of CXRT, and 14/15 (100%) of IMRT had no loco-regional disease (LRD); 1 IMRT pt died from distant metastasis (DM). At 18 months, 25/35 (72%) in CXRT and 14/15 (93.5%) in IMRT had no LRD or DM. Most common acute side effects in the CXRT were Grade 1 vomiting/cystitis/diarrhea and Grade 2 nausea/skin reactions/proctitis. One pt developed vesicovaginal fistula (VVF) after 50Gy by EBRT. Most common acute side effects in the IMRT were Grade1 nausea/vomiting/cystitis/proctitis/diarrhea. Two pts had grade 3 neutropenia in the 5th week of RT. QOL was better in IMRT (p <.01) based on functional, symptom, single items, and global scales except for pain, insomnia, loss of appetite. Diarrhea, financial problems were worse in the CXRT (p<.05). Chronic complications such as radiation induced proctitis in 5 patients, and sub-acute intestinal obstruction in 2 patients during follow-up period in CXRT vs. IMRT (p < 0.001). Conclusions: IMRT is superior to CXRT with fewer chronic side effects and similar acute side effects and treatment responses. This is the first randomized clinical trial of these treatments in cervical cancer.
Vulvar cancer: Presentation and treatment variation among races.
Authors: Rosin Jennifer , Silberstein Peter T.
Published: March 2020

5611

Background: Vulvar cancer is the fourth most common gynecologic malignancy. We analyzed variation among races in treatment, histology and stage at presentation using the National Cancer Database (NCDB). Methods: Between 2000 and 2010, 51,157 women from 1338 hospitals across the US were reported to the NCDB with vulvar cancer. Differences were assessed using Chi square analysis. Results: Caucasian patients with vulvar carcinoma in situ received no first course treatment significantly less than African American or Hispanic patients (3% vs 6% and 7%, p<0.05). No treatment for stage I and II vulvar cancer was also significantly less than African American patients (1.4% vs 2.5%, p<0.05). African Americans overall chose radical surgery less often than Caucasians (13% vs 16%, p<0.05), but local tumor excision more (29% vs 24%, p<0.05). African Americans and Hispanics chose no surgery of primary sites significantly more than Caucasians (14% and 15% vs 9%, p<0.05). As expected, squamous cell carcinoma accounts for over 90% of vulvar cancer cases reported. However, Asian-Pacific Islanders had a significantly higher proportion of Extramammary Paget’s disease when compared to Caucasians, African Americans, or Hispanics (20% vs 4.3%, 0.6%, 3.2%. p<0.05). African Americans had the lowest proportion of Extramammary Paget’s compared to any other race for all stages (0.6%, p<0.05). African Americans presented as vulvar carcinoma in situ more often than any other race (33% vs 25-29%, p<0.05). Conclusions: This is the largest study analyzing racial differences in treatment, histology and stage at presentation in women with vulvar cancer. Caucasians were least likely to opt for no first course treatment overall. African Americans were most likely to choose no treatment and, when having surgery, preferred local excision over radical vulvectomy.
A meta-analysis of endocrine therapy trials in early breast cancer (BC) evaluating the impact of obesity: Are aromatase inhibitors (AIs) optimal therapy in obese ER+ BC?
Authors: Pugliano Lina , Zardavas Dimitrios , Paesmans Marianne , Sestak Ivana , Gelber Richard D. , Cuzick Jack M. , Dowsett Mitchell , Awada Ahmad , Piccart-Gebhart Martine J. , De Azambuja Evandro
Published: March 2020

575

Background: Obesity is an adverse prognostic factor in BC. Mixed results are reported for the relative efficacy of AIs compared to tamoxifen (T) in obese ER+ BC patients. Our purpose was to conduct a meta-analysis of adjuvant randomised trials of AIs vs T assessing the impact of body mass index (BMI). Methods: We identified four studies evaluating BMI and endocrine therapy. Of these, 3 were randomised (non-steroidal AIs vs T) and were evaluable for the aggregation of results for DFS and OS in our meta-analysis. We extracted published data from ATAC, ABCSG-12 and BIG01-98, analyzed according to standard meta-analytic techniques. Results: A total of 11,383 patients were included in our study. BMI>25 is associated with reduced disease free survival (DFS) and a trend towards worse overall survival (OS) (Table 1). A significantly shorter DFS was seen for patients with BMI>25 treated with an AI while a trend was seen for OS. Reduced relative efficacy was seen for DFS for AIs compared to T for BMI<25 (HR=0.78; 95%CI 0.66- 0.91; p=0.002) and a trend for BMI>25 (HR=0.85; 95%CI 0.70- 1.02; p=0.08). The test for interaction was not significant (p=0.48), with similar results for OS for BMI<25 (HR=0.79; 95%CI 0.63-0.9; p=0.009) and BMI>25 (HR=0.98; 95%CI 0.61-1.60; p=0.95). The test for interaction was not significant (p=0.37). Notably, significant heterogeneity in patients treated with anastrozole and a BMI>25 did not allow a comparison between anastrozole and letrozole. Conclusions: BMI>25 has a negative prognostic effect in BC. AIs demonstrate improved outcomes in normal weight BC patients (BMI<25). Obesity was associated with observed relative reduced efficacy of AIs; however, we were not able to detect a significant interaction between BMI and treatment effect. Further analyses into the differing impact of type of AIs on BC outcomes in obese patients are warranted. [Table: see text]
The haplotype of three polymorphisms in the SATB1 promoter-region and impact on survival in breast cancer patients.
Authors: Heubner Martin Leonhard , Kimmig Rainer , Siffert Winfried , Ulrich Frey
Published: March 2020

584

Background: Special AT-rich sequence binding protein 1 (SATB1) has regulatory effects on gene expression and appears to play an important role in tumor progression. We screened the promoter region of the SATB1 gene for polymorphisms, evaluated the corresponding haplotypes regarding alterations in promoter activity in vitro and analyzed the impact of these haplotypes on the clinical course of breast cancer patients. Methods: 241 caucasian breast cancer patients who had been treated were enrolled in this retrospective analysis. The median follow up time was 93 months (4-155 months). PCR products from DNA of 10 healthy unrelated volunteers were analyzed to identify new polymorphisms within the promoter region. Genotyping was conducted using restriction length polymorphism and pyrosequencing. PCR constructs with the respective alleles from the four most frequent haplotypes were cloned into the vector pGEM-Teasy (Promega Corporation, Madison, WI, USA) and then transferred into the luc2-containing reporter vector pGl 4.10 Vector (Promega) for transfection of HEK293 cells. The pGl 4.73 Vector (Promega), containing hRluc, was used for norming the transfection rates. Results: Sequencing the region -3807bp to -2828 upstream from ATG of ten healthy blood donors, we found three single nucleotide polymorphisms SNPs consisting of base exchanges, -3600T>C, -3363A>G and -2984C>T.The SATB1 -3600T/-3363A/-2984C haplotype had a lower promoter activity than all other constructs in vitro and showed a significant association with the nodal status (p=0.049). Kaplan-Meier survival analysis revealed a significantly better survival for homozygous SATB1 -3600T/-3363A/-2984C haplotype carriers compared with heterozygous or the other haplotypes (p=0.033). Conclusions: The SATB1 -3600T/-3363A/-2984C haplotype is associated with lower promoter activity and appears to impact upon survival in breast cancer patients.
Predictive value of tumor infiltrating lymphocytes (TIL) for response to breast cancer neoadjuvant chemotherapy (NCT).
Authors: Garcia-Martinez Elena , Luengo-Gil Gines , Chaves Asuncion , Velazquez Lorena , Gonzalez-Billalabeitia Enrique , Vicente-Conesa Maria Angeles , Garcia Teresa , Garcia-Garre Elisa , Vicente Vicente , Ayala Francisco
Published: March 2020

585

Background: The association of tumor microenvironment immune response with outcome after breast cancer (BC) NCT has been suggested by several studies. However, the relevance of each TIL subpopulation is still controversial. The objective of this study was to evaluate the predictive and prognostic value of TIL before and after NCT in patients with BC. Methods: We analyzed TIL and CD68 cells in pre- and post-chemotherapy biopsies of BC patients treated with NCT (80.4% sequential AC-docetaxel). A tissue microarray with paired pre- and post-NCT biopsies was built, and stained with immunohistochemistry (IHC) for CD3, CD4, CD8, CD20, FOXP3 and CD68. Morphometric analysis (TIL count/mm2) was performed after slide scanning and digitalization. Results: We included 121 consecutive patients with invasive BC, most of them with stages IIB (28%) or IIIA-C (56.4%). IHC phenotype: 50.4% Her2- hormone-sensitive (HS), 13.2% Her2+ HS, 10.7% Her2+ non-HS, and 21.5% triple negative. Pathologic complete response (pCR): 17.4%. Median overall survival (OS) and disease free survival (DFS) has not been reached (median follow-up: 60 months). Higher than median pre-NCT TIL infiltration was predictive of pCR to NCT: CD3 > 172/mm2 (p=0.001; Hazard Ratio [HR]: 9,61, 95% confidence interval [95%CI] 2.49–37.02); CD4 > 67/mm2 (p=0.001; HR: 8.82, 95%CI 2.43–31.96); CD20 > 42/mm2 (p=0.001; HR: 8.71, 95%CI 2.31–32.74). Logistic regression multivariate models including grade and IHC phenotype confirmed the independent predictive value of higher pre-NCT CD3, CD4, and CD20 for pCR. In the group of patients with HS Her2- BC without pCR (n=44), higher infiltration (cut-point: median value) by some TIL subpopulations and by CD68 cells in post-NCT residual tumor associated to lower DFS: CD8 > 37/mm2 (log-rank; p=0.04), CD20 > 14/mm2 (p=0.07) and CD68> 39/mm2 (p=0.06). Conclusions: Higher pre-treatment CD3, CD4 and CD20 TIL predicted pRC in patients with invasive BC receiving anthracyclines and taxanes NCT, while higher infiltration of residual tumor by CD8 associated to worse DFS in patients with HS Her2- BC without pCR after NCT. TIL might be useful as predictive factors in the setting of NCT for BC [Supported by GEICAM-Beca Ana Balil].
Management of breast cancer during pregnancy: Results of a large registry from a single institution.
Authors: Peccatori Fedro , Sarno Maria Anna , Azim Hatem Abdel , Gentilini Oreste Davide , Galimberti Viviana , Martella Stefano , Pruneri Giancarlo , Renne Giuseppe , Scarfone Giovanna , Fumagalli Monica , Sangalli Claudia , Locatelli Marzia Adelia , Rotmensz Nicole , Lambertini Matteo , Colleoni Marco , Goldhirsch Aron
Published: March 2020

589

Background: Given the rising trend of delaying pregnancy to later in life, more women are diagnosed with breast cancer during pregnancy. Management is still controversial and relies on expert guidelines. Thus the experience of single centres with high patients’ volume remains of interest. Methods: All breast cancer patients (pts) diagnosed at the European Institute of Oncology (IEO) in Milan were included in a specific registry since 1995. Results: Out of 8340 patients < 47 y/o registered up to Dec 2012, 167 were diagnosed during pregnancy (2%). Median age was 36 years (24-47y). Median gestational age was 18 weeks (1-38 w). 73 % pts had a pT1-2 tumor, with positive nodes in 48%. 9,6% had luminal A, 38% luminal B, 26% basal like and 16% HER2+ tumors, according to St Gallen criteria. 29/167 pts (17%) opted for an induced abortion. Of the remaining 97 pts, 81 (84%) underwent definitive surgery during pregnancy; 58 (72%) and 23 pts (28%) had quadrantectomy and mastectomy, respectively. Immediate breast reconstruction was performed in 13 cases. Sentinel node procedure (SLN) was performed in 42 pts (52%), with positive axilla in 10 pts. 41 pts (51%) received chemotherapy during pregnancy. Regimens included weekly epirubicin (24 pts), EC/AC (12 pts), FAC/FEC (3 pts), q21 epirubicin (2 pts). No G3-G4 toxicities were reported. No pregnancy complications were observed, with the exception of 1 case of premature delivery at 28 weeks. Median gestational age at delivery was 36 weeks (29-40 w). No major malformations were observed. Gestational age at birth and birth-weight were similar in babies who received chemotherapy in-utero (36 w and 2555g) and in babies who did not receive gestational chemotherapy (37w and 2600g). At a median follow-up of 42 months (range: 1-178 m), all children had normal neurological and physical development with no late adverse effects observed. Conclusions: Managing breast cancer during pregnancy should follow standard practice as in non-pregnant pts. Surgeries like SLN and breast reconstruction were performed with no serious complications. Our results further emphasize the safety of anthracycline-based gestational chemotherapy without major effects on pregnancy course or fetal health.
ER as a predictor of early breast cancer (EBC) outcomes in patients.
Authors: O'Shaughnessy Joyce , Loesch David M. , Paul Devchand , Stokoe Christopher T. , Pippen John E. , Blum Joanne Lorraine , Krekow Lea , Holmes Frankie Ann , Vukelja Svetislava J. , Lindquist Deborah , Sandbach John F. , Sedlacek Scot M. , Wang Yunfei , Jones Stephen E.
Published: March 2020

590

Background: Some ER-negative (ER-) breast cancers express low levels of estrogen receptors and approximately 12% express androgen receptors (Traina, T, et al. ASCO, 2012). Whether young premenopausal women (age <40) with ER- breast cancer (BC) who are more likely to retain ovarian function after adjuvant chemotherapy have a worse outcome than older women with ER- disease has not been widely investigated. Methods: We analyzed 2 adjuvant US Oncology BC studies: 99-016, 1830 BC patients randomized to doxorubicin/cyclophosphamide (AC)→Paclitaxel (P) (AC/P) vs AP→weekly P (no cyclophosphamide [C]) (AP/wP); and 01-062, 2611 patients randomized to AC→docetaxel (T) vs AC→T plus capecitabine (XT). ER+ patients received standard endocrine therapy following chemotherapy. Five-year DFS results did not show significant differences between the treatment arms on either study. The outcomes were analyzed for 5-year DFS by age ≤40yrs and >40yrs and by ER status. Results: In the two studies combined, ER- patients ≤40 had a superior DFS (84%) than ER- patients >40 (80%), while ER+ patients ≤40 had a worse 5-yr DFS (83%) than ER+ patients >40 (89%), although these findings were of borderline significance (see Table below). In 99-016, omitting C did not adversely affect outcomes in either age group, regardless of ER status. Conclusions: We did not observe worse outcomes in ER- patients ≤40 years compared to those >40 years in 2 US Oncology adjuvant chemotherapy trials, suggesting no adverse impact of assumed greater ovarian function following adjuvant chemotherapy in patients ≤40yrs. ER+ patients ≤40 had a worse DFS than ER+ patients >40. Omitting C in ER- patients ≤40 or >40 did not adversely affect outcome. [Table: see text]
4EVER: Assessment of circulating tumor cells with a novel, filtration-based method, in a phase IIIb multicenter study for postmenopausal, HER2- negative, estrogen receptor-positive, advanced breast cancer patients.
Authors: Fasching Peter A. , Gumbrecht Walter , Fehm Tanja N , Haeberle Lothar , Muth Mathias , Sickert Daniel , Pugia Michael , Friedrich Katja , Matzas Mark , Lueftner Diana , Beckmann Matthias W. , Hadji Peyman , Kreuzeder Julia , Lux Michael P , Janni Wolfgang , Schneeweiss Andreas , Belleville Erik , Decker Thomas , Grischke Eva-Maria , Tesch Hans
Published: March 2020

591

Background: The presence of circulating tumor cells (CTCs) has been shown to be of prognostic relevance for patients with early and advanced breast cancer (BC). The usefulness of CTC assessments depends on accurate cell counts and corresponding analysis of molecular targets. The aim of this sub study was to assess the feasibility of a novel, integrated CTC platform for automated cellular protein and nucleic acid analysis in a prospective multi-center study. Methods: The German 4EVER study included patients with postmenopausal, metastastic, ER positive, HER2 negative BC, who progressed after therapy with a non-steroidal aromatase inhibitor and were treated with exemestane and the mTOR inhibitor everolimus. Baseline blood samples (TransFix vaccum tubes, Cytomark, Caltag Medsystems Ltd.) were used for CTC analysis and processed on the modified Versant kPCR Sample Prep system using 8µm pore size Whatman Nuclepore track-etched membranes (GE Healthcare Piscataway, NJ). After CTC capture, immunostaining was performed for Cytokeratin 8/18/19 and CD45. CTCs were detected by image analytics after fluorescence scanning microscopy using a dedicated software solution implemented by Siemens. The data is summarized and correlated with baseline clinical characteristics. Results: CTC counts and clinical data were available for 111 blood samples (91.7%). CTCs were found in 75 patients (67,6%), 13 patients having 1 CTC, 38 having 2-9 CTCs and 24 patients having 10 or more CTCs. In an exploratory analysis the presence of CTCs was correlated with baseline patient and tumor characteristics. There were no associations with primary TNM stage, hormone receptor status or tumor type. Conclusions: CTC assessment with this novel filtration based method was feasible in a multi-center study setting. The CTC positivity rate was within the expected range. The follow-up of this study will give first insights, how the CTC measures of this platform can be used as a prognostic tool. As this CTC assessment platform was developed to perform additional automated cellular protein and nucleic acid analysis, the usefulness might derive from these analytic tools as well. Clinical trial information: NCT01626222.
Efficacy of cabozantinib (Cabo) in medullary thyroid cancer (MTC) patients with RAS or RET mutations: Results from a phase III study.
Authors: Sherman Steven I. , Cohen Ezra E.W. , Schoffski Patrick , Elisei Rossella , Schlumberger Martin , Wirth Lori J. , Mangeshkar Milan , Aftab Dana T. , Clary Douglas O. , Brose Marcia S.
Published: March 2020

6000

Background: Cabo extends progression-free survival (PFS) in patients (pts) with progressive, metastatic MTC (Schöffski, J Clin Oncol 30, 2012). Mutations in the RET oncogene are associated with most hereditary cases and ~half of sporadic cases of MTC. RAS gene mutations have recently been identified in subsets of RET wild type (wt) cases. Therefore, we investigated the association of RET (a prospectively defined endpoint) and RAS mutations (a post hoc analysis) with efficacy outcomes in the phase 3 study of cabo in MTC. Methods: Pts enrolled into the double-blind, placebo-controlled phase III trial were evaluated for the presence of somatic and germline RET mutations using Sanger and next generation methods. A subset of pts determined to be RET wt (44 pts) or RET unknown (41 pts) were then evaluated for tumor-associated mutations in KRAS, NRAS, and HRAS in codons 12, 13, and 61 by next generation sequencing. Impact of RET and RAS gene mutation status was evaluated with respect to PFS and tumor response rate (RR) according to RECIST. Results: RET status was determined in 65% of the study pts (215/330), of which 79% harbored an activating mutation, and 21% were RET wt. All RET mutational subgroups (RET mutated, RET wt, and RET unknown) showed hazard ratios indicating PFS benefit from cabo treatment, and demonstrated RRs between 22% and 32%. However pts harboring a RET mutation had longer median PFS on cabo (60 wks) than pts with wt RET (25 wks, PFS difference p=0.0001). Also, pts with the poor prognosis mutation RET M918T showed a longer median PFS on cabo treatment (61 wks) than pts with any other RET mutation (36 wks, PFS difference p=0.009). Patients with hereditary MTC had similar PFS to those with sporadic disease, and the presence of the common RET polymorphism G691S had no effect on either PFS or RR. Sixteen of 85 tested pts (5% of total study pts) with wt or unknown RET status were found to harbor a RAS gene mutation. The RAS-mutated pts showed a similar RR (31%) and PFS (47 wks) as RET mutated pts (32% and 60 wks). Conclusions: While hazard ratios indicate PFS improvement for all RET subgroups on cabo, the extent of benefit may depend in part on RET genotype. Cabo treatment benefit is also seen in pts harboring a RAS mutation. Clinical trial information: NCT00704730.