Pan-cancer whole-genome analyses of metastatic solid tumours.

Metastatic cancer is a major cause of death and is associated with poor treatment efficacy. A better understanding of the characteristics of late-stage cancer is required to help adapt personalized treatments, reduce overtreatment and improve outcomes. Here we describe the largest, to our knowledge, pan-cancer study of metastatic solid tumour genomes, including whole-genome sequencing data for 2,520 pairs of tumour and normal tissue, analysed at median depths of 106× and 38×, respectively, and surveying more than 70 million somatic variants. The characteristic mutations of metastatic lesions varied widely, with mutations that reflect those of the primary tumour types, and with high rates of whole-genome duplication events (56%). Individual metastatic lesions were relatively homogeneous, with the vast majority (96%) of driver mutations being clonal and up to 80% of tumour-suppressor genes being inactivated bi-allelically by different mutational mechanisms. Although metastatic tumour genomes showed similar mutational landscape and driver genes to primary tumours, we find characteristics that could contribute to responsiveness to therapy or resistance in individual patients. We implement an approach for the review of clinically relevant associations and their potential for actionability. For 62% of patients, we identify genetic variants that may be used to stratify patients towards therapies that either have been approved or are in clinical trials. This demonstrates the importance of comprehensive genomic tumour profiling for precision medicine in cancer.

PAZEC: a Dutch Gynaecological Oncology Group open-label, multicenter, phase II study of pazopanib in metastatic and locally advanced hormone-resistant endometrial cancer.

OBJECTIVE: There is a continued need for improvement of second-line systemic treatment for metastatic and/or recurrent endometrial cancer. METHODS: In this phase II, open-label study, eligible patients had histologically or cytologically confirmed endometrial cancer, documented progressive disease, and a WHO performance status of ≤2. All participants received treatment with pazopanib 800 mg once daily until progression, unacceptable toxicity, or patient refusal. The primary endpoint was progression-free survival at 3 months, with secondary outcomes of overall response rate, progression-free survival, overall survival, and toxicity. The study was powered to demonstrate 50% progression-free survival at 3 months with α=0.05 and ß=80%. RESULTS: Between January 2011 and February 2016, 60 eligible patients were included (intention-to-treat population). Median age was 68 (range, 53-85) years. Previous treatment included pelvic radiotherapy (58%), chemotherapy (90%), and hormonal therapy (43%). Three-month progression-free survival was 63.3% in the intention-to-treat population, with median progression-free survival and overall survival of 3.4 and 7.5 months, respectively. Overall response rate was 8.3%, and median follow-up 7.6 months. The most common grade 3 or higher adverse events were gastrointestinal toxicity in 21% of participants, including two patients with a gut perforation, one fatal gastrointestinal hemorrhage, one enterocutaneous fistula, and one fatal enterovaginal fistula. Extensive peritoneal disease existed in 80% of the patients with severe gastrointestinal toxicity. A definite correlation with previous radiotherapy could not be established. CONCLUSIONS: Pazopanib met its primary endpoint of 3 months' progression-free survival in advanced endometrial cancer (63.3%), but response rates were modest. There may be a correlation for rare but severe gastrointestinal toxicity with previous treatments and/or disease site that has yet to be elucidated.

WEE1 inhibitor adavosertib in combination with carboplatin in advanced TP53 mutated ovarian cancer: A biomarker-enriched phase II study.

OBJECTIVE: In the first part of this phase II study (NCT01164995), the combination of carboplatin and adavosertib (AZD1775) was shown to be safe and effective in patients with TP53 mutated platinum-resistant ovarian cancer (PROC). Here, we present the results of an additional safety and efficacy cohort and explore predictive biomarkers for resistance and response to this combination treatment. METHODS: This is a phase II, open-label, non-randomized study. Patients with TP53 mutated PROC received carboplatin AUC 5 mg/ ml·min intravenously and adavosertib 225 mg BID orally for 2.5 days in a 21-day cycle. The primary objective is to determine the efficacy and safety of carboplatin and adavosertib. Secondary objectives include progression-free survival (PFS), changes in circulating tumor cells (CTC) and exploration of genomic alterations. RESULTS: Thirty-two patients with a median age of 63 years (39-77 years) were enrolled and received treatment. Twenty-nine patients were evaluable for efficacy. Bone marrow toxicity, nausea and vomiting were the most common adverse events. Twelve patients showed partial response (PR) as best response, resulting in an objective ORR of 41% in the evaluable patients (95% CI: 23%-61%). The median PFS was 5.6 months (95% CI: 3.8-10.3). In patients with tumors harboring CCNE1 amplification, treatment efficacy was slightly but not significantly better. CONCLUSIONS: Adavosertib 225 mg BID for 2.5 days and carboplatin AUC 5 could be safely combined and showed anti-tumor efficacy in patients with PROC. However, bone marrow toxicity remains a point of concern, since this is the most common reason for dose reductions and dose delays.

The association between patient satisfaction with information and adherence to oral anticancer agents.

INTRODUCTION: Adherence to anticancer agents is a critical factor in achieving adequate clinical response, and became a major challenge for patients and caregivers since the increased substitution of parenteral cytostatic by oral drugs. One of the factors that influences adherence is how well informed patients are about their therapy. This study assesses the association between patient satisfaction with information about oral anticancer agents and adherence. MATERIALS AND METHODS: This study was conducted among patients (≥18 years) who began oral anticancer therapy. Patients satisfaction with information and adherence were assessed using validated questionnaires. Adherence was also assessed using refill data. Logistic regression was applied to assess the association between overall patient satisfaction with information and both self-reported adherence and adherence based on an MPR value of above 80%. RESULTS: In total, 124 patients were included in the study. The median (IQR) satisfaction with information was 15.0(4) on a scale of 0-17. Eighty-two percent of participants reported adherence, while the refill data demonstrated that 64.5% of patients had an adherence rate of 80% or higher. Overall satisfaction with information was not significantly associated with self-reported adherence (OR adj 0.98 [95% CI 0.85-1.15]) or refill-based adherence (OR adj 1.11 [95% CI 0.99-1.24]). CONCLUSION: The findings indicate no significant relationship between patient satisfaction with information and adherence. The population was highly satisfied with information about the oral anticancer agents, which indicates a high level of satisfaction with usual care. However, the refill data reveals that 35.5% of patients were not adherent.

Frailty and checkpoint inhibitor toxicity in older patients with melanoma.

BACKGROUND: Immune checkpoint inhibitors (ICIs) can cause immune-related adverse events (irAEs) that range from mild to life-threatening. Age itself does not seem to be a predictor for the occurrence of irAEs. It is unknown whether frailty plays a role in the occurrence of irAEs. Therefore, the authors assessed whether irAEs and their sequelae occur more often in frail patients than in fit patients according to the Geriatric 8 (G8) assessment. METHODS: Patients with melanoma aged 70 years and older who were about to start ICI therapy and were screened with the G8 assessment were enrolled in this prospective, observational study. Patients were classified by the G8 as either fit or frail. The primary outcome was the occurrence of grade ≥3 irAEs. RESULTS: In total, 92 patients were included for statistical analyses, 26 (29%) of whom were classified as frail. Grade ≥3 irAEs occurred in 20% of patients. There was no significant difference in the occurrence of grade ≥3 irAEs between fit and frail patients (17% vs 27%; P = .26). Frail patients were admitted to the hospital because of irAEs significantly more often than fit patients (29% vs 54%; P = .02) and showed a trend toward increased length of hospitalization (5 vs 8 days; P = .06) and more frequent use of immunosuppressants or ICI discontinuation for irAEs (36% vs 58%; P = .06). CONCLUSIONS: Although frailty appears to be unrelated to the occurrence of severe irAEs, it is an indicator of irAE-related adverse sequelae, such as hospital admission. Screening for frailty can be of added value in the shared decision-making process for older patients who qualify for ICI treatment.

The attributive value of comprehensive surgical staging in clinically early-stage epithelial ovarian carcinoma: A systematic review and meta-analysis.

BACKGROUND: Tumor positivity and upstaging rates from various surgical staging steps performed in clinically early-stage epithelial ovarian carcinoma (EOC) vary widely in literature. AIM: To quantify tumor positivity and upstaging rates for all staging surgery steps in EOC patients. Differences between subgroups based on their clinical and histological characteristics are explored. METHODS: A systematic search using synonyms of 'ovarian cancer', 'neoplasm staging', and 'neoplasm metastasis' was conducted in PubMed, Embase, and the Cochrane Library. Meta-analysis was performed on 23 included studies, comprising 5194 clinical stage I or II EOC patients who underwent comprehensive surgical staging. Studies were assessed using the Newcastle-Ottawa Scale risk-of-bias tool. Pooled proportions and 95% confidence intervals were calculated using an inverse variance weighted random-effects model. RESULTS: Overall upstaging rate of clinically early-stage EOC patients was 18.7% (95%CI: 14.1-23.4%). Serous histology or high grade EOC showed the highest upstaging rate at 35.3% (95%CI: 21.8-48.7%) and 40.9% (95%CI: 35.6-46.2%). Lymph node involvement resulted in an upstaging rate of 8.7% (95%CI: 6.2-11.3%). Tumor was identified in uterus, cytology, peritoneal biopsies, omentum and appendix in 6.2% (95%CI: 1.8-10.7%), 18.4% (95%CI: 13.8-22.9%), 9.7% (95%CI: 3.8-15.6%), 5.2% (95%CI: 1.7-8.8%) and 3.6% (95%CI: 0.0-7.5%) of EOC patients. The corresponding upstaging rates were 5.9% (95%CI: 1.4-10.4%), 8.5% (95%CI: 1.8-15.2%), 3.5% (95%CI: 1.0-6.0%), 3.9% (95%CI: 1.4-6.3%) and 1.6% (95%CI: 0.0-3.4%), respectively. CONCLUSION: The attributive value of comprehensive surgical staging in clinically early-stage EOC patients remains substantial, particularly in serous and high grade tumors.

Phase II study of definitive chemoradiation for locally advanced squamous cell cancer of the vulva: An efficacy study.

OBJECTIVE: To evaluate feasibility of chemoradiation as alternative for extensive surgery in patients with locally advanced vulvar cancer and to report on locoregional control, toxicity and survival. METHODS: In a multicenter, prospective phase II trial patients with locally advanced vulvar cancer were treated with locoregional radiotherapy combined with sensitizing chemotherapy (capecitabine). Treatment feasibility, percentage locoregional control, survival and toxicity were evaluated. RESULTS: 52 patients with mainly T2/T3 disease were treated according to the study protocol in 10 centers in the Netherlands from 2007 to 2019. Full dose radiotherapy (tumor dose of 64.8Gy) was delivered in 92% and full dose capecitabine in 69% of patients. Most prevalent acute ≥ grade 3 toxicities were regarding skin/mucosa and pain (54% and 37%). Late ≥grade 3 toxicity was reported for skin/mucosa (10%), fibrosis (4%), GI incontinence (4%) and stress fracture or osteoradionecrosis (4%). Twelve weeks after treatment, local clinical complete response (cCR) and regional control (RC) rates were 62% and 75%, respectively. After 2 years, local cCR persisted in 22 patients (42%) and RC was 58%. Thirty patients (58%) had no evidence of disease at end of follow-up (median 35 months). In 9 patients (17%) extensive surgery with stoma formation was needed. Progression free survival was 58%, 51% and 45% and overall survival was 76%, 66%, 52% at 1,2, and 5 years. CONCLUSIONS: Definitive capecitabine-based chemoradiation as alternative for extensive surgery is feasible in locally advanced vulvar cancer and results in considerable locoregional control with acceptable survival rates with manageable acute and late toxicity.

Impact of hormonal biomarkers on response to hormonal therapy in advanced and recurrent endometrial cancer.

BACKGROUND: Approximately 20% of women with endometrial cancer have advanced-stage disease or suffer from a recurrence. For these women, prognosis is poor, and palliative treatment options include hormonal therapy and chemotherapy. Lack of predictive biomarkers and suboptimal use of existing markers for response to hormonal therapy have resulted in overall limited efficacy. OBJECTIVE: This study aimed to improve the efficacy of hormonal therapy by relating immunohistochemical expression of estrogen and progesterone receptors and estrogen receptor pathway activity scores to response to hormonal therapy. STUDY DESIGN: Patients with advanced or recurrent endometrial cancer and available biopsies taken before the start of hormonal therapy were identified in 16 centers within the European Network for Individualized Treatment in Endometrial Cancer and the Dutch Gynecologic Oncology Group. Tumor tissue was analyzed for estrogen and progesterone receptor expressions and estrogen receptor pathway activity using a quantitative polymerase chain reaction-based messenger RNA model to measure the activity of estrogen receptor-related target genes in tumor RNA. The primary endpoint was response rate defined as complete and partial response using the Response Evaluation Criteria in Solid Tumors. The secondary endpoints were clinical benefit rate and progression-free survival. RESULTS: Pretreatment biopsies with sufficient endometrial cancer tissue and complete response evaluation were available in 81 of 105 eligible cases. Here, 22 of 81 patients (27.2%) with a response had estrogen and progesterone receptor expressions of >50%, resulting in a response rate of 32.3% (95% confidence interval, 20.9-43.7) for an estrogen receptor expression of >50% and 50.0% (95% confidence interval, 35.2-64.8) for a progesterone receptor expression of >50%. Clinical benefit rate was 56.9% for an estrogen receptor expression of >50% (95% confidence interval, 44.9-68.9) and 75.0% (95% confidence interval, 62.2-87.8) for a progesterone receptor expression of >50%. The application of the estrogen receptor pathway test to cases with a progesterone receptor expression of >50% resulted in a response rate of 57.6% (95% confidence interval, 42.1-73.1). After 2 years of follow-up, 34.3% of cases (95% confidence interval, 20-48) with a progesterone receptor expression of >50% and 35.8% of cases (95% confidence interval, 20-52) with an estrogen receptor pathway activity score of >15 had not progressed. CONCLUSION: The prediction of response to hormonal treatment in endometrial cancer improves substantially with a 50% cutoff level for progesterone receptor immunohistochemical expression and by applying a sequential test algorithm using progesterone receptor immunohistochemical expression and estrogen receptor pathway activity scores. However, results need to be validated in the prospective Prediction of Response to Hormonal Therapy in Advanced and Recurrent Endometrial Cancer (PROMOTE) study.

Gastric cancer during pregnancy: A report on 13 cases and review of the literature with focus on chemotherapy during pregnancy.

INTRODUCTION: Gastric cancer during pregnancy is extremely rare and data on optimal treatment and possible chemotherapeutic regimens are scarce. The aim of this study is to describe the obstetric and maternal outcome of women with gastric cancer during pregnancy and review the literature on antenatal chemotherapy for gastric cancer. MATERIAL AND METHODS: Treatment and outcome of patients registered in the International Network on Cancer, Infertility and Pregnancy database with gastric cancer diagnosed during pregnancy were analyzed. RESULTS: In total, 13 women with gastric cancer during pregnancy were registered between 2002 and 2018. Median gestational age at diagnosis was 22 weeks (range 6-30 weeks). Twelve women were diagnosed with advanced disease and died within 2 years after pregnancy, most within 6 months. In total, eight out of 10 live births ended in a preterm delivery because of preeclampsia, maternal deterioration, or therapy planning. Two out of six women who initiated chemotherapy during pregnancy delivered at term. Two neonates prenatally exposed to chemotherapy were growth restricted and one of them developed a systemic infection with brain abscess after preterm delivery for preeclampsia 2 weeks after chemotherapy. No malformations were reported. CONCLUSIONS: The prognosis of gastric cancer during pregnancy is poor, mainly due to advanced disease at diagnosis, emphasizing the need for early diagnosis. Antenatal chemotherapy can be considered to reach fetal maturity, taking possible complications such as growth restriction, preterm delivery, and hematopoietic suppression at birth into account.

Characteristics of patients with cervical cancer during pregnancy: a multicenter matched cohort study. An initiative from the International Network on Cancer, Infertility and Pregnancy.

BACKGROUND: Treatment of cervical cancer during pregnancy is often complex and challenging. This study aimed to analyze current patterns of practice in the management of pregnant patients diagnosed with cervical cancer. METHODS: This was a matched cohort study comprising patients managed for cervical cancer during pregnancy from six European centers. Patient information was retrieved from the dataset of the International Network for Cancer, Infertility and Pregnancy from 1990 to 2012. Each center matched its patients with two non-pregnant controls for age (±5 years) and International Federation of Gynecology and Obstetrics (FIGO) 2009 stage. Information on age, histological type, grade, lymphovascular space invasion, stage, tumor size, method of diagnosis, site of recurrence, delivery, date of recurrence, and date of death was recorded. Progression-free survival was compared using multivariable Cox proportional hazards regression. RESULTS: A total of 132 pregnant patients and 256 controls were analyzed. The pregnant patients (median age 34 years, range 21-43) were diagnosed at a median gestational age of 18.4 weeks of pregnancy (range 7-39). Stage distribution during pregnancy was 14.4% for stage IA, 47.0% for IB1, 18.9% for IB2, and 19.7% for II-IV. For treatment during pregnancy, 17.4% of the patients underwent surgery, 16.7% received neoadjuvant chemotherapy, 26.5% delayed their treatment, 12.9% had a premature delivery, and 26.5% had their pregnancy terminated. Median follow-up was 84 months (67 months for pregnant and 95 months for non-pregnant patients). The unadjusted hazard ratio of pregnancy for progression-free survival was 1.18 (95% confidence interval 0.74 to 1.88). CONCLUSION: Surgery and chemotherapy is increasingly used in the management of pregnant patients with cervical cancer and prognosis is similar to that of non-pregnant patients.

The predictive value of symptoms for anxiety in hospice inpatients with advanced cancer.

ABSTRACTObjective:Insight into symptoms as predictors for anxiety may help to foster early identification of anxiety and to ameliorate anxiety management. The aim of this study was to determine which frequently occurring symptoms are predictors for anxiety in advanced cancer patients recently admitted to a hospice. METHOD: Symptom burden was measured in patients admitted to a hospice who died ≤3 month after admission using the Utrecht Symptom Diary. This is a Dutch-translated and adapted version of the Edmonton Symptom Assessment System to self-assess the 11 most prevalent symptoms and overall well-being on a 0-10 numerical rating scale. Multiple linear regression analysis was employed to analyze the predictive value of fatigue, nausea, pain, dyspnea, depressed mood, insomnia, and well-being on anxiety. RESULTS: A total of 211 patients were included, 42% of whom were men, and the median age was 71 years (range = 31-95). Anxiety was uncommon and rarely severe: 25% had a score ≥1, and 14% had a score >3. After correction for age, gender, and marital status, depressed mood (p = 0.00) and dyspnea (p = 0.01) were independent predictors for anxiety and explained 23% of the variance in anxiety. SIGNIFICANCE OF RESULTS: Hospice inpatients with advanced cancer who suffer from dyspnea and/or depressed mood are at increased risk for anxiety. Treatment of dyspnea and depressed mood may contribute to adequate anxiety management. Further research should explore other factors associated with anxiety, especially in the psychological, social, and spiritual domains.

Genomic and transcriptomic plasticity in treatment-naive ovarian cancer.

Intra-tumor heterogeneity is a hallmark of many cancers and may lead to therapy resistance or interfere with personalized treatment strategies. Here, we combined topographic mapping of somatic breakpoints and transcriptional profiling to probe intra-tumor heterogeneity of treatment-naïve stage IIIC/IV epithelial ovarian cancer. We observed that most substantial differences in genomic rearrangement landscapes occurred between metastases in the omentum and peritoneum versus tumor sites in the ovaries. Several cancer genes such as NF1, CDKN2A, and FANCD2 were affected by lesion-specific breakpoints. Furthermore, the intra-tumor variability involved different mutational hallmarks including lesion-specific kataegis (local mutation shower coinciding with genomic breakpoints), rearrangement classes, and coding mutations. In one extreme case, we identified two independent TP53 mutations in ovary tumors and omentum/peritoneum metastases, respectively. Examination of gene expression dynamics revealed up-regulation of key cancer pathways including WNT, integrin, chemokine, and Hedgehog signaling in only subsets of tumor samples from the same patient. Finally, we took advantage of the multilevel tumor analysis to understand the effects of genomic breakpoints on qualitative and quantitative gene expression changes. We show that intra-tumor gene expression differences are caused by site-specific genomic alterations, including formation of in-frame fusion genes. These data highlight the plasticity of ovarian cancer genomes, which may contribute to their strong capacity to adapt to changing environmental conditions and give rise to the high rate of recurrent disease following standard treatment regimes.

Hormone Receptor Expression and Activity for Different Tumour Locations in Patients with Advanced and Recurrent Endometrial Carcinoma.

BACKGROUND: Response to hormonal therapy in advanced and recurrent endometrial cancer (EC) can be predicted by oestrogen and progesterone receptor immunohistochemical (ER/PR-IHC) expression, with response rates of 60% in PR-IHC > 50% cases. ER/PR-IHC can vary by tumour location and is frequently lost with tumour progression. Therefore, we explored the relationship between ER/PR-IHC expression and tumour location in EC. METHODS: Pre-treatment tumour biopsies from 6 different sites of 80 cases treated with hormonal therapy were analysed for ER/PR-IHC expression and classified into categories 0-10%, 10-50%, and >50%. The ER pathway activity score (ERPAS) was determined based on mRNA levels of ER-related target genes, reflecting the actual activity of the ER receptor. RESULTS: There was a trend towards lower PR-IHC (33% had PR > 50%) and ERPAS (27% had ERPAS > 15) in lymphogenic metastases compared to other locations (p = 0.074). Hematogenous and intra-abdominal metastases appeared to have high ER/PR-IHC and ERPAS (85% and 89% ER-IHC > 50%; 64% and 78% PR-IHC > 50%; 60% and 71% ERPAS > 15, not significant). Tumour grade and previous radiotherapy did not affect ER/PR-IHC or ERPAS. CONCLUSIONS: A trend towards lower PR-IHC and ERPAS was observed in lymphogenic sites. Verification in larger cohorts is needed to confirm these findings, which may have implications for the use of hormonal therapy in the future.

Response to Systemic Therapies in Ovarian Adult Granulosa Cell Tumors: A Literature Review.

For adult granulosa cell tumors (aGCTs), the preferred treatment modality is surgery. Chemotherapy and anti-hormonal therapy are also frequently used in patients with recurrent aGCT. We aimed to review the existing literature on the response to chemotherapy and anti-hormonal therapy in patients with aGCT. Embase and MEDLINE were searched from inception to November 2021 for eligible studies. Objective response rate (ORR) was calculated as the total number of cases with a complete response (CR) or a partial response (PR). Disease control rate (DCR) was defined as the sum of cases with CR, PR or stable disease (SD). A total of 10 studies were included that reported on chemotherapy and 13 studies were included that reported on anti-hormonal therapy. The response rates of the 56 chemotherapy regimens that could be evaluated resulted in an ORR of 30% and DCR of 58%. For anti-hormonal therapy, the results of 73 regimens led to an ORR of 11% and a DCR of 66%. Evidence on systemic therapy in aGCT only is limited. For both chemotherapy and anti-hormonal therapy, the ORR is limited, but the response is considerably higher when patients achieving SD are included. New approaches are needed to provide more evidence and standardize treatment in aGCT.

Patient-Reported Outcomes During Checkpoint Inhibition: Insight into Symptom Burden in Daily Clinical Practice.

CONTEXT: While praised for inducing durable anti-tumour responses, immune checkpoint inhibitors (ICI) also cause immune-related adverse events (irAEs) that can vary in severity and affect health-related quality of life (HRQL). OBJECTIVES: This study was performed to provide insight into the course of symptoms and the influence of irAEs on HRQL measured with the treatment-specific Utrecht Symptom Diary Immunotherapy (USD-I). METHODS: In this observational cohort study, melanoma or non-small lung cancer (NSCLC) patients treated with PD(L)1-inhibitors between February 2016 and December 2018 were included. Data on symptoms, wellbeing and influence of side effects on HRQL were obtained using the patient-scored, treatment-specific USD-I, which was completed as part of routine care. Patients scored symptom intensity on a 0-10 numeric rating scale (NRS); NRS≥3 considered clinically relevant. RESULTS: A total of 162 melanoma (55%) or NSCLC (45%) patients completed 1493 USDs (median seven per patient). Most common patient-reported clinically relevant symptoms were: inactivity, fatigue, pain, cough and sleeping problems. Symptom prevalence decreased during treatment. Patients generally reported a low influence of side effects on HRQL. A higher number of clinically relevant symptoms at a certain time point correlated with poorer wellbeing. CONCLUSIONS: These data illustrate that ICI-treatment is generally well tolerated. However, especially the number of clinically relevant symptoms can impact patients wellbeing. Systematic use of an ICI-tailored PROM could create a window to discuss symptoms in a structured way which may promote personalized care during treatment.

Distinct Genomic Profiles Are Associated with Treatment Response and Survival in Ovarian Cancer.

The majority of patients with ovarian cancer ultimately develop recurrent chemotherapy-resistant disease. Treatment stratification is mainly based on histological subtype and stage, prior response to platinum-based chemotherapy, and time to recurrent disease. Here, we integrated clinical treatment, treatment response, and survival data with whole-genome sequencing profiles of 132 solid tumor biopsies of metastatic epithelial ovarian cancer to explore genome-informed stratification opportunities. Samples from primary and recurrent disease harbored comparable numbers of single nucleotide variants and structural variants. Mutational signatures represented platinum exposure, homologous recombination deficiency, and aging. Unsupervised hierarchical clustering based on genomic input data identified specific ovarian cancer subgroups, characterized by homologous recombination deficiency, genome stability, and duplications. The clusters exhibited distinct response rates and survival probabilities which could thus potentially be used for genome-informed therapy stratification for more personalized ovarian cancer treatment.

Antiangiogenic tyrosine kinase inhibition related gastrointestinal perforations: a case report and literature review.

Anti-VEGF (vascular endothelial growth factor) therapy with the monoclonal antibody bevacizumab can cause gastrointestinal (GI) perforations. In recent years it became apparent that GI perforations also occur during treatment with antiangiogenic tyrosine kinase inhibitors (TKIs). It is of clinical importance to consider (vague) abdominal complaints during antiangiogenic treatment as a sign of a GI perforation. To illustrate this serious complication, we report four cases of antiangiogenic treatment related GI perforations. In three cases this was due to antiangiogenic TKI treatment. Reported risk factors of GI perforations due to bevacizumab include the presence of a primary tumor in situ and recent history of endoscopy or abdominal radiotherapy. Pathology assessments of surgical removal of the perforated intestinal part reveal that perforations are predominantly seen at the tumor or anastomotic site, in case of carcinomatosis or diverticulitis or when GI obstruction or an intra-abdominal abscess is present. Whether the same risk factors may be involved in antiangiogenic TKI related GI perforations is unknown. The underlying mechanisms responsible for GI perforation during antiangiogenic treatment is unknown, but disturbance of host cell homeostasis of immune cells as well as platelet-endothelial cell interactions may play an important role. In conclusion, while clinical awareness that antiangiogenic treatment can cause GI perforations is critical for current medical practice, it is also very important to get more insight in its underlying mechanisms so that this life-threatening complication may be prevented in the near future.

Functional decline after surgery in older patients with head and neck cancer.

INTRODUCTION: In addition to classical endpoints such as survival and complication rates, other outcomes such as quality of life and functional status are increasingly recognized as important endpoints, especially for elderly patients. However, little is known about the long-term effect of surgery with regard to these other outcomes. Our aim is to investigate the functional status and self-reported health status of patients ≥ 70 years one year after surgery for head and neck cancer. METHODS: We present one-year follow-up data of patients ≥ 70 year who underwent surgery for HNC. During an interview by telephone, functional status was evaluated by using the Katz-15 Index of Independence questionnaire including six items covering basic Activities of Daily Living (ADL) and nine items covering Instrumental Activities of Daily Living (IADL). Measurements were compared with those obtained preoperatively. RESULTS: In total, 126 patients were included and eventually we collected follow-up data of 68 patients. There was a statistically significant decrease in functional status on the total Katz-15 and on the IADL questionnaire scores one year after surgery (mean 1.34 versus 2.42,p-value 0.00 and mean 1.21 versus 1.94,p-value 0.00). There was no significant change concerning ADL dependence (p-value 0.18) and cognitive status (p-value 0.11). The self-reported health status improved postoperatively, although not statistically significantly so (mean 67.36 versus 71.25,p-value 0.12). CONCLUSION: Approximately-one year after surgery for HNC, there is a significant decline in functional status indicating a higher level of dependency.

Use of a Symptom Diary on Oncology Wards: Effect on Symptom Management and Recommendations for Implementation.

BACKGROUND: Management of symptoms is essential in reducing the symptom burden of cancer patients. The effect of symptom diaries on symptom management to date has been evaluated only in ambulatory settings. OBJECTIVE: The aims of this study were to identify the key facilitators for successful implementation of symptom diaries on oncology wards from patients' and professionals' perspectives and to evaluate implementation outcomes. METHODS: In 2 cycles of action research, the Utrecht Symptom Diary (USD) was implemented on 3 oncology wards and a daycare unit. Key facilitators for implementation were identified by thematic coding of interviews. The effect of the implementation was evaluated in cycle II in a pretest-posttest design. We performed statistical tests (Mann-Whitney/t test/χ2) on Symptom Management Performance items in questionnaires and medical records. RESULTS: We interviewed 25 patients, 8 doctors, and 25 nurses. Seven key facilitators for implementation emerged. After implementation of the USD in cycle II, Symptom Management Performance was significantly (P < .05) improved for patients (3/12 items, n = 33 pretest/26 posttest) and professionals (6/12 items, n = 21 pretest/19 posttest). Significantly more symptoms (P = .00), working hypotheses (P = .023), treatment plans (P = .00), and interventions (P = .00) were reported (n = 47 pretest/47 posttest). CONCLUSIONS: Implementation of the USD significantly improved symptom management in oncology wards. We recommend (1) using a diagnosis-specific diary; (2) making clear, individualized working-arrangements; (3) training professionals; (4) using the plan-do-check-act cycle; (5) acting multidisciplinary; (6) providing guidelines and training; and (7) assuring adequate information communications technology (ICT). IMPLICATIONS: Symptom diaries are increasingly used, but implementation is challenging. This study provides knowledge on their benefits and an evidence-based strategy for implementation with positive outcomes achieved in patient care.

Validation of the G8 screening tool in older patients with cancer considered for surgical treatment.

BACKGROUND: The Geriatric 8 (G8) has proven to be one of the most sensitive frailty-screening tools for older patients with cancer undergoing systemic treatment. In this study we validated whether the G8 is also suitable for identifying impairments in their comprehensive geriatric assessment (CGA) in older patients with cancer undergoing surgery. Thereby, we investigated the differences in postoperative outcomes between the fit and frail patients classified by the G8. METHODS: Patients ≥70 years with a surgery indication because of a (suspected) malignant disease were prospectively enrolled. In all patients, a CGA was performed. The G8 results were assessed in parallel. The diagnostic value of the G8 was determined by comparing the result with the CGA as a reference test. Deficits in CGA was defined as ≥ two impairments of the CGA. Postoperative complications were retrospectively obtained from the medical record and compared between the fit and frail patients. RESULTS: In total, 143 patients were enrolled. The sensitivity, specificity, and negative predictive value of the G8 were 82% (95% CI 70-91), 63% (95% CI 52-73), and 85% (95% CI 75-91). In the patients with an impaired G8, a significantly prolonged hospital stay, higher rate of delirium, and higher 1-year mortality rate were seen. CONCLUSION: The G8 is a simple and useful screening tool for identifying deficits in CGA in older patients with cancer requiring surgery. Second, we concluded that patients with an impaired G8 are more at risk for a complicated recovery from surgery.