Prognosis of uterine corpus cancer after tamoxifen treatment for breast cancer

Tamoxifen increases the risk of uterine corpus cancer. Since only few, mostly small, studies have examined prognosis of uterine corpus cancer following tamoxifen, we conducted a large retrospective cohort study to further investigate this. We examined histopathologic and immunohistochemical characteristics of 332 patients with uterine corpus cancer following breast cancer, according to tamoxifen use. Survival was examined in the same patients combined with 309 patients from a previous study with updated follow-up. Histological review of all cancers was performed. Long-term tamoxifen users showed a higher proportion of non-endometrioid tumors than non-users (32.7% vs. 17.4%, P = 0.004), especially serous adenocarcinomas and carcinosarcomas. An increased proportion of FIGO stage III and IV tumors was also observed (20.0% vs. 11.3%, P = 0.049). Within FIGO stage I, both short-term and long-term tamoxifen users showed a higher proportion of tumors limited to the endometrium than non-users (35.7% vs. 22.9%, P = 0.049 and 0.004 respectively). Uterine corpus cancers in long-term tamoxifen users were more often steroid receptor-negative (ERα, PRA and PRB, P < 0.05) and P53-positive (P = 0.015). Three-year uterine corpus cancer-specific survival was worse for long-term tamoxifen users than for non-users (82% vs. 93% P = 0.0001). The survival difference remained after adjustment for histopathologic and immunohistochemical characteristics (hazard ratio (HR) for ≥2 years tamoxifen = 2.4; 95% CI = 1.2–4.6). In conclusion, this large study clearly shows that tamoxifen-associated tumors have less favorable histological features and a worse survival. Our results can be applied when weighing risks and benefits of tamoxifen versus other hormonal agents used in the prevention and treatment of breast cancer. TAMARISK (Tamoxifen Associated Malignancies: Aspects of Risk)-group of the Comprehensive Cancer Centers (CCC): O. Visser (CCC Amsterdam), R. A. M. Damhuis (CCC Rotterdam), W. J. Louwman (CCC South Netherlands), J. A. A. M. van Dijck (CCC East Netherlands), Y. Westerman (CCC Middle Netherlands), M. J. M. Dirx (CCC Limburg), M. L. E. A. Jansen-Landheer (CCC West), L. de Munck (CCC Northern Netherlands), S. Siesling (CCC Stedendriehoek Twente).     

Long‐term efficacy and predictive correlates of response to nivolumab in Japanese patients with esophageal cancer

The long‐term efficacy of nivolumab in esophageal squamous cell carcinoma and its association with disease biomarkers are currently not well known. Therefore, we investigated the association in Japanese patients with treatment‐refractory advanced esophageal cancer who participated in an open‐label, single‐arm, multicenter phase II study. Patients received nivolumab 3 mg/kg i.v. every 2 weeks until disease progression or unacceptable toxicity, and were followed up for 2 years after the initial dosing of the last patient. Archival tissue samples were collected before treatment and analyzed for programmed death ligand‐1 (PD‐L1) and CD8⁺ status of tumors and tumor‐infiltrating lymphocytes (TILs) and human leukocyte antigen class 1. Efficacy end‐points included objective response rate (ORR), overall survival (OS), progression‐free survival (PFS), time to response, and duration of response. Of 65 enrolled patients (83% male), 64 were evaluable for efficacy and 41 (63%) for biomarkers. The ORR, median OS, and survival rate were 17.2%, 10.78 months, and 17.2%, respectively. Time to response was 1.45 months and duration of response was 11.17 months. The PD‐L1 positivity of tumor cells was possibly associated with better PFS (2.04 vs 1.41 months, cut‐off 1%) and OS (11.33 vs 6.24 months, cut‐off 1%). Median OS was prolonged in patients with a median number of TILs greater than 63.75% vs 63.75% or less (11.33 vs 7.85 months). Nivolumab showed continued long‐term efficacy, as seen by the stability of PFS and OS, in Japanese patients with esophageal squamous cell carcinoma. Further investigation of PD‐L1 tumor expression and TILs as potential biomarkers for predicting patients likely to benefit from nivolumab therapy is warranted.     

KEYNOTE‐025: Phase 1b study of pembrolizumab in Japanese patients with previously treated programmed death ligand 1–positive advanced non–small‐cell lung cancer

Pembrolizumab, a humanized monoclonal antibody against programmed death 1 (PD‐1), has been shown to improve overall survival (OS) in patients with previously treated advanced non–small‐cell lung cancer (NSCLC) with programmed death ligand 1 (PD‐L1) tumor proportion score (TPS) ≥1%. We report safety and efficacy results from the phase 1b KEYNOTE‐025 study, which evaluated pembrolizumab in Japanese patients with previously treated NSCLC. Eligible patients had histologically/cytologically confirmed advanced NSCLC with PD‐L1 TPS ≥1% and had received ≥1 platinum‐doublet chemotherapy. Patients received pembrolizumab 10 mg/kg once every 3 weeks for 2 years or until disease progression/unacceptable toxicity. Primary objectives were to evaluate the safety of pembrolizumab in patients with PD‐L1 TPS ≥1% and the objective response rate (ORR) per RECIST version 1.1 in patients with PD‐L1 TPS ≥50%. Thirty‐eight patients were enrolled and received ≥1 pembrolizumab dose. The median (range) age was 66.0 (41‐78) years, and 61% had received ≥2 prior systemic therapies. Eleven patients (29%) experienced grade 3‐5 treatment‐related adverse events (AE); 9 patients (24%) experienced immune‐mediated AE and infusion reactions, with pneumonitis (11%; any grade) being most common. Among evaluable patients with PD‐L1 TPS ≥50% (n = 11), ORR was 27% (95% CI, 6‐61). Among evaluable patients with PD‐L1 TPS ≥1% (n = 37), ORR was 22% (95% CI, 10‐38). Median (95% CI) progression‐free survival and OS were 3.9 (2.0‐6.2) months and 19.2 (8.0‐26.7) months, respectively. In summary, pembrolizumab was generally well tolerated and showed promising antitumor activity in Japanese patients with previously treated PD‐L1–expressing NSCLC. Outcomes were consistent with those from the phase 3 KEYNOTE‐010 study. (Trial registration number: ClinicalTrials.gov, NCT02007070.)     

Pembrolizumab monotherapy in Japanese patients with advanced ovarian cancer: Subgroup analysis from the KEYNOTE‐100

Interim results from the two‐cohort, phase 2 KEYNOTE‐100 study (NCT02674061) of 376 patients with previously treated advanced recurrent ovarian cancer (ROC) showed that pembrolizumab monotherapy was associated with an objective response rate (ORR) of 8.0% (95% CI, 5.4‐11.2). We present outcomes for the Japanese patients (n = 21) enrolled in KEYNOTE‐100. Patients with epithelial ROC had received either 1‐3 prior chemotherapy lines and had platinum‐free interval or treatment‐free interval (PFI; TFI) of 3‐12 months (cohort A) or 4‐6 prior chemotherapy lines and had PFI/TFI of ≥3 months (cohort B). All patients received pembrolizumab 200 mg every 3 weeks as monotherapy for 2 years or until progression, death, unacceptable toxicity or consent withdrawal. Primary objectives were ORR per RECIST v1.1 for each cohort and higher programmed death ligand‐1 (PD‐L1) tumor expression. The relationship between PD‐L1 expression (measured as combined positive score [CPS]) and ORR was assessed. Twenty‐one Japanese patients (cohort A, n = 19; cohort B, n = 2) were treated. The median (range) age was 57 (37‐78) years; 19 (90.5%) patients had ECOG status of 0 and 16 (76.2%) patients had stage III‐IV disease. ORR was 19.0% (95% CI, 5.4‐41.9) and seemed to increase with increasing PD‐L1 expression. A total of 13 (61.9%) patients had treatment‐related adverse events (TRAE), and 5 (23.8%) had grade 3‐4 TRAE. There were no treatment‐related deaths in this subpopulation. Pembrolizumab monotherapy was associated with antitumor activity in Japanese patients with ROC, with no new safety signals identified in this subpopulation. The data suggested a trend toward higher PD‐L1 expression among some patients with higher ORR.     

Impact of tumor microenvironment on the efficacy of epidermal growth factor receptor‐tyrosine kinase inhibitors in patients with EGFR‐mutant non‐small cell lung cancer

We retrospectively investigated the impact of the tumor microenvironment (TME) on the efficacy of epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (TKIs) as first‐line treatment in 70 patients with advanced EGFR‐mutant non‐small cell lung cancer and who were seen at Osaka City University Hospital (Osaka, Japan) between August 2013 and December 2017. Using immunohistochemical staining with 28‐8 and D7U8C Abs, the tumor proportion score was assessed for programmed cell death‐1 ligand‐1 (PD‐L1), as high (50% or more) or low (less than 50%), and ligand‐2 (PD‐L2) expression, respectively. The extent of CD8⁺ tumor‐infiltrating lymphocytes was evaluated on a scale of 0‐3, with 0‐1 as low and 2‐3 as high. The TME of the 52 evaluable pretreatment specimens was categorized into 4 subtypes, according to the respective PD‐L1 tumor proportion and CD8⁺ scores, as follows: (a) high/high (13.5%, n = 7); (b) low/low (42.3%, n = 22); (c) high/low (17.3%, n = 9); and (d) low/high (26.9%, n = 14). Expression of PD‐L2 was significantly the highest in type 1 (57.1% vs 4.5% vs 11.1% vs 7.1%, respectively; P = .0090). Response rate was significantly the lowest in type 1 (14.3% vs 81.8% vs 66.7% vs 78.6%, respectively; P = .0085). Progression‐free survival was the shortest in type 1 and the longest in type 4 (median, 2.4 vs 11.3 vs 8.4 vs 17.5 months, respectively; P = .00000077). The efficacy of EGFR‐TKIs differed according to the TME, and the phenotype with high PD‐L1 and CD8⁺ expression might be the subset that would poorly benefit from such treatment.     

Locally advanced cervical cancer associated with complete uterine prolapse

LOIZZI V., CORMIO G., SELVAGGI L., CARRIERO C. & PUTIGNANO G. (2010) European Journal of Cancer Care
Locally advanced cervical cancer associated with complete uterine prolapse Although uterine prolapse and carcinoma of the uterine cervix are not rare event, their association is very uncommon. An 86‐year‐old patient gravida 8, para 5 was admitted for vaginal bleeding from a uterine prolapse of 20 years of duration. On physical examination, a complete third‐degree prolapsed uterus with an ulcerated lesion of 12 cm in maximum diameter involving both the anterior and posterior lips of the cervix was observed. Because of the poor performance status and high American Society of Anesthesiology scoring, the patient was admitted for a vaginal hysterectomy with upper vaginectomy in spinal anesthesia. However, she died of pulmonary embolism 20 days after surgery. A case of a cervical cancer with a complete uterine prolapse of 20 years of duration is reported. We believe that this case typically rare to see in a developed country might be a useful addition to the few published reports.     

Microsatellite instability and mismatch repair protein expressions in lymphocyte‐predominant breast cancer

The frequency of microsatellite instability (MSI) is reportedly extremely low in breast cancer, despite widespread clinical expectations that many patients would be responsive to immune‐checkpoint inhibitors (ICI). Considering that some triple‐negative breast cancers (TNBC) responded well to ICI in a clinical trial and that a high density of tumor‐infiltrating lymphocytes (TILs) is frequently observed in other cancers with high levels of microsatellite instability (MSI‐H), we hypothesized that some TNBC with a high density of TILs would be MSI‐H. Medullary carcinoma (MedCa) of the breast, a rare histological type, is characterized by a high density of TILs. Considering that MedCa of the colon is often MSI‐H, we suspected that MedCa in breast cancer might also include MSI‐H tumors. Therefore, we conducted MSI tests on such breast cancers with a high density of TILs. The MSI status of 63 TIL‐high TNBC and 38 MedCa tumors, all from Asian women who had undergone curative surgery, were determined retrospectively. DNA mismatch repair (MMR) proteins and PD‐L1 expression were also investigated immunohistochemically. All samples were microsatellite stable, being negative for all microsatellite markers. TIL‐high TNBC with low MLH1 protein had higher levels of PD‐L1 in stromal immune cells (P = .041). MedCa tumors showed significantly higher PD‐L1 expression in immune cells than in TIL‐high TNBC (<.001). We found that MSI‐H tumors were absent in TIL‐high breast cancers. Examination of MMR proteins, not a purpose of Lynch syndrome screening, may merit further studies to yield predictive information for identifying patients who are likely to benefit from ICI.     

Immunohistochemical expression of P-glycoprotein in cases of uterine cervical cancer

Background Expression of P-glycoprotein (P-GP), which is the product of the multidrug resistance gene,MDR1, and its relation to the conventional clinicopathological prognostic factors and prognosis in cervical cancer were examined. Methods The relationship between immunohistochemical expression of P-GP and accumulative survival rate and the conventional clinicopathological prognostic factors of 119 cases of uterine cervical cancer was examined. In addition, the relation of P-GP expression before and after administration of platinum drugs to total platinum concentration in tumor tissue was examined in 19 cases. Results The expression rate of P-GP was 0% (stage 0), 37.7% (stage I), 49.0% (stage II), 83.3% (stage III), and 100% (stage IV). The P-GP expression rates in the groups with and without parametrial invasion were 65.8% and 29.6%, respectively (P<0.001). The accumulative survival rate in the group positive for P-GP was significantly lower than that in the group negative for P-GP in stage II (P=0.0298). The median relative ratio of intratumor platinum concentration to serum level in group A (P-GP had already been expressed before administration of platinum drug), group B (P-GP was not expressed either before or after administration of platinum drug) and group C (P-GP was expressed after administration of platinum drug) was 1.82, 7.45, and 2.70, respectively. Conclusion The expression of P-GP in the cases of uterine cervical cancer could be associated with conventional clinicopathologic prognostic factors and the efficacy of radiation therapy and chemotherapy.     

Prognostic value of programmed death‐ligand 1 expression in patients with stage III colorectal cancer

The programmed death‐1/programmed death‐ligand 1 (PD‐L1) pathway is a negative feedback pathway that suppresses the activity of T cells. Previous studies reported that high PD‐L1 expression on tumor cells (TC) was associated with poor survival in patients with colorectal cancer; however, the prognostic evaluation of these studies was limited because they included patients at various disease stages. The purpose of the present study was to evaluate the relationship between PD‐L1 status in the immune microenvironment and the clinicopathological features of stage III colorectal cancer. Two hundred and thirty‐five patients were included in the analysis. PD‐L1 expression on TC and tumor‐infiltrating mononuclear cells (TIMC) was evaluated by immunohistochemistry. The median follow‐up of thisi study was 52.9 months. A total of 8.1% of stage III colorectal cancer showed high PD‐L1 expression on TC and 15.3% showed high PD‐L1 expression on TIMC. Patients with high PD‐L1 expression on TC had significantly shorter disease‐free survival (DFS) than patients with low expression (hazard ratio [HR] 2.36; 95% confidence interval [CI], 1.21–4.62; P = 0.012). In addition, patients with high PD‐L1 expression on TIMC were associated with longer DFS than patients with low expression (HR 0.40; 95% CI, 0.16–0.98; P = 0.046). These findings suggest that PD‐L1 expression status may be a new predictor of recurrence for stage III colorectal cancer patients and highlight the necessity of evaluating PD‐L1 expression on TC and TIMC separately in the tumor microenvironment.     

Immunotherapy revolutionises non-small-cell lung cancer therapy: Results,perspectives and new challenges

Immune checkpoint inhibitors (ICIs) are antibodies that target key signalling pathways such as programmed death 1 (PD1)/programmed death-ligands 1 and 2 (PDL1 and PDL2) to improve anti-tumour immune responses. Until recently, nivolumab was the only ICI validated for advanced non-small-cell lung cancer (NSCLC) in a second-line treatment setting. Results from recent phase II and phase III randomised trials testing other ICIs have been presented. In Keynote-024, pembrolizumab, an anti-PD1 antibody, was reported to have great efficacy in the first-line treatment of PDL1 ≥ 50% tumours (30% of screened tumours), with a progression-free survival (PFS, median) of 10.4 months versus 6.0 months with chemotherapy (CT; hazard ratio [HR] = 0.50; 95% confidence interval [95% CI] 0.37–0.68, P < 0.001), overall response rate (ORR) of 45% versus 28% with CT (P = 0.0011), and a 1-year overall survival (OS) of around 70%. In contrast, Checkmate-026 reported that nivolumab failed to show any benefit compared with standard platinum-based CT, with a PFS (median) in the PDL1 ≥ 5% NSCLC group of 4.2 months (nivolumab) versus 5.9 months (CT; HR = 1.15: 95% CI 0.91–1.45, P = 0.25). No benefit was observed in the PDL1 ≥ 50% subgroup. An encouraging report of the efficacy of pembrolizumab in addition to CT in first-line treatment in unselected NSCLC was also presented (Keynote-021) with an ORR of 55% versus 29% with CT alone (P = 0.0016). Atezolizumab, an anti-PDL1 antibody, showed efficacy for second-line treatment compared with docetaxel (OAK phase III study) with an OS (median) of 13.8 months versus 9.6 months with docetaxel. These results suggest a new paradigm for the treatment of advanced NSCLC using pembrolizumab for the first-line treatment of PDL1 ≥ 50% tumours.     

CD4/CD8 ratio is a prognostic factor in IgG nonresponders among peptide vaccine‐treated ovarian cancer patients

The identification of useful biomarkers is an urgent issue in cancer treatment, particularly for immunotherapy, as only some patients experience benefits from this treatment. The early induction of the IgG response has been reported as a useful biomarker of favorable prognosis for cancer patients treated with a personalized peptide vaccination, but a portion of these patients (IgG nonresponders) fail to achieve an early induction of IgG response yet experience long‐term survival. It is thus necessary to identify other biomarkers of favorable prognosis among these patients. Here we report the usefulness of classical T‐cell markers (ie, the CD8 content and the CD4/CD8 ratio in peripheral blood) in IgG nonresponders among advanced or recurrent ovarian cancer patients treated with a personalized peptide vaccination. Among IgG nonresponders (n = 25), the overall survival (OS) of the increased‐CD8 group (n = 7) was significantly longer than that of the decreased‐CD8 group (n = 18; P = .018), and the OS of the patients with a decreased CD4/CD8 ratio (n = 10) was significantly longer than that of the patients with an increased ratio (n = 15; P = .0055). Thus, an increased content of CD8 and a decreased CD4/CD8 ratio are each favorable prognosis markers in IgG nonresponders treated with a personalized peptide vaccination.     

Nivolumab Monotherapy and Nivolumab Plus Ipilimumab in Recurrent Small Cell Lung Cancer: Results From the CheckMate 032 Randomized Cohort

IntroductionNivolumab monotherapy is approved in the United States for third-line or later metastatic small cell lung cancer based on pooled data from nonrandomized and randomized cohorts of the multicenter, open-label, phase 1/2 trial of nivolumab ± ipilimumab (CheckMate 032; NCT01928394). We report updated results, including long-term overall survival (OS), from the randomized cohort.MethodsPatients with small cell lung cancer and disease progression after one to two prior chemotherapy regimens were randomized 3:2 to nivolumab 3 mg/kg every 2 weeks or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four cycles followed by nivolumab 3 mg/kg every 2 weeks. Patients were stratified by number of prior chemotherapy regimens and treated until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by blinded independent central review.ResultsOverall, 147 patients received nivolumab and 96 nivolumab plus ipilimumab. Minimum follow-up for ORR/progression-free survival/safety was 11.9 months (nivolumab) and 11.2 months (nivolumab plus ipilimumab). ORR increased with nivolumab plus ipilimumab (21.9% versus 11.6% with nivolumab; odds ratio: 2.12; 95% confidence interval: 1.06–4.26; p = 0.03). For long-term OS, minimum follow-up was 29.0 months (nivolumab) versus 28.4 months (nivolumab plus ipilimumab); median (95% confidence interval) OS was 5.7 (3.8–7.6) versus 4.7 months (3.1–8.3). Twenty-four–month OS rates were 17.9% (nivolumab) and 16.9% (nivolumab plus ipilimumab). Grade 3 to 4 treatment-related adverse event rates were 12.9% (nivolumab) versus 37.5% (nivolumab plus ipilimumab), and treatment-related deaths were n =1 versus n = 3, respectively.ConclusionsWhereas ORR (primary endpoint) was higher with nivolumab plus ipilimumab versus nivolumab, OS was similar between groups. In each group, OS remained encouraging with long-term follow-up. Toxicities were more common with combination therapy versus nivolumab monotherapy.     

Clinical outcome of elderly patients with unresectable pancreatic cancer treated with gemcitabine plus S-1, S-1 alone,or gemcitabine alone: Subgroup analysis of a randomised phase III trial,GEST study.

BackgroundIn the GEST study of unresectable pancreatic cancer, S-1 demonstrated non-inferiority compared to gemcitabine, but gemcitabine plus S-1 (GS) did not show superiority over gemcitabine for overall survival (OS). We performed subgroup analysis of these data focused on the efficacy and safety of these regimens as a first-line treatment for elderly patients.MethodsElderly patients (≥70 years, n = 261) treated for unresectable pancreatic cancer (GS: n = 90, S-1: n = 85 and gemcitabine: n = 86) were analysed.ResultsNo significant differences between the GS, S-1, or gemcitabine groups in OS (median: 10.2, 8.0 and 8.5 months, respectively) or objective response rates (27.6%, 25.3% and 14.3%, respectively) were noted. Grade ≥III adverse haematological events were observed more frequently in GS-treated than in S-1- or gemcitabine-treated elderly patients (p < 0.001 and p = 0.016, respectively). Four of 8 patients aged ≥80 years experienced serious adverse events.ConclusionsS-1 and gemcitabine are both efficacious options for treatment of elderly patients with unresectable pancreatic cancer. Conversely, first-line treatment of elderly patients with GS should only be used after careful consideration.     

Personalized peptide vaccination for cervical cancer patients who have received prior platinum‐based chemotherapy

A feasibility study was performed to evaluate the immunological efficacy and safety of a personalized peptide vaccine (PPV) for cervical cancer patients who have received platinum‐based chemotherapy. A total of 24 patients with standard chemotherapy‐resistant cervical cancer, including 18 recurrent cases, were enrolled in this study and received a maximum of 4 peptides based on HLA‐A types and IgG levels to the vaccine candidate peptides in pre‐vaccination plasma. The parental protein expression of most of the vaccine peptides was confirmed in the cervical cancer tissues. No vaccine‐related systemic grade 3 or 4 adverse events were observed in any patients. Due to disease progression, 2 patients failed to complete the first cycle of vaccinations (sixth vaccination). Cytotoxic T‐lymphocyte (CTL) or IgG responses specific for the peptides used for vaccination were augmented in half of cases after the first cycle. The median overall survival was 8.3 months. The clinical responses of the evaluable 18 cases consisted of 1 case with a partial response and 17 cases with disease progression; the remaining 6 cases were not evaluable. Performance status, injection site skin reaction and circulating PD‐1⁺CD4⁺ T‐cells were significantly prognostic of overall survival, and multivariate analysis also indicated that the performance status and circulating PD‐1⁺CD4⁺ T‐cells were prognostic. Because of the safety and immunological efficacy of PPV and the possible prolongation of overall survival, further clinical trials of PPV at a larger scale in advanced or recurrent cervical cancer patients who have received prior platinum‐based chemotherapy are recommended.     

Feasibility study of a Response Surveillance Program in locally advanced mid and low rectal cancer to increase organ preservation

BackgroundAssessment of tumor response in rectal cancer after neoadjuvant treatment by MRI (Tumour Regression Grade, TRG 1–5) is well standardized. The overall timing and method of defining complete response (cCR) remain controversial. The aim of this work was to evaluate the feasibility of a defined Response Surveillance Program (RSP) to increase organ preservation for locally advanced rectal cancer after neoadjuvant treatment.MethodsA standardized program of clinical (CR), radiological (RR) and metabolic (MR) assessment of tumor response is defined over a 6 month period from completion of NACRT with formal assessment performed every 2 months (M). Patients with TRG1-3 at M2 and TRG1-2 at M4 continue in the program up to M6 assessment. Patients managed with this protocol from 2016 to 2020 were analyzed. The primary endpoint was rectal preservation rate. Secondary endpoints included disease-free survival and overall survival at 3 years.Result314 potentially suitable patients were enrolled in the RSP and 50 patients completed the six month program and were successfully enrolled into watch and wait. Fourteen (28%) were T2 tumor stage, 27 (54%) T3 and nine (18%) were T4. During watch and wait, patients with locoregional recurrence (n = 11) were treated with local excision (n = 3), endocavitary radiotherapy (n = 1), TME (n = 5) and APR (n = 2). With a median follow-up of 32 months, the rectal preservation rate was 88%, with a 3-year disease-free survival of 67% and an overall survival of 98%.ConclusionThis study validates the feasibility of the practical implementation of a Response Surveillance Program to increase organ preservation rates without compromising oncological outcomes in rectal cancer.     

Accurate expression of PD‐L1/L2 in lung adenocarcinoma cells: A retrospective study by double immunohistochemistry

The percentage of programmed death ligand 1 (PD‐L1) positivity in cancer cells, named as the tumor proportion score, is considered to be a predictive biomarker for anti‐PD‐1/PD‐L1 therapy in lung cancer. PD‐L1 is expressed on not only cancer cells but also on immune cells, including macrophages. Although previous studies related to PD‐L1/2 expression in cancer tissues have been generally based on single immunohistochemistry (IHC), in the present study, we attempted to evaluate accurate PD‐L1/2 expression in cancer cells in lung adenocarcinoma cells using double IHC to also evaluate macrophages. Of the 231 patients, PD‐L1 expression was negative in 169 patients (73.2%), 1%‐49% positive in 47 patients (20.3%), and ≥50% positive in 15 patients (6.5%). Interestingly, PD‐L1 positivity was decreased when using double IHC compared with the estimation by single IHC. High PD‐L1 expression was associated with high‐grade cancer cells and in higher stage cancer. PD‐L2 was negative in 109 patients (47.2%), 1%‐49% positive in 50 patients (21.6%), and ≥50% positive in 72 patients (31.2%). The number of PD‐L2‐positive patients was increased in cases that had an epidermal growth factor receptor (EGFR) mutation and in lower stage cancer. Thirty‐five patients (15.2%) were positive for both PD‐L1 and PD‐L2, whereas 81 patients (35.1%) were negative for both PD‐L1 and PD‐L2. Log‐rank analysis showed that progression‐free survival and overall survival were significantly the longest in the PD‐L1‐negative and PD‐L2‐positive groups (P < .0001 and P = .0120). We observed lower PD‐L1 or PD‐L2 expression in lung adenocarcinoma than previously reported. Double IHC for macrophages may help clinicians to evaluate PD‐L1 or PD‐L2 expression specifically in cancer cells.     

Comparison of oncological outcomes and major complications between laparoscopic radical hysterectomy and abdominal radical hysterectomy for stage IB1 cervical cancer with a tumour size less than 2 cm

ObjectiveTo compare the oncological outcomes and major complications of laparoscopic radical hysterectomy (LRH) and abdominal radical hysterectomy (ARH) for stage IB1 cervical cancer (FIGO 2009) with a tumour size less than 2 cm.MethodsWe retrospectively compared the oncological outcomes and major complications of 1207 stage IB1 cervical cancer patients with a tumour size less than 2 cm who received LRH (n = 546) or ARH (n = 661) in 37 hospitals.Results(1) There was no significant difference in 3-year overall survival (OS; 97.3% vs. 98.5%, P = 0.288) or 3-year disease-free survival (DFS; 95.1% vs. 95.4%, P = 0.792) between LRH (n = 546) and ARH (n = 661).(2) The rate of any 1 complication refers to the incidence of one or more complications in a patient, which was higher with LRH than ARH (OR = 4.047, 95% CI = 2.035–8.048, P < 0.001). Additionally, intraoperative complications occurred with LRH (OR = 12.313, 95% confidence intervals [CI] = 1.571–96.493, P = 0.017), and postoperative complications (OR = 3.652, 95% CI = 1.763–7.562, P < 0.001) were higher with LRH than ARH. The ureteral injury rate was higher with LRH than with ARH (1.50% vs. 0.20%, OR = 9.814, 95% CI = 1.224–78.712, P = 0.032). The ureterovaginal fistula rate was higher with LRH than ARH. The rates of obturator nerve injury, bladder injury, vesicovaginal fistula, rectovaginal fistula, venous thromboembolism, bowel obstruction, chylous leakage, pelvic haematoma, and haemorrhage were similar between the groups.ConclusionsThe oncological outcomes of LRH and ARH for stage IB1 cervical cancer patients with a tumour size less than 2 cm do not differ significantly. However, incidences of any 1 complication, intraoperative complications, and postoperative complications were higher with LRH than ARH, with complications manifesting mainly as ureteral injury and uterovaginal fistula.     

Real-world safety of nivolumab in patients with non-small-cell lung cancer in Japan: Postmarketing surveillance

Postmarketing surveillance of Japanese patients with unresectable, previously treated, advanced or recurrent non-small-cell lung cancer treated with nivolumab was undertaken during the conditional approval period. The study aim was to evaluate the occurrence of treatment-related adverse events of nivolumab in the real world. Patients were registered between December 2015 and March 2016 at 536 sites. Nivolumab was given intravenously (3 mg/kg every 2 weeks); the observation period was 12 months after the first dose of nivolumab. Patients were evaluated for safety (n = 3601; 18.2% ≥75 years, 22.4% ECOG performance status ≥2) and effectiveness (n = 3570). The frequencies of any grade and grade 3 or higher treatment-related adverse events were 47.1% and 15.9%, respectively. The most frequent treatment-related adverse events (any grade) were interstitial lung disease (6.4%), hypothyroidism (5.7%), and diarrhea (4.4%). Treatment-related adverse events of special interest (priority items) occurring at a frequency of 5% or more were adverse events related to interstitial lung disease, thyroid dysfunction, liver dysfunction, colitis/severe diarrhea, infusion reaction, and infusion reaction within 24 hours. Significant risk factors for these priority items were identified by competing risk analysis: interstitial lung disease (previous/comorbid interstitial lung disease, abnormal findings on chest imaging, and smoking history); liver dysfunction (previous/comorbid liver disease, smoking history, and metastasis); thyroid dysfunction (previous/comorbid thyroid disease and performance status); and colitis/severe diarrhea (treatment line 2 vs ≥3). The 12-month survival rate was 40.7%. In conclusion, the safety profile of nivolumab in this postmarketing surveillance was similar to that in clinical trials, and no new safety signals were identified. The study was registered with the Japan Pharmaceutical Information Center (clinicaltrials.jp: Japic-163271).     

Risk of uterine cancer for BRCA1 and BRCA2 mutation carriers

BackgroundWhether BRCA1 and BRCA2 mutation carriers have a clinically relevant elevated risk of uterine cancer has implications for risk-reducing surgery.AimThis multicentre, prospective cohort study assessed uterine cancer risk for mutation carriers compared with the general population.MethodsEligible mutation carriers were enrolled in the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab) cohort study, had a uterus present and no history of uterine cancer at cohort entry. Epidemiological, lifestyle and clinical data were collected at cohort entry and updated three-yearly. Cancer events were verified using pathology reports. Follow-up was censored at death or last contact. Relative risk of uterine cancer was estimated using the standardised incidence ratio (SIR), with the expected number of cases determined using population-based data for Australia.ResultsOf 1,111 mutation carriers in kConFab, 283 were excluded due to prior hysterectomy (N = 278), prior uterine cancer (N = 2) or being non-residents (N = 3). After a median follow-up of 9.0 years, five incident uterine cancers were reported in the 828 eligible women (419 had prior breast cancer and 160 had prior tamoxifen use), compared to 2.04 expected (SIR = 2.45; 95% confidence interval [CI]: 0.80–5.72; P = 0.11). In 438 BRCA1 mutation carriers and 390 BRCA2 mutation carriers, three and two incident cases of uterine cancer were reported, respectively, compared to 1.04 expected (SIR = 2.87; 95% CI: 0.59–8.43; P = 0.18) and 0.99 expected (SIR = 2.01; 95% CI: 0.24–7.30; P = 0.52), respectively. All cases were endometrioid subtype, International Federation of Gynaecology and Obstetrics stage I–II disease. No serous uterine cancers were reported.ConclusionsOur findings are consistent with those from most other reports and do not support routine risk-reducing hysterectomy for BRCA1 and BRCA2 mutation carriers.     

Safety and Efficacy of Nivolumab in Patients With Advanced Non–Clear Cell Renal Cell Carcinoma: Results From the Phase IIIb/IV CheckMate 374 Study

BackgroundThe open-label phase IIIb/IV CheckMate 374 study (NCT02596035) was conducted to validate the safety and efficacy of flat-dose nivolumab 240 mg every 2 weeks (Q2W) in previously treated advanced/metastatic renal cell carcinoma. Three cohorts included patients with predominantly clear cell histology, non–clear cell histologies, or brain metastases. We report safety and efficacy from the advanced non–clear cell RCC (nccRCC) cohort of CheckMate 374.MethodsEligible patients received 0 to 3 prior systemic therapies. Patients received nivolumab 240 mg Q2W for ≤24 months or until confirmed progression or unacceptable toxicity. The primary endpoint was incidence of high-grade (grade 3-5) immune-mediated adverse events (IMAEs). Exploratory endpoints included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).ResultsForty-four patients had advanced nccRCC (papillary [n = 24], chromophobe [n = 7], unclassified [n = 8], other [n = 5]); 34.1% received ≥1 prior systemic regimen in the advanced/metastatic setting. With median follow-up of 11 (range, 0.4-27) months, no all-cause grade 3-5 IMAEs or treatment-related grade 5 adverse events were reported. ORR was 13.6% (95% confidence interval [CI], 5.2-27.4), with 1 complete response (chromophobe) and 5 partial responses (papillary [n = 2], chromophobe [n = 1], collecting duct [n = 1], and unclassified [n = 1] histology). Median PFS was 2.2 months (95% CI, 1.8-5.4). Median OS was 16.3 months (95% CI, 9.2-not estimable).ConclusionsSafety of flat-dose nivolumab 240 mg Q2W was consistent with previous results. Clinically meaningful efficacy was observed with responses in several histologies, supporting nivolumab as a treatment option for patients with advanced nccRCC, a patient population with high unmet need.