• Prognostic significance of positive circumferential resection margin post neoadjuvant chemotherapy in patients with esophageal or gastro-esophageal junction adenocarcinoma

  Patrao, Ana; Papaxoinis, Georgios; Kordatou, Zoe; Weaver, Jamie M; Owen-Holt, Vikki; Alkhaffaf, B; Galloway, S; Mansoor, Was; University of Manchester Division of Cancer Sciences, The Christie NHS Foundation Trust, Manchester, UK (2019)

  BACKGROUND: The aim of the present study was to assess the prognosis of patients with esophageal or gastroesophageal junction (E/GEJ) adenocarcinoma extending beyond the muscularis propria layer (?ypT3) and positive circumferential resection margin (CRM), post neoadjuvant chemotherapy. METHODS: 177 patients were retrospectively studied. The majority (94.9%) received ECX (epirubicin, cisplatin, capecitabine), and all had clear proximal/distal resection margins. CRM was defined as positive (CRM+) when it was directly infiltrated (infiltrated CRM) or when tumor cells were detected within 1 mm from CRM (close CRM) and as negative (CRM-) when tumor cells were found in a distance > 1 mm from CRM. RESULTS: CRM+ was found in 83 patients (46.9%). Of them, infiltrated CRM was recorded in 36 (20.3%) and close CRM in 47 (26.6%). Adjuvant chemotherapy was administered to 132 patients (74.6%). Lymphovascular invasion and primary site in the lower esophagus were independently associated with higher risk of CRM+. Patients with infiltrated CRM, compared to those with close CRM and those CRM-, had the shortest median time-to-relapse (11.4 vs. 15.6 vs. 22.1 months, respectively, p?=?0.005) and overall survival (18.7 vs. 23.1 vs. 38.8 months, respectively, p = 0.001). However, CRM status was not an independent predictor of poor outcome. Symptomatic isolated locoregional recurrences were rare in both CRM+ and CRM-patients (4/56 [7.1%] vs. 5/52 [9.6%], p?=?0.736), as well as in infiltrated vs. non-infiltrated CRM (CRM- and close CRM) (0/26 [0%] vs. 9/82 [11.0%], p?=?0.110). CONCLUSION: Although CRM status is associated with poor outcome, it does not represent an independent prognostic factor. The status of CRM did not significantly influence the pattern of cancer relapse
• Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma

  Rini, I; Plimack, R; Stus, V; Gafanov, R; Hawkins, Robert E; Nosov, D; Pouliot, F; Alekseev, B; Soulieres, D; Melichar, B; Vynnychenko, I; Kryzhanivska, A; Bondarenko, I; Azevedo, SJ; Borchiellini, D; Szczylik, C; Markus, M; McDermott, S; Bedke, J; Tartas, S; Chang, H; Tamada, S; Shou, Q; Perini, F; Chen, M; Atkins, B; Powles, T; Cleveland Clinic Taussig Cancer Institute, Cleveland (2019)

  BACKGROUND: The combination of pembrolizumab and axitinib showed antitumor activity in a phase 1b trial involving patients with previously untreated advanced renal-cell carcinoma. Whether pembrolizumab plus axitinib would result in better outcomes than sunitinib in such patients was unclear. METHODS: In an open-label, phase 3 trial, we randomly assigned 861 patients with previously untreated advanced clear-cell renal-cell carcinoma to receive pembrolizumab (200 mg) intravenously once every 3 weeks plus axitinib (5 mg) orally twice daily (432 patients) or sunitinib (50 mg) orally once daily for the first 4 weeks of each 6-week cycle (429 patients). The primary end points were overall survival and progression-free survival in the intention-to-treat population. The key secondary end point was the objective response rate. All reported results are from the protocol-specified first interim analysis. RESULTS: After a median follow-up of 12.8 months, the estimated percentage of patients who were alive at 12 months was 89.9% in the pembrolizumab-axitinib group and 78.3% in the sunitinib group (hazard ratio for death, 0.53; 95% confidence interval [CI], 0.38 to 0.74; P<0.0001). Median progression-free survival was 15.1 months in the pembrolizumab-axitinib group and 11.1 months in the sunitinib group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.57 to 0.84; P<0.001). The objective response rate was 59.3% (95% CI, 54.5 to 63.9) in the pembrolizumab-axitinib group and 35.7% (95% CI, 31.1 to 40.4) in the sunitinib group (P<0.001). The benefit of pembrolizumab plus axitinib was observed across the International Metastatic Renal Cell Carcinoma Database Consortium risk groups (i.e., favorable, intermediate, and poor risk) and regardless of programmed death ligand 1 expression. Grade 3 or higher adverse events of any cause occurred in 75.8% of patients in the pembrolizumab-axitinib group and in 70.6% in the sunitinib group. CONCLUSIONS: Among patients with previously untreated advanced renal-cell carcinoma, treatment with pembrolizumab plus axitinib resulted in significantly longer overall survival and progression-free survival, as well as a higher objective response rate, than treatment with sunitinib. (Funded by Merck Sharp & Dohme; KEYNOTE-426 ClinicalTrials.gov number, NCT02853331.).
• A systematic review of the role of penile rehabilitation in prostate cancer patients receiving radiotherapy and androgen deprivation therapy

  Doherty, Wesley; Bridge, P; Radiotherapy Department, Christie Hospital NHS Trust, Manchester, UK (2019)

  INTRODUCTION/BACKGROUND: Treatment-induced erectile dysfunction (ED) is a common side effect of radiotherapy and androgen deprivation therapy (ADT) that impacts on patient quality of life. Penile rehabilitation interventions including pharmacologic and physical therapies aim to reduce the impact of ED. Despite The National Institute for Health and Care Excellence guidelines recommending access to ED services, penile rehabilitation is not widely discussed or implemented. This systematic review aimed to appraise the evidence base for penile rehabilitation and identify evidence-based recommendations for practice. METHODS: A systematic review of the evidence base was undertaken using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The Scopus and Medline (EBSCO) databases were searched for articles relevant to penile rehabilitation interventions for prostate radiotherapy patients. Study quality was graded using the Oxford Levels of Evidence and the Scottish Intercollegiate Guidelines Network. RESULTS: This study identified 19 articles on penile rehabilitation in prostate radiotherapy patients, consisting of eight randomized controlled trials, three systematic reviews, and eight case studies. Findings confirmed the value of early use of phosphodiesterase type 5 inhibitors. DISCUSSION: Despite the range of available physical and pharmaceutical interventions, relevant research focussed solely on the use of phosphodiesterase type 5 inhibitors. Themes from the reviewed articles indicated that timing of intervention was important with early on-going dosage most useful. There was also an identified need for ongoing prophylactic use during ADT. Evidence, in general, was of low quality and based on quantitative data only. CONCLUSION: Additional research into the wider range of penile rehabilitation interventions is urgently required to ensure patients have access to those therapies that are most appropriate for them. A paradigm shift toward qualitative research in the field of penile rehabilitation for prostate cancer patients treated with radiotherapy and ADT may be of value in future studies.
• Genome-wide association study of germline variants and breast cancer-specific mortality

  Escala-Garcia, M; Guo, Q; Dork, T; Canisius, S; Keeman, R; Dennis, J; Beesley, J; Lecarpentier, J; Bolla, K; Wang, Q; Abraham, J; Andrulis, L; Anton-Culver, H; Arndt, V; Auer, L; Beckmann, W; Behrens, S; Benitez, J; Bermisheva, M; Bernstein, L; Blomqvist, C; Boeckx, B; Bojesen, E; Bonanni, B; Borresen-Dale, L; Brauch, H; Brenner, H; Brentnall, A; Brinton, L; Broberg, P; Brock, W; Brucker, Y; Burwinkel, B; Caldas, C; Caldes, T; Campa, D; Canzian, F; Carracedo, A; Carter, D; Castelao, E; Chang-Claude, J; Chanock, J; Chenevix-Trench, G; Cheng, D; Chin, F; Clarke, L; Cordina-Duverger, E; Couch, J; Cox, G; Cox, A; Cross, S; Czene, K; Daly, B; Devilee, P; Dunn, A; Dunning, M; Durcan, L; Dwek, M; Earl, M; Ekici, B; Eliassen, H; Ellberg, C; Engel, C; Eriksson, M; Evans, G; Figueroa, J; Flesch-Janys, D; Flyger, H; Gabrielson, M; Gago-Dominguez, M; Galle, E; Gapstur, M; Garcia-Closas, M; Garcia-Saenz, A; Gaudet, M; George, A; Georgoulias, V; Giles, G; Glendon, G; Goldgar, E; Gonzalez-Neira, A; Alnaes, G; Grip, M; Guenel, P; Haeberle, L; Hahnen, E; Haiman, A; Hakansson, N; Hall, P; Hamann, U; Hankinson, S; Harkness, F; Harrington, A; Hart, N; Hartikainen, JM; Hein, A; Hillemanns, P; Hiller, L; Holleczek, B; Hollestelle, A; Hooning, J; Hoover, N; Hopper, L; Howell, Anthony; Huang, G; Humphreys, K; Hunter, J; Janni, W; John, M; Jones, E; Jukkola-Vuorinen, A; Jung, A; Kaaks, R; Kabisch, M; Kaczmarek, K; Kerin, J; Khan, S; Khusnutdinova, E; Kiiski, I; Kitahara, M; Knight, A; Ko, D; Koppert, B; Kosma, M; Kraft, P; Kristensen, N; Kruger, U; Kuhl, T; Lambrechts, D; Le, L; Lee, E; Lejbkowicz, F; Li, L; Lindblom, A; Lindstrom, S; Linet, M; Lissowska, J; Lo, Y; Loibl, S; Lubinski, J; Lux, P; MacInnis, J; Maierthaler, M; Maishman, T; Makalic, E; Mannermaa, A; Manoochehri, M; Manoukian, S; Margolin, S; Martinez, E; Mavroudis, D; McLean, C; Meindl, A; Middha, P; Miller, N; Milne, L; Moreno, F; Mulligan, M; Mulot, C; Nassir, R; Neuhausen, L; Newman, T; Nielsen, F; Nordestgaard, G; Norman, A; Olsson, H; Orr, N; Pankratz, S; Park-Simon, W; Perez, A; Perez-Barrios, C; Peterlongo, P; Petridis, C; Pinchev, M; Prajzendanc, K; Prentice, R; Presneau, N; Prokofieva, D; Pylkas, K; Rack, B; Radice, P; Ramachandran, D; Rennert, G; Rennert, S; Rhenius, V; Romero, A; Roylance, R; Saloustros, E; Sawyer, J; Schmidt, DF; Schmutzler, K; Schneeweiss, A; Schoemaker, J; Schumacher, F; Schwentner, L; Scott, J; Scott, C; Seynaeve, C; Shah, M; Simard, J; Smeets, A; Sohn, C; Southey, C; Swerdlow, J; Talhouk, A; Tamimi, M; Tapper, J; Teixeira, R; Tengstrom, M; Terry, B; Thone, K; Tollenaar, M; Tomlinson, I; Torres, D; Truong, T; Turman, C; Turnbull, C; Ulmer, U; Untch, M; Vachon, C; van Asperen, J; van den Ouweland, W; van Veen, M; Wendt, C; Whittemore, S; Willett, W; Winqvist, R; Wolk, A; Yang, R; Zhang, Y; Easton, F; Fasching, A; Nevanlinna, H; Eccles, M; Pharoah, P; Schmidt, K; Radiotherapy Department, Christie Hospital NHS Trust, Manchester, UK (2019)

  BACKGROUND: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. METHODS: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). RESULTS: We did not find any variant associated with breast cancer-specific mortality at P?<?5?×?10-8. For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP?=?7%, P?=?1.28?×?10-7, hazard ratio [HR]?=?0.88, 95% confidence interval [CI]?=?0.84-0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP?=?11%, P?=?1.38?×?10-7, HR?=?1.27, 95% CI?=?1.16-1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster. CONCLUSIONS: We uncovered germline variants on chromosome 7 at BFDP?<?15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.
• Preliminary safety and efficacy of first-line pertuzumab combined with trastuzumab and taxane therapy for HER2-positive locally recurrent or metastatic breast cancer (PERUSE)

  Bachelot, T; Ciruelos, E; Schneeweiss, A; Puglisi, F; Peretz-Yablonski, T; Bondarenko, I; Paluch-Shimon, S; Wardley, Andrew M; Merot, L; du, Y; Easton, V; Lindegger, N; Miles, D; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands (2019)

  BACKGROUND: Pertuzumab combined with trastuzumab and docetaxel is the standard first-line therapy for HER2-positive metastatic breast cancer, based on results from the phase III CLEOPATRA trial. PERUSE was designed to assess the safety and efficacy of investigator-selected taxane with pertuzumab and trastuzumab in this setting. PATIENTS AND METHODS: In the ongoing multicentre single-arm phase IIIb PERUSE study, patients with inoperable HER2-positive advanced breast cancer (locally recurrent/metastatic) (LR/MBC) and no prior systemic therapy for LR/MBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab (8?mg/kg loading dose, then 6?mg/kg every 3 weeks [q3w]) and pertuzumab (840?mg loading dose, then 420?mg q3w) until disease progression or unacceptable toxicity. The primary end point was safety. Secondary end points included overall response rate (ORR) and progression-free survival (PFS). RESULTS: Overall, 1436 patients received at least one treatment dose (initially docetaxel in 775 patients, paclitaxel in 589, nab-paclitaxel in 65; seven discontinued before starting taxane). Median age was 54 years; 29% had received prior trastuzumab. Median treatment duration was 16 months for pertuzumab and trastuzumab, and 4 months for taxane. Compared with docetaxel-containing therapy, paclitaxel-containing therapy was associated with more neuropathy (all-grade peripheral neuropathy 31% vs 16%) but less febrile neutropenia (1% vs 11%) and mucositis (14% vs 25%). At this preliminary analysis (52 months' median follow-up), median PFS was 20.6 (95% CI 18.9-22.7) months overall (19.6, 23.0 and 18.1 months with docetaxel, paclitaxel and nab-paclitaxel, respectively). ORR was 80% (95% CI 78-82%) overall (docetaxel 79%, paclitaxel 83%, nab-paclitaxel 77%). CONCLUSIONS: Preliminary findings from PERUSE suggest that the safety and efficacy of first-line pertuzumab, trastuzumab and taxane for HER2-positive LR/MBC are consistent with results from CLEOPATRA. Paclitaxel appears to be a valid alternative taxane backbone to docetaxel, offering similar PFS and ORR with a predictable safety profile.

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