Optimising primary molecular profiling in non-small cell lung cancer.

INTRODUCTION: Molecular profiling of NSCLC is essential for optimising treatment decisions, but often incomplete. We assessed the efficacy of protocolised molecular profiling in the current standard-of-care (SoC) in a prospective observational study in the Netherlands and measured the effect of providing standardised diagnostic procedures. We also explored the potential of plasma-based molecular profiling in the primary diagnostic setting. METHODS: This multi-centre prospective study was designed to explore the performance of current clinical practice during the run-in phase using local SoC tissue profiling procedures. The subsequent phase was designed to investigate the extent to which comprehensive molecular profiling (CMP) can be maximized by protocolising tumour profiling. Successful molecular profiling was defined as completion of at least EGFR and ALK testing. Additionally, PD-L1 tumour proportions scores were explored. Lastly, the additional value of centralised plasma-based testing for EGFR and KRAS mutations using droplet digital PCR was evaluated. RESULTS: Total accrual was 878 patients, 22.0% had squamous cell carcinoma and 78.0% had non-squamous NSCLC. Stage I-III was seen in 54.0%, stage IV in 46.0%. Profiling of EGFR and ALK was performed in 69.9% of 136 patients included in the run-in phase, significantly more than real-world data estimates of 55% (p<0.001). Protocolised molecular profiling increased the rate to 77.0% (p = 0.049). EGFR and ALK profiling rates increased from 77.9% to 82.1% in non-squamous NSCLC and from 43.8% to 57.5% in squamous NSCLC. Plasma-based testing was feasible in 98.4% and identified oncogenic driver mutations in 7.1% of patients for whom tissue profiling was unfeasible. CONCLUSION: This study shows a high success rate of tissue-based molecular profiling that was significantly improved by a protocolised approach. Tissue-based profiling remains unfeasible for a substantial proportion of patients. Combined analysis of tumour tissue and circulating tumour DNA is a promising approach to allow adequate molecular profiling of more patients.

Combined Cabazitaxel and Carboplatin Treatment of Metastatic Castration Resistant Prostate Cancer Patients, With Innate or Acquired Resistance to Cabazitaxel Monotherapy.

BACKGROUND: There is new interest in platinum-based treatment of patients with metastatic castration resistant prostate cancer (mCRPC), to which a subgroup responds. Although platinum sensitivity is suggested to be associated with aggressive disease features and distinct molecular profiles, identification of responders is a clinical challenge. In this study, we selected patients who displayed PSA progression during cabazitaxel monotherapy, for combined cabazitaxel and carboplatin treatment. METHODS: In this retrospective study, mCRPC patients received carboplatin and cabazitaxel after biochemical progression following at least 2 cabazitaxel monotherapy cycles. We assessed PSA response, Time to PSA Progression (TTpsa) and Time to Radiographic Progression (TTrad). For a subset of patients, mutational analysis of BRCA-1, BRCA-2, ATM, PTEN, P53 and RB1 was performed. RESULTS: Forty-five patients were included, after a median of 4 (3-6) cycles of cabazitaxel monotherapy. Patients received a median of 3 (2-5) cycles of combined cabazitaxel and carboplatin, on which 12 (26.6%) patients had a PSA decline ≥ 50% from baseline. TTpsa was 2 (1-5) months and TTrad 3 (2-6) months. Adverse events were predominantly grade 1-2. Of the 29 (64.4%) patients evaluable for molecular signature, 6 (13.3%) had BRCA1, BRCA2 or ATM mutations and 12 (26.7%) had a PTEN, P53 or RB1 mutations. The occurrence of these mutations was not associated with any clinical outcome measure. CONCLUSIONS: In this study we showed that patients with PSA progression during cabazitaxel monotherapy could benefit from the addition of carboplatin to cabazitaxel, while prospective identification of these patients remains a clinical challenge.

Nivolumab and ipilimumab in the real-world setting in patients with mesothelioma.

OBJECTIVES: Nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA-4) is a new first-line treatment combination for patients with pleural mesothelioma. Nivolumab-ipilimumab improved the survival, however, 30.3% of the patients suffered from grade 3-4 treatment related adverse events (TRAE's) and TRAE's led to discontinuation in 23.0% of all patients. Here, we present the first real-world data of nivolumab plus ipilimumab in patients with malignant mesothelioma treated in two mesothelioma expert centers. METHODS: Clinical data of patients with mesothelioma treated with nivolumab and ipilimumab were prospectively collected. Clinical parameters were obtained every visit, CT scans were evaluated every 12 weeks and adverse events were assessed continuously during the treatment. Data on grade 2-5 TRAE's and activity (overall response rate (ORR), duration of response (DOR), disease control rate (DCR), median progression-free survival (mPFS) and median overall survival (mOS) were reported. RESULTS: Between January 2021 and August 2022, 184 patients were treated with nivolumab plus ipilimumab. The median follow-up was 12.1 months (95 %CI 11.1 - 13.1). Grade 3-4 TRAEs were seen in 27.7 % of the patients and 25.0 % discontinued immunotherapy treatment early because of TRAE's. ORR was 21.7 % (95 % CI 15.7-27.7), median DOR was 5.7 months (IQR 3.2-8.7) and DCR at 12 weeks 56.0 % (95 % CI 48.8-63.2). The mPFS was 5.5 months (95 %CI 4.1-6.9), mOS was 14.1 months (95 % CI 11.1-18.2). CONCLUSIONS: Nivolumab plus ipilimumab had an equal efficacy in a real-world comparable population but also a high risk of TRAE's, leading to discontinuation of treatment in 25% of the patients.

Histopathological concordance between prostate biopsies and radical prostatectomy specimens-implications of transrectal and transperineal biopsy approaches.

BACKGROUND: This study aimed to evaluate the histopathological concordance rates between prostate biopsies and radical prostatectomy specimens according to the applied biopsy approach (transrectal or transperineal). METHODS: We studied patients who had been newly diagnosed with clinically significant prostate cancer and who underwent a radical prostatectomy between 2018 and 2022. Patients were included if they underwent a prebiopsy magnetic resonance imaging and if they had not been previously treated for prostate cancer. Histopathological grading on prostate biopsies was compared with that on radical prostatectomy specimens. Univariable and multivariable logistic regression analyses were performed to assess the effect of the applied biopsy approach on histopathological concordance. Additional analyses were performed to assess the effect of the applied biopsy approach on American Urological Association risk group migration, defined as any change in risk group after radical prostatectomy. RESULTS: In total, 1058 men were studied, of whom 49.3% (522/1058) and 50.7% (536/1058) underwent transrectal and transperineal prostate biopsies, respectively. Histopathological disconcordance was observed in 37.8% (400/1058) of men while American Urological Association risk group migration was observed in 30.2% (320/1058) of men. A transperineal biopsy approach was found to be independently associated with higher histopathological concordance rates (OR 1.33 [95% CI 1.01-1.75], p = 0.04) and less American Urological Association risk group migration (OR 0.70 [95% CI 0.52-0.93], p = 0.01). CONCLUSIONS: The use of a transperineal biopsy approach improved histopathological concordance rates compared to the use of a transrectal biopsy approach. A transperineal biopsy approach may provide more accurate risk stratification for clinical decision-making. Despite recent improvements, histopathologic concordance remains suboptimal and should be considered before initiating management.

Trastuzumab-Emtansine and Osimertinib Combination Therapy to Target HER2 Bypass Track Resistance in EGFR Mutation-Positive NSCLC.

Introduction: EGFR tyrosine kinase inhibitor improved the survival of patients with metastatic EGFR mutation-positive (EGFRm+) NSCLC. Despite high response rates, resistance develops inevitably in every patient. In up to 13%, HER2 protein overexpression is found on progression. We hypothesized that dual blockade of EGFR and HER2 by osimertinib combined with trastuzumab-emtansine (T-DM1) could reinduce tumor responses. Methods: In this multicenter, single-arm, phase 1-2 study (NCT03784599), patients with EGFRm+ NSCLC, progressing on osimertinib and HER2 overexpression were included. Patients were treated with T-DM1 3.6 mg/kg (intravenously) every 3 weeks and osimertinib 80 mg once a day. Primary end points were objective response rate (ORR) at 12 weeks and safety. Responses were assessed every 6 weeks (Response Evaluation Criteria in Solid Tumors 1.1). Sample size was calculated using Simon's two-stage minimax design (H0 = 41%, H1 > 55%, 80% power, one-sided type I error 10%: a ORR 16 of 36 was needed to proceed to 58 patients). Results: From January 2019 to April 2021, 27 patients were enrolled. ORR after 12 weeks of treatment was 4% (1 of 27). Median progression-free survival was 2.8 months (95% confidence interval: 1.4-4.6 mo). Most frequent treatment-related adverse events of any grade were fatigue, diarrhea, and nausea, among these, grade 3 in four patients. There were no grade 4 or 5 therapy-related adverse events. Conclusions: TRAEMOS (Trastuzumab-Emtansine and Osimertinib) is the first trial combining T-DM1 and osimertinib in patients with EGFRm+ NSCLC to target HER2 overexpression at osimertinib resistance. Safety profile was favorable compared with cytotoxic chemotherapy; but treatment revealed limited efficacy. Further clinical evaluation of this regimen is not warranted.

Trastuzumab and pertuzumab combination therapy for advanced pre-treated HER2 exon 20-mutated non-small cell lung cancer.

INTRODUCTION: In 1-3% of non-small cell lung cancer (NSCLC) human epidermal growth factor 2 (HER2) mutations are identified as a genomic driver. Nevertheless, no HER2-targeted treatment is approved for NSCLC. In the Drug Rediscovery Protocol (DRUP), patients are treated with off-label drugs based on their molecular profile. Here, we present the results of the cohort 'trastuzumab/pertuzumab for HER2 exon20 mutation positive (HER2m+) NSCLC'. METHODS: Patients with treatment refractory, advanced HER2m+ NSCLC with measurable disease (RECISTv1.1) were eligible. Treatment with intravenous trastuzumab combined with pertuzumab every 3 weeks was administered. The primary end-point was clinical benefit (CB: either objective response or stable disease ≥ 16 weeks). Patients were enrolled using a Simon-like 2-stage design, with 8 patients in stage 1 and up to 24 patients in stage 2 if at least 1 patient had CB in stage 1. At baseline, a biopsy for biomarker analysis, including whole genome sequencing, was obtained. RESULTS: Twenty-four evaluable patients were enrolled and treated between May 2017 and August 2020. CB was observed in 9 patients (38%); including an objective response rate of 8.3% (2 patients had a partial response) and 7 patients with stable disease ≥ 16 weeks. The most frequently observed HER2 mutation was p.Y772_A775dup (71%, n = 20). Median follow-up was 13 months, median progression-free survival and overall survival 4 (95% CI 3-6) and 10 months (95% CI 4 - not reached), respectively. Whole genome sequencing data (available for 67% of patients) confirmed the inclusion mutation in all cases. No unexpected toxicity was observed. CONCLUSION: Despite the fact that the study did meet its primary end-point, trastuzumab/pertuzumab was only marginally active in a subset of patients with heavily pre-treated HER2m+ NSCLC.

Can serum human epididymis protein 4 (HE4) support the decision to refer a patient with an ovarian mass to an oncology hospital?

INTRODUCTION: The value of serum human epididymis protein 4 (HE4) in guiding referral decisions in patients with an ovarian mass remains unclear, because the majority of studies investigating HE4 were performed in oncology hospitals. However, the decision to refer is made at general hospitals with a low ovarian cancer prevalence. We assessed accuracies of HE4 in differentiating benign or borderline from malignant tumors in patients presenting with an ovarian mass at general hospitals. METHOD: Patients with an ovarian mass were prospectively included between 2017 and 2021 in nine general hospitals. HE4 and CA125 were preoperatively measured and the risk of malignancy index (RMI) was calculated. Histological diagnosis was the reference standard. RESULTS: We included 316 patients, of whom 195 had a benign, 39 had a borderline and 82 had a malignant ovarian mass. HE4 had the highest AUC of 0.80 (95%CI 0.74-0.86), followed by RMI (0.71, 95%CI 0.64-0.78) and CA125 (0.69, 95%CI 0.62-0.75). Clinical setting significantly influenced biomarker performances. Applying age-dependent cut-off values for HE4 resulted in a better performance than one cut-off. Addition of HE4 to RMI resulted in a 32% decrease of unnecessary referred patients, while the number of correctly referred patients remained the same. CONCLUSION: HE4 is superior to RMI in predicting malignancy in patients with an ovarian mass from general hospitals. The addition of HE4 to the RMI improved HE4 alone. Although, there is still room for improvement, HE4 can guide referral decisions in patients with an ovarian mass to an oncology hospital.

Limiting systemic endocrine overtreatment in postmenopausal breast cancer patients with an ultralow classification of the 70-gene signature.

PURPOSE: Guidelines recommend endocrine treatment for estrogen receptor-positive (ER+) breast cancers for up to 10 years. Earlier data suggest that the 70-gene signature (MammaPrint) has potential to select patients that have an excellent survival without chemotherapy and limited or no tamoxifen treatment. The aim was to validate the 70-gene signature ultralow-risk classification for endocrine therapy decision making. METHODS: In the IKA trial, postmenopausal patients with non-metastatic breast cancer had been randomized between no or limited adjuvant tamoxifen treatment without receiving chemotherapy. For this secondary analysis, FFPE tumor material was obtained of ER+HER2- patients with 0-3 positive lymph nodes and tested for the 70-gene signature. Distant recurrence-free interval (DRFI) long-term follow-up data were collected. Kaplan-Meier curves were used to estimate DRFI, stratified by lymph node status, for the three predefined 70-gene signature risk groups. RESULTS: A reliable 70-gene signature could be obtained for 135 patients. Of the node-negative and node-positive patients, respectively, 20% and 13% had an ultralow-risk classification. No DRFI events were observed for node-negative patients with an ultralow-risk score in the first 10 years. The 10-year DRFI was 90% and 66% in the low-risk (but not ultralow) and high-risk classified node-negative patients, respectively. CONCLUSION: These survival analyses indicate that the postmenopausal node-negative ER+HER2- patients with an ultralow-risk 70-gene signature score have an excellent 10-year DRFI after surgery with a median of 1 year of endocrine treatment. This is in line with published results of the STO-3-randomized clinical trial and supports the concept that it is possible to reduce the duration of endocrine treatment in selected patients.

The role of surgery in the treatment of oligoprogression after systemic treatment for advanced non-small cell lung cancer.

OBJECTIVES: Patients with advanced stage non-small cell lung cancer (NSCLC) are generally considered incurable. The mainstay of treatment for these patients is systemic therapy. The addition of local treatment, including surgery, remains controversial. Oligoprogression is defined as advanced stage NSCLC with limited progression of disease after a period of prolonged disease stabilisation or after a partial or complete response on systemic therapy. In this retrospective study we evaluated outcome and survival of patients who underwent a resection for oligoprogression after systemic therapy for advanced stage NSCLC. MATERIALS AND METHODS: Patients with oligoprogression after systemic treatment for advanced NSCLC who were operated in the Antoni van Leeuwenhoek Hospital were included. Patient and treatment characteristics were collected in relation to progression free survival (PFS) and overall survival (OS). RESULTS: Between January 2015 and December 2019, 28 patients underwent surgery for an oligoprogressive lesion (primary tumor lung (n = 12), other metastatic site (n = 16)). Median age at time of resection was 60 years (39-86) and 57% were female. Postoperative complications were observed in 2 patients (7%). Progression of disease after resection of the oligoprogressive site was observed in 17 patients (61%). Median PFS was 7 months since date of resection (95% CI 6.0-25.0) and median OS was not reached. Seven patients (25%) died during follow-up. Age was predictive for OS and clinical T4 stage was predictive for PFS. M1 disease at initial presentation was predictive for better PFS compared to patients who were diagnosed with M0 disease initially. Patients who underwent resection because of oligoprogression of the primary lung tumour had a better PFS, when compared to oligoprogression of another metastastic site. CONCLUSION: Surgical resection of an oligoprogressive lesion in patients with advanced NSCLC treated with systemic treatment is feasible and might be considered in order to achieve long term survival.

Health-related quality of life after prophylactic cranial irradiation for stage III non-small cell lung cancer patients: Results from the NVALT-11/DLCRG-02 phase III study.

BACKGROUND AND PURPOSE: The NVALT-11/DLCRG-02 phase III trial (clinicaltrials.gov identifier: NCT01282437) showed that, after standard curative intent treatment, prophylactic cranial irradiation (PCI) decreased the incidence of symptomatic brain metastases (BM) in stage III non-small cell lung cancer (NSCLC) patients compared to observation. In this study we assessed the impact of PCI on health-related quality of life (HRQoL). In addition, an exploratory analysis was performed to assess the impact of neurocognitive symptoms and symptomatic BM on HRQoL. MATERIALS AND METHODS: Stage III NSCLC patients were randomized between PCI and observation. HRQoL was measured using the EuroQol 5D (EQ-5D-3L), EORTC QLQ-C30 and QLQ-BN20 instruments at completion of standard curative intent treatment and 4 weeks, 3, 6, 12, 24 and 36 months thereafter. Generalized linear mixed effects (GLM) models were used to assess the impact of PCI compared to observation over time on three HRQoL metrics: the EORTC QLQ-C30 global health status and the EQ-5D-3L utility and visual analogue scale (EQ VAS) scores. RESULTS: In total, 86 and 88 patients were included in the PCI and observation arm, with a median follow-up of 48.5 months (95% CI 39-54 months). Baseline mean HRQoL scores were comparable between the PCI and observation arm for the three HRQoL metrics. In the GLM models, none of the HRQoL metrics were clinically relevant or statistically significantly different between the PCI and the observation arm (p-values ranged between 0.641 and 0.914). CONCLUSION: No statistically significant nor a clinically relevant impact of PCI on HRQoL was observed.

Prediction of response to anti-PD-1 therapy in patients with non-small-cell lung cancer by electronic nose analysis of exhaled breath.

BACKGROUND: Immune checkpoint inhibitors have improved survival outcome of advanced non-small-cell lung cancer (NSCLC). However, most patients do not benefit. Therefore, biomarkers are needed that accurately predict response. We hypothesized that molecular profiling of exhaled air may capture the inflammatory milieu related to the individual responsiveness to anti-programmed death ligand 1 (PD-1) therapy. This study aimed to determine the accuracy of exhaled breath analysis at baseline for assessing nonresponders versus responders to anti-PD-1 therapy in NSCLC patients. METHODS: This was a prospective observational study in patients receiving checkpoint inhibitor therapy using both a training and validation set of NSCLC patients. At baseline, breath profiles were collected in duplicate by a metal oxide semiconductor electronic nose (eNose) positioned at the rear end of a pneumotachograph. Patients received nivolumab or pembrolizumab of which the efficacy was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 at 3-month follow-up. Data analysis involved advanced signal-processing and statistics based on independent t-tests followed by linear discriminant and receiver operating characteristic (ROC) analysis. RESULTS: Exhaled breath data of 143 NSCLC patients (training: 92, validation: 51) were available at baseline. ENose sensors contributed significantly (P < 0.05) at baseline in differentiating between patients with different responses at 3 months of anti-PD-1 treatment. The eNose sensors were combined into a single biomarker with an ROC-area under the curve (AUC) of 0.89 [confidence interval (CI) 0.82-0.96]. This AUC was confirmed in the validation set: 0.85 (CI 0.75-0.96). CONCLUSION: ENose assessment was effective in the noninvasive prediction of individual patient responses to immunotherapy. The predictive accuracy and efficacy of the eNose for discrimination of immunotherapy responder types were replicated in an independent validation set op patients. This finding can potentially avoid application of ineffective treatment in identified probable nonresponders.

Laryngo-esophageal dysfunction free survival and propensity score matched analysis comparing organ preservation and total laryngectomy in hypopharynx cancer.

AIMS: To assess the functional outcomes of patients treated for hypopharynx cancer and to obtain an unbiased estimate of survival difference between patients treated with chemoradiotherapy (CRT) or total laryngectomy (TL). METHODS: Retrospective cohort study of all patients treated with curative intent for T1-T4 squamous cell carcinoma of the hypopharynx in The Netherlands Cancer Institute (1990-2013). Functional outcome following radiotherapy (RT) or CRT was measured using laryngo-esophageal dysfunction free survival rate (LDFS). Using propensity score (PS) matched analysis, we compared survival outcome of TL to CRT in T2-T4 patients. RESULTS: We included 343 patients with T1T4 hypopharynx cancer. LDFS 2 and 5-years following CRT was respectively 44 and 32%. Following RT this was 39 and 30%. Patients were matched on the following variables: age, gender, TNM classification, subsite of tumor, decade of diagnosis, prior cancer, smoking, ACE27 score, BMI hemoglobin, albumin, and leukocyte level. With PS matching, we were able to match 26 TL patients with 26 CRT patients. The OS rates for TL and CRT in this matched cohort were respectively 56% and 46% at 5 years and 35% and 17% at 10 years. CONCLUSION: In conclusion, functional outcomes following RT or CRT are suboptimal and require improved treatment strategies or rehabilitation efforts. The OS results challenge the preposition that CRT and TLE are equivalent in terms of survival.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy versus palliative systemic chemotherapy in stomach cancer patients with peritoneal dissemination, the study protocol of a multicentre randomised controlled trial (PERISCOPE II).

BACKGROUND: At present, palliative systemic chemotherapy is the standard treatment in the Netherlands for gastric cancer patients with peritoneal dissemination. In contrast to lymphatic and haematogenous dissemination, peritoneal dissemination may be regarded as locoregional spread of disease. Administering cytotoxic drugs directly into the peritoneal cavity has an advantage over systemic chemotherapy since high concentrations can be delivered directly into the peritoneal cavity with limited systemic toxicity. The combination of a radical gastrectomy with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has shown promising results in patients with gastric cancer in Asia. However, the results obtained in Asian patients cannot be extrapolated to Western patients. The aim of this study is to compare the overall survival between patients with gastric cancer with limited peritoneal dissemination and/or tumour positive peritoneal cytology treated with palliative systemic chemotherapy, and those treated with gastrectomy, CRS and HIPEC after neoadjuvant systemic chemotherapy. METHODS: In this multicentre randomised controlled two-armed phase III trial, 106 patients will be randomised (1:1) between palliative systemic chemotherapy only (standard treatment) and gastrectomy, CRS and HIPEC (experimental treatment) after 3-4 cycles of systemic chemotherapy.Patients with gastric cancer are eligible for inclusion if (1) the primary cT3-cT4 gastric tumour including regional lymph nodes is considered to be resectable, (2) limited peritoneal dissemination (Peritoneal Cancer Index < 7) and/or tumour positive peritoneal cytology are confirmed by laparoscopy or laparotomy, and (3) systemic chemotherapy was given (prior to inclusion) without disease progression. DISCUSSION: The PERISCOPE II study will determine whether gastric cancer patients with limited peritoneal dissemination and/or tumour positive peritoneal cytology treated with systemic chemotherapy, gastrectomy, CRS and HIPEC have a survival benefit over patients treated with palliative systemic chemotherapy only. TRIAL REGISTRATION: clinicaltrials.gov NCT03348150 ; registration date November 2017; first enrolment November 2017; expected end date December 2022; trial status: Ongoing.

Selecting the optimal position of CDK4/6 inhibitors in hormone receptor-positive advanced breast cancer - the SONIA study: study protocol for a randomized controlled trial.

BACKGROUND: Combining cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors with endocrine therapy is an effective strategy to improve progression-free survival in hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. There is a lack of comparative data to help clinicians decide if CDK4/6 inhibitors can best be added to first- or second-line endocrine therapy. Improvement in median progression-free survival in first-line studies is larger than in second-line studies, but CDK4/6 inhibitors have not consistently shown to improve overall survival or quality of life. They do come with added toxicity and costs, and many patients have lasting disease remission on endocrine therapy alone. No subgroup has been identified to select patients who are most likely to benefit from the addition of CDK4/6 inhibition in any line of treatment. Altogether, these factors make that the optimal strategy for using CDK4/6 inhibitors in clinical practice is unknown. METHODS: The SONIA study is an investigator-initiated, multicenter, randomized phase III study in patients with HR+/HER2-negative advanced breast cancer. Patients are randomly assigned to receive either strategy A (first-line treatment with a non-steroidal aromatase inhibitor combined with CDK4/6 inhibition, followed on progression by fulvestrant) or strategy B (first-line treatment with a non-steroidal aromatase inhibitor, followed on progression by fulvestrant combined with CDK4/6 inhibition). The primary objective is to test whether strategy A is more effective than strategy B. The primary endpoint is time from randomization to second objective progression (PFS2). Secondary endpoints include overall survival, safety, quality of life, and cost-effectiveness. Five-hundred seventy-four events yield 89% power to show that strategy A has statistically significant, clinically meaningful superior PFS2 (according to ESMO-MCBS) in a log-rank test at the two-sided 95% confidence level. Given an accrual period of 42 months and an additional 18 months follow-up, inclusion of 1050 evaluable patients is required. DISCUSSION: This study design represents daily clinical practice, and the results will aid clinicians in deciding when adding CDK4/6 inhibitors to endocrine therapy will benefit their patients most. Additional biomarker analyses may help to optimize patient selection. TRIAL REGISTRATION: http://clinicaltrials.gov: NCT03425838 (8 February 2018). EudraCT-number: 2017-002334-23 (29 September 2017).

Serum HE4 is correlated to prognostic factors and survival in patients with endometrial cancer.

The extent of surgery and the decision for adjuvant treatment in patients with endometrial cancer (EC) depend on the presence of risk factors for lymph node metastases and disease recurrence. Postoperative markers such as myometrial infiltration and specific mutations can select patients for adjuvant treatment but will not influence surgical planning. A biomarker stratifying patients into low-risk and high-risk groups before surgery could identify patients who benefit from more extensive surgery. Therefore, we evaluated the correlation of serum biomarker HE4 with clinical and recently identified prognostic pathological variables and survival. Patients treated for endometrial cancer between 1994 and 2014 were included. Serum HE4 concentration was measured in preoperatively obtained samples. A total of 88 patients were eligible for analysis. The majority (64%) was diagnosed with endometrioid-type adenocarcinoma. Serum HE4 concentration is significantly associated with stage of disease (p = 0.001), deep myometrial invasion (p < 0.001), exact depth of myometrial invasion (≥4 mm) (p = 0.01), tumour-free distance to serosa (≤7 mm) (p < 0.001), extensive lymph vascular space invasion (p = 0.04) and cervical involvement (p = 0.001). HE4 concentration and nodal involvement were correlated, although not significant (p = 0.17). Serum HE4 is an independent prognostic factor for recurrence-free survival (HR 5.12 per 10-fold increase in HE4, 95% CI 1.54-17.1) and overall survival (HR 7.48 per 10-fold increase in HE4, 95% CI 1.76-31.7). HE4 is a prognostic marker in endometrial cancer and is helpful in addition to other variables for the preoperative risk stratification of patients with endometrial cancer.

Incidence of lymph node metastases in clinical early-stage mucinous and seromucinous ovarian carcinoma: a retrospective cohort study.

OBJECTIVE: The use of lymph node sampling during staging procedures in clinical early-stage mucinous ovarian carcinoma (MOC) is an ongoing matter of debate. Furthermore, the incidence of lymph node metastases (LNM) in MOC in relation to tumour grade (G) is unknown. We aimed to determine the incidence of LNM in clinical early-stage MOC per tumour grade. DESIGN: Retrospective study with data from the Dutch Pathology Registry (PALGA). SETTING: The Netherlands, 2002-2012. POPULATION OR SAMPLE: Patients with MOC. METHODS: Histology reports on patients with MOC diagnosed in the Netherlands between 2002 and 2012 were obtained from PALGA. Reports were reviewed for diagnosis, tumour grade and presence of LNM. Clinical data, surgery reports and radiology reports of patients with LNM were retrieved from hospital files. MAIN OUTCOME MEASURES: Incidence of LNM, disease-free survival (DFS). RESULTS: Of 915 patients with MOC, 426 underwent lymph node sampling. Cytoreductive surgery was performed in 267 patients. The other 222 patients received staging without lymph node sampling. In eight of 426 patients, LNM were discovered by sampling. In four of 190 (2.1%) patients with G1 MOC, LNM were present, compared with one of 115 (0.9%) patients with G2 MOC and three of 22 (13.6%) patients with G3 MOC. Tumour grade was not specified in 99 patients. Patients with clinical early-stage MOC had no DFS benefit from lymph node sampling. CONCLUSIONS: LNM are rare in early-stage G1 and G2 MOC without clinical suspicion of LNM. Therefore, lymph node sampling can be omitted in these patients. TWEETABLE ABSTRACT: Lymph node sampling can be omitted in clinical early-stage G1 and G2 mucinous ovarian cancer.

PET/CT with 18F-FDG predicts short-term outcome in stage II/III breast cancer patients upstaged to N2/3 nodal disease.

INTRODUCTION: 18F-FDG PET/CT has high positive predictive value for the detection of avid lymph node metastases in breast cancer patients. We analysed the effect of upstaging lymph nodes by PET/CT on short-term outcome in stage II/III breast cancer patients. PATIENTS AND METHODS: A total of 278 stage II/III primary breast cancer patients (mean age 48.9 years, range 19-75 years) were re-staged with 18F-FDG PET/CT before start of pre-operative systemic treatment (PST). Patients were divided in three groups based on risk for local recurrence: a low - (T2N0), intermediate - (T0-2N1 and T3N0) and a high-risk group (T0-3N2-3, T3N1 and T4). Within these groups we looked at local recurrence-free survival (LRFS), recurrence-free survival (RFS) and overall survival (OS) within the first 3 years of follow-up. RESULTS: With a median follow-up (FU) of 50 months the RFS, LRFS and OS were 87%, 88% and 92% respectively for the whole group. PET/CT upstaged 43 patients from the low- and intermediate risk group to the high-risk group, based on detection of ≥4 avid axillary nodes or occult N2/3-disease. Patients upstaged with PET/CT had more events for all three analyses compared to the original risk groups, which resulted in a significantly worse RFS (69.8%; p = 0.03) a nearly significantly worse LRFS (p = 0.052) and no effect in OS (p = 0.433). DISCUSSION: Additional PET/CT staging allows breast cancer patients to be treated according to the true stage, still stage II/III breast cancer patients upstaged to N2/3 by PET/CT have worse short-term outcome, despite adjustment of treatment, than patients staged high-risk with conventional imaging.

Uterine serous carcinoma: a historic evaluation of therapy.

UNLABELLED: Summary OBJECTIVE: Uterine serous carcinoma (USC) is an aggressive, histological subtype of endometrial cancer with a poor prognosis. This study evaluates the additional effect of staging surgery above total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH+BSO) on the use of adjuvant therapy and subsequent survival outcomes in clinical early-stage USC patients. MATERIALS AND METHODS: This retrospective cohort study includes 75 women treated for clinical early-stage USC. RESULTS: In 33 (44%) clinical early-stage patients surgical staging was performed and 15 patients (45%) proved to have lymphatic or abdominal metastasis. Use of adjuvant therapy was similar in patients, both staged with no metastasis (n = 18) and patients who underwent TAH and BSO only (n = 42, p = 0.17). No significant survival difference was found between surgically staged and TAH+BSO patients. CONCLUSIONS: Surgical staging proved to be important to determine stage of disease and hence prognosis. Surgical staging did not lead to selective avoidance of adjuvant therapy in patients with no metastasis.

St. Gallen endocrine response classes predict recurrence rates over time.

BACKGROUND: In 2007 the St. Gallen consensus panel defined three endocrine response classes: highly endocrine responsive (ER-H), incomplete endocrine responsive (ER-I) and non-endocrine responsive tumours (ER-N). However, it is uncertain whether ER-I tumours are less responsive than ER-H tumours. We investigated whether recurrence rates vary over time between response classes. Additionally, we investigated the most predictive response class definition for tamoxifen benefit. PATIENTS AND METHODS: We recollected tumours from 646 patients who participated in a randomized trial of adjuvant tamoxifen vs. OBSERVATION: Estrogen receptor (ER), progesterone receptor (PgR), HER2 status and tumour grade were revised centrally. St. Gallen classes were evaluated for recurrence free interval (RFI). Change in hazards over time was assessed. Subsequently, 6 alternative response class definitions were compared to optimize the cut-off for PgR and ER. RESULTS: Schoenfeld residuals indicate a failure of proportional hazards between the endocrine response groups (p = 0.0001). The HR for recurrence risk shifted over time with the ER-H group initially being at lower risk (HR ER-H vs. ER-I 0.5), but after six years the recurrence risk increased (HR 1.9). The cut-off values for ER and PgR that statistically best discriminated RFI in the first 4 years for lymph node positive patients were ER ≥ 50% and PgR ≥ 75%. CONCLUSION: We demonstrated a marked variability in endocrine therapy benefit. Patients with ER-H tumours have a larger benefit during adjuvant tamoxifen and in the first years after accomplishing of the therapy, but suffer from late recurrences. This might have implications for optimal treatment duration.