Real-world outcomes associated with bevacizumab combined with chemotherapy in platinum-resistant ovarian Cancer.

OBJECTIVES: The addition of bevacizumab to chemotherapy for platinum-resistant (PL-R) ovarian cancer (OC) improved progression-free (PFS) but not overall survival (OS) in clinical trials. We explored real-world outcomes in Ontario, Canada, and compared survival in the pre- and post-bevacizumab era. METHODS: Administrative databases were utilized to identify all patients treated with bevacizumab for PL-R OC. Time on treatment (ToT) was used as surrogate for PFS. Median OS was determined using the Kaplan-Meier method. Factors associated with ToT/OS were identified using a Cox proportional hazard model. A before and after comparative effectiveness analysis was performed to determine mOS for patients treated pre- and post-bevacizumab approval. RESULTS: From 2017 to 2019, 176 patients received bevacizumab. Median ToT was 3 months and OS was 11 months. Sixty-four percent received liposomal doxorubicin and 34% received paclitaxel. ToT (6 vs 3 months; HR 0.44; p < 0.0001) and OS (14 vs 9 months; HR 0.45; p = 0.0089) were longer with bevacizumab/paclitaxel. OS was not significantly different pre- and post-bevacizumab funding (8 vs 9 months; HR 1.01; 0.937). Median OS increased for those receiving paclitaxel (6 vs 11 months), but those in the post group were younger, more likely to have undergone primary surgery and had less co-morbidities. CONCLUSION: Real-world outcomes with bevacizumab in PL-R OC are inferior to those in the pivotal clinical trial. Survival has not significantly improved since funding became publicly available, indicating a substantial efficacy-effectiveness gap between trial and real-world outcomes. Median OS and ToT were significantly better when bevacizumab was given with paclitaxel.

Real-world outcomes associated with use of front-line bevacizumab in ovarian cancer.

BACKGROUND: In the pivotal ICON7 study, addition of bevacizumab to front-line treatment of ovarian cancer (OC) significantly improved overall survival (OS) (p = 0.03) in a high-risk subgroup of patients with suboptimally debulked/unresectable stage III or IV disease, leading to approval in Ontario, Canada in March 2016. Here we describe utilization of bevacizumab for front-line, high-risk OC and determine outcomes in routine clinical practice. METHODS: Provincial administrative databases were utilized to identify all patients treated with front-line bevacizumab following its approval. Median OS (mOS) was determined using the Kaplan-Meier method. Factors associated with OS were identified using a Cox proportional hazard model. A comparative effectiveness analysis was performed to determine mOS pre- (2006-2016) and post- (2016-2019) approval. RESULTS: From March 2016 to October 2019, 282 patients received bevacizumab. Mean age was 64 years old, and 58% had stage IV disease. Median survival was 29 months and was longer in stage III (37 months) compared to stage IV disease (28 months). In a comparative effectiveness analysis of patients with stage IV serous OC, post-approval uptake of bevacizumab was low (23%). Median OS was similar pre (26 months) and post (27 months) approval (HR 0.92, 0.75-1.12, p = 0.383). CONCLUSIONS: Survival in real-world patients treated with front-line bevacizumab is shorter than in pivotal clinical trials. Survival in stage IV serous patients has not significantly improved post public reimbursement of bevacizumab. This analysis was limited by poor uptake, however mOS was similar in patients who did and did not receive bevacizumab.

CA-125 Early Dynamics to Predict Overall Survival in Women with Newly Diagnosed Advanced Ovarian Cancer Based on Meta-Analysis Data.

(1) Background: Cancer antigen 125 (CA-125) is a protein produced by ovarian cancer cells that is used for patients' monitoring. However, the best ways to analyze its decline and prognostic role are poorly quantified. (2) Methods: We leveraged individual patient data from the Gynecologic Cancer Intergroup (GCIG) meta-analysis (N = 5573) to compare different approaches summarizing the early trajectory of CA-125 before the prediction time (called the landmark time) at 3 or 6 months after treatment initiation in order to predict overall survival. These summaries included observed and estimated measures obtained by a linear mixed model (LMM). Their performances were evaluated by 10-fold cross-validation with the Brier score and the area under the ROC (AUC). (3) Results: The estimated value and the last observed value at 3 months were the best measures used to predict overall survival, with an AUC of 0.75 CI 95% [0.70; 0.80] at 24 and 36 months and 0.74 [0.69; 0.80] and 0.75 [0.69; 0.80] at 48 months, respectively, considering that CA-125 over 6 months did not improve the AUC, with 0.74 [0.68; 0.78] at 24 months and 0.71 [0.65; 0.76] at 36 and 48 months. (4) Conclusions: A 3-month surveillance provided reliable individual information on overall survival until 48 months for patients receiving first-line chemotherapy.

Clinical outcome and biomarker assessments of a multi-centre phase II trial assessing niraparib with or without dostarlimab in recurrent endometrial carcinoma.

This multi-centre, non-randomized, open-label, phase II trial (NCT03016338), assessed niraparib monotherapy (cohort 1, C1), or niraparib and dostarlimab (cohort 2, C2) in patients with recurrent serous or endometrioid endometrial carcinoma. The primary endpoint was clinical benefit rate (CBR), with ≥5/22 overall considered of interest. Secondary outcomes were safety, objective response rate (ORR), duration of response, progression free survival and overall survival. Translational research was an exploratory outcome. Potential biomarkers were evaluated in archival tissue by immunohistochemistry and next generation sequencing panel. In C1, 25 patients were enrolled, and CBR was 20% (95% CI: 9-39) with median clinical benefit duration of 5.3 months. The ORR was 4% (95% CI: 0-20). In C2, 22 patients were enrolled, and the CBR was 31.8% (95% CI: 16-53) with median clinical benefit duration of 6.8 months. The ORR was 14% (95% CI: 3-35). No new safety signals were detected. No significant association was detected between clinical benefit and IHC markers (PTEN, p53, MMR, PD-L1), or molecular profiling (PTEN, TP53, homologous recombination repair genes). In conclusion, niraparib monotherapy did not meet the efficacy threshold. Niraparib in combination with dostarlimab showed modest activity.

State of the Biomarker Science in Ovarian Cancer: A National Cancer Institute Clinical Trials Planning Meeting Report.

PURPOSE: Despite therapeutic advances in the treatment of ovarian cancer (OC), 5-year survival remains low, and patients eventually die from recurrent, chemotherapy-resistant disease. The National Cancer Gynecologic Cancer Steering Committee identified the integration of scientifically defined subgroups as a top strategic priority in clinical trial planning. METHODS: A group of experts was convened to review the scientific literature in OC to identify validated predictive biomarkers that could inform patient selection and treatment stratification. Here, we report on these findings and their potential for use in future clinical trial design on the basis of hierarchal evidence grading. RESULTS: The biomarkers were classified on the basis of mechanistic targeting, including DNA repair and replication stress, immunotherapy and tumor microenvironment, oncogenic signaling, and angiogenesis. Currently, BRCA mutations and homologous recombination deficiency to predict poly (ADP-ribose) polymerase inhibitor response are supported in OC by the highest level of evidence. Additional biomarkers of response to agents targeting the pathways above have been identified but require prospective validation. CONCLUSION: Although a number of biomarkers of response to various agents in OC have been described in the literature, high-level evidence for the majority is lacking. This report highlights the unmet need for identification and validation of predictive biomarkers to guide therapy and future trial design in OC.

Neoadjuvant and Adjuvant Systemic Therapy for Newly Diagnosed Stage II-IV Epithelial Ovary, Fallopian Tube, or Primary Peritoneal Carcinoma: A Practice Guideline.

BACKGROUND: This study aims to provide guidance for the use of neoadjuvant and adjuvant systemic therapy in women with newly diagnosed stage II-IV epithelial ovary, fallopian tube, or primary peritoneal carcinoma. METHODS: EMBASE, MEDLINE, and Cochrane Library were investigated for relevant systematic reviews and phase III trials. Articles focusing on consolidation and maintenance therapies were excluded. RESULTS: For women with potentially resectable disease, primary cytoreductive surgery, followed by six to eight cycles of intravenous three-weekly paclitaxel and carboplatin is recommended. For those with a high-risk profile for primary cytoreductive surgery, neoadjuvant chemotherapy can be an option. Adjuvant chemotherapy with six cycles of dose-dense weekly paclitaxel plus three-weekly carboplatin can be considered for women of Japanese descent. In women with stage III or IV disease, the incorporation of bevacizumab concurrent with paclitaxel and carboplatin is not recommended for use as adjuvant therapy unless bevacizumab is continued as maintenance therapy. Intravenous paclitaxel plus intraperitoneal cisplatin and paclitaxel can be considered for stage III optimally debulked women who did not receive neoadjuvant chemotherapy. However, intraperitoneal administration of chemotherapy with bevacizumab should not be considered as an option for stage II-IV optimally debulked women. DISCUSSION: The recommendations represent a current standard of care that is feasible to implement and valued by both clinicians and patients.

The needs of gynecological cancer survivors at the end of primary treatment: A scoping review and proposed model to guide clinical discussions.

OBJECTIVE: Gynecological cancer (GC) survivors have unmet needs when they complete primary cancer treatment. Despite this, no known research has summarized these needs and survivors' suggestions to address them. We conducted a scoping review to fill these gaps and develop a model useful to guide clinical discussions and/or interventions. METHODS: English, full length, and accessible primary studies describing the needs of GC survivors were included. No restrictions on date nor country of publication were applied. Two reviewers screened and extracted data, which was verified by a third reviewer. RESULTS: Seventy-one studies met the inclusion criteria for data extraction. Results were thematically grouped into seven dimensions: physical needs, sexuality-related concerns, altered self-image, psychological wellbeing, social support needs, supporting the return to work, and healthcare challenges and preferences. After consulting with a stakeholder group (a GC survivor, clinicians, and researchers), the dimensions were summarized into a proposed model to guide clinical assessments and/or interventions. CONCLUSION: Results illuminate the diverse needs of GC survivors as they complete primary cancer treatment and their recommendations for care to meet these needs. PRACTICE IMPLICATIONS: The resulting model can be used to guide assessments, discussions and/or interventions to optimally prepare GC survivors for transition out of primary cancer treatment.

Practice Patterns and Outcomes of Novel Targeted Agents for the Treatment of ERBB2-Positive Metastatic Breast Cancer.

Importance: Clinical trials have shown that the addition of pertuzumab to trastuzumab-based chemotherapy for first-line treatment of ERBB2-positive metastatic breast cancer is associated with considerable improvement in overall survival (OS). In the second-line setting, trastuzumab emtansine (T-DM1) improves OS compared with capecitabine/lapatinib in patients previously treated with trastuzumab-based chemotherapy. However, there are few data describing long-term real-world outcomes with these agents. Objective: To describe practice patterns and outcomes associated with pertuzumab and T-DM1 in routine clinical practice. Design, Setting, and Participants: This population-based retrospective cohort study used the Ontario Cancer Registry linked to electronic treatment databases to identify all patients treated with pertuzumab and T-DM1 following reimbursement approval in Ontario, Canada, which has a single-payer public health system. Participants included women with stage IV ERBB2-positive metastatic breast cancer receiving treatment with pertuzumab for first-line metastatic indication from December 2013 through December 2017, and those treated with T-DM1 from May 2014 through December 2017. Pertuzumab and T-DM1 cohorts were analyzed separately. Data were analyzed December 2019 to December 2020. Exposures: Treatment with pertuzumab or T-DM1. Main Outcomes and Measures: The primary outcome was OS, determined using the Kaplan-Meier method. Factors associated with OS were identified using a Cox proportional hazard model. Results: The median (interquartile range [IQR]) age of the 795 women who received pertuzumab and 506 women who received T-DM1 was 57 (49-67) and 56 (48-66) years, respectively. Among the cohort of patients who received pertuzumab, the median (IQR) OS and time on treatment was 43 (16.2-unavailable) and 14 (6.0-26.2) months, respectively. In the T-DM1 cohort, the proportion of pertuzumab-naive patients decreased over time from 68 of 91 [74.7%] in 2014 to 16 of 89 [18.0%] in 2017 (P < .001). The median (IQR) OS and time on treatment was 15 (6.7-27.7) and 4 (1.4-9.0) months, respectively. Median OS was shorter for patients with prior pertuzumab treatment than in the pertuzumab-naive subgroup (12 vs 19 months; adjusted hazard ratio, 0.70; 95% CI, 0.55-0.89; P = .004). Conclusions and Relevance: In this population-based cohort study, the survival of patients treated with pertuzumab and T-DM1 in routine practice appeared inferior to results from pivotal clinical trials. Differences in outcome likely reflect differences in patient population and previous lines of therapy in routine practice. Further work is needed to understand the effectiveness of T-DM1 after pertuzumab exposure.

Neoadjuvant and adjuvant systemic therapy for newly diagnosed stage II- IV epithelial ovary, fallopian tube, or primary peritoneal carcinoma: A systematic review.

BACKGROUND: To systematically review neoadjuvant and adjuvant therapy options for women with newly diagnosed stage II-IV ovarian cancer. METHODS: Phase III trials were searched using MEDLINE, EMBASE, and Cochrane Library. Maintenance therapies were excluded. RESULTS: Thirty-three trials were included. For women with high-risk profiles that would contraindicate upfront cytoreductive surgery, neoadjuvant chemotherapy can be an option. In the post-surgical adjuvant setting, the three-weekly regimen consisting of paclitaxel and carboplatin remains the standard of care. Docetaxel may be offered to those who are unable to tolerate paclitaxel. Intraperitoneal cisplatin and paclitaxel increased OS for stage III optimally debulked women (GOG 172). The intraperitoneal regimens in GOG 252 offered no survival benefit and some harms in terms of toxicity and quality of life. CONCLUSIONS: There is no evidence to support adding a third agent to the standard carboplatin and paclitaxel. Results of the iPocc study will clarify the role of intraperitoneal chemotherapy.

Influence of the competing risk of death on estimates of disease recurrence in trials of adjuvant endocrine therapy for early-stage breast cancer: A secondary analysis of MA.27, MA.17 and MA.17R.

BACKGROUND: Many women diagnosed with early-stage hormone-sensitive breast cancer die of causes other than their breast cancer. These competing risks can create challenges in analysing and clearly communicating data on risk of breast cancer recurrence or death. Here, we quantify the impact of competing risks on estimates of disease recurrence and benefit from therapy. PATIENTS AND METHODS: Using data from the MA.27, MA.17 and MA.17R trials of adjuvant endocrine therapy in early breast cancer, we compared Kaplan-Meier (KM) and competing risk methods for disease-free survival (DFS) and distant recurrence-free survival (DRFS). Each trial was analysed separately. In KM analyses, participants were censored at the time of non-breast cancer death. Competing risk analyses comprised cumulative incidence functions in which non-breast cancer death was a competing risk. RESULTS: Non-breast cancer deaths were observed more often in older participants, in those with lower risk of breast cancer and after longer follow-up. Compared with conventional analyses, estimates of the proportion of participants with DFS or DRFS events were lower in competing risk analyses, with this difference increasing over the course of follow-up. The absolute treatment benefit was similar or modestly lower in competing risk analyses. CONCLUSION: Compared with KM methods, competing risk analyses result in lower estimates of DFS and DRFS events and similar or modestly lower absolute benefit from experimental endocrine therapy. Over a long time horizon, competing risk methods may be preferable to KM methods when estimating future risk of recurrence in early-stage hormone-sensitive breast cancer. CLINICAL TRIALS REGISTRATION: Clinicaltrials.gov; NCT00003140, NCT00754845, NCT00066573.

The Voices of Young Women with Breast Cancer: Providing Support and Information for Improved Fertility Preservation Discussions.

Purpose: Fertility is a concern for young women with breast cancer. We explore patient experiences with fertility discussions at diagnosis to identify barriers and preferences to patient-centered delivery of care. Methods: A qualitative study was conducted on consecutive, female breast cancer survivors, 39 years of age or younger at diagnosis and within 2 years of diagnosis, who attended routine outpatient follow-up at a large academic teaching center. Interviews lasted 30 minutes and were transcribed verbatim. Thematic analysis was conducted to explore experiences around fertility discussions. Strength of the theme was determined by examining the frequency of a response. Data collection and analysis continued until theoretical saturation was reached. Results: Analysis comprised 50 women with a median age of 34.5 years (range 25-39 years). Thirty-nine women (78%) had completed university education. Thirty-three women (66%) recalled having fertility preservation discussions at diagnosis. The most common themes identified include the following: (i) the requirement for more patient support, (ii) improving information, (iii) integration of patient values, (iv) creating options for patients, (v) financial limitations, and (vi) the need to look beyond the immediate impact. Conclusions: In this contemporary cohort of young adult breast cancer survivors, fertility discussion experiences at diagnosis remain suboptimal. Improved information and a focus on individual patient desires can improve experiences.

The role of niraparib for the treatment of ovarian cancer.

Epithelial ovarian cancer (EOC) remains a leading cause of cancer death in women. Approximately 10-15% of patients with EOC harbor a genetic predisposition due to mutations in BRCA1/2 genes. In the recurrent setting, prolonging time to platinum-resistance may improve progression-free survival. In BRCA1/2 mutated ovarian cancer, the use of a polyadenosine diphosphate-ribose polymerase inhibitors has been studied in the maintenance and recurrent setting. In the pivotal Phase III NOVA trial, maintenance therapy post platinum response with niraparib significantly improved outcomes in all subgroups, leading to the first polyadenosine diphosphate-ribose polymerase inhibitors approval by the US FDA in this setting. In this review, we will focus on the role of niraparib in the treatment of EOC.

Perceived Barriers to Goals of Care Discussions With Patients With Advanced Cancer and Their Families in the Ambulatory Setting: A Multicenter Survey of Oncologists.

BACKGROUND: Earlier goals of care (GOC) discussions in patients with advanced cancer are associated with less aggressive end-of-life care including decreased use of medical technologies. Unfortunately, conversations often occur late in the disease trajectory when patients are acutely unwell. Here, we evaluate practitioner perspectives of patient, family, physician, and external barriers to early GOC discussions in the ambulatory oncology setting. METHODS: A previously published survey to assess barriers to GOC discussions among clinicians on inpatient medical wards was modified for the ambulatory oncology setting and distributed to oncologists from 12 centers in Ontario, Canada. Physicians were asked to rank the importance of various barriers to having GOC discussions (1 = extremely unimportant to 7 = extremely important). RESULTS: Questionnaires were completed by 30 (24%) of 127 physicians. Respondents perceived patient- and family-related factors as the most important barriers to GOC discussions. Of these, patient difficulty accepting prognosis or desire for aggressive treatment were perceived as most important. Patients' inflated expectation of treatment benefit was also considered an important barrier to discontinuing active cancer-directed therapy. While physician barriers were ranked lower than patient-related factors, clinicians' self-identified difficulty estimating prognosis and uncertainty regarding treatment benefits were also considered important. Patient's refusal for referral was the most highly rated barrier to early palliative care referral. Most respondents were nonetheless very or extremely willing to initiate (90%) or lead (87%) GOC discussions. CONCLUSION: Oncologists ranked patient- and family-related factors as the most important barriers to GOC discussions, while clinicians' self-identified difficulty estimating prognosis and uncertainty regarding treatment benefits were also considered important. Further work is required to assess patient preferences and perceptions and develop targeted interventions.

Is hormonal therapy effective in advanced endometrial cancer? A systematic review and meta-analysis.

BACKGROUND: Hormonal therapy (HT) is used commonly in the treatment of advanced endometrial cancer (EC). However, a 2010 Cochrane Review did not show a survival benefit for HT. Here, we quantify its effects and explore the influence of clinico-pathologic factors and hormone receptor (HR) status on overall response rates (ORR). METHODS: A systematic search of electronic databases identified publications of HT in advanced EC. Data from individual studies reporting ORR, median progression-free (PFS) or overall survival (OS) were weighted by individual study sample size and pooled in a meta-analysis. Outcomes of estrogen (ER) and progesterone receptor (PgR) subgroups were collected. Studies of first- and second-line HT were analyzed independently. Mixed studies were included if subgroup data based on previous HT exposure were provided. Meta-regression was performed to evaluate the influence of clinico-pathologic factors on outcomes. RESULTS: Thirty-nine studies were included, with seven providing subgroup data based on HR status. First-line HT was associated with a mean ORR of 21.6% and clinical benefit rate (CBR) of 36.7%. Median PFS and OS were 2.8 and 10.2months respectively. ORR was 20.4% in clinical trials and 25.3% in observational studies. Magnitude of ORR was lower in older age, adenosquamous histology and high grade. ORR was higher in ER+ (26.5%) and PgR+ (35.5%) disease, and lower in ER- (9.2%) or PgR- (12.1%) tumors. Second-line ORR was 18.5%. CBR was 35.8%, but was significantly associated with timing of stable disease assessments in first- and second-line. Meta-regression performed in mixed and second-line studies showed an association between previous HT and greater ORR (ß 0.561; p=0.024), suggesting potential confounding by indication (re-treatment of good responders to first-line HT). CONCLUSION: HT is associated with modest ORR in advanced EC, and is greatest in HR+ tumors. Response rates in second-line are likely dependent on response to previous HT.

Bone Modifier Use as Adjuvant Therapy for Early Breast Cancer.

PURPOSE OF REVIEW: Many studies have examined the effects of adjuvant bisphosphonates on long-term breast cancer outcomes. However, results have been inconsistent. Here, we review the evidence for their role in early breast cancer. RECENT FINDINGS: In a recent meta-analysis, no significant decreases in recurrence or breast cancer mortality were observed in the overall population. In postmenopausal women, statistically significant, but modest, reductions in distant recurrence were observed, driven by decreased bone recurrence. This translated to decreased breast cancer mortality. While most individual studies were not performed exclusively in postmenopausal patients and were not adequately powered to detect subgroup effects based on menopausal status, observed effects were highly consistent. Adjuvant bisphosphonates in postmenopausal women should be considered in individual cases of high-risk patients, where the absolute benefit justifies associated risks. There is no evidence supporting their routine use in premenopausal women except in selected patients receiving ovarian function suppression.

Capecitabine in early breast cancer: A meta-analysis of randomised controlled trials.

PURPOSE: Capecitabine is an effective therapy for metastatic breast cancer. Its role in early breast cancer is uncertain due to conflicting data from randomised controlled trials (RCTs). METHODS: PubMed and major conference proceedings were searched to identify RCTs comparing standard chemotherapy with or without capecitabine in the neoadjuvant or adjuvant setting. Hazard ratios (HRs) for disease-free survival (DFS) and overall survival (OS), as well as odds ratios (ORs) for toxicities were extracted or calculated and pooled in a meta-analysis. Subgroup analysis compared triple-negative breast cancer (TNBC) to non-TNBC and whether capecitabine was given in addition to or in place of standard chemotherapy. Meta-regression was used to explore the influence of TNBC on OS. RESULTS: Eight studies comprising 9302 patients were included. In unselected patients, capecitabine did not influence DFS (hazard ratio [HR] 0.99, p = 0.93) or OS (HR 0.90, p = 0.36). There was a significant difference in DFS when capecitabine was given in addition to standard treatment compared with in place of standard treatment (HR 0.92 versus 1.62, interaction p = 0.002). Addition of capecitabine to standard chemotherapy was associated with significantly improved DFS in TNBC versus non-TNBC (HR 0.72 versus 1.01, interaction p = 0.02). Meta-regression showed that adding capecitabine to standard chemotherapy was associated with improved OS in studies with higher proportions of patients with TNBC (R = -0.967, p = 0.007). Capecitabine increased grade 3/4 diarrhoea (odds ratio [OR] 2.33, p < 0.001) and hand-foot syndrome (OR 8.08, p < 0.001), and resulted in more frequent treatment discontinuation (OR 3.80, p < 0.001). CONCLUSION: Adding capecitabine to standard chemotherapy appears to improve DFS and OS in TNBC, but increases adverse events in keeping with its known toxicity profile.

Is the neutrophil-to-lymphocyte ratio prognostic of survival outcomes in gynecologic cancers? A systematic review and meta-analysis.

BACKGROUND: Presence of a high neutrophil-to-lymphocyte ratio (NLR) has been associated with increased mortality in several malignancies. Here, we quantify the effect of NLR on survival in patients with gynecologic cancers, and examine the effect of clinico-pathologic factors on its prognostic value. METHODS: A systematic search of electronic databases was conducted to identify publications exploring the association of pre-treatment blood NLR with overall survival (OS) and event-free survival (EFS) among patients with ovarian, endometrial and cervical cancers. Data from studies reporting a hazard ratio (HR) and 95% confidence interval (CI) or a p-value (P) were weighted by generic inverse-variance and pooled in a random effects meta-analysis. Subgroup analyses were conducted according to primary tumor type. Meta-regression was performed to evaluate the influence of clinico-pathologic factors on the HR for OS and EFS. All statistical tests were two-sided. RESULTS: Twenty-six studies comprising 10,530 patients were included. Studies used different cut-offs to classify high NLR (range 0.89 to 5.03). The median cut-off for high NLR was 2.95 among twenty-six studies reporting a HR for OS, and 2.79 in seventeen studies reporting EFS outcomes. NLR greater than the cut-off was associated with worse OS (HR 1.65, 95% CI=1.44 to 1.89; P<0.001) and EFS (HR 1.57, 95% CI=1.35 to 1.82; P<0.001). This association was present in all tumor types. Most studies were comprised of patients with both early-stage and advanced disease. In cervical cancer, significant associations between NLR and OS were observed in studies of early- and mixed-stage patients and regression analysis showed a greater magnitude of effect in patients with locally advanced disease and in those who received both chemotherapy and radiation. CONCLUSIONS: High NLR is associated with an adverse OS and EFS in patients with gynecologic malignancies.

Cardiovascular toxicity of angiogenesis inhibitors in treatment of malignancy: A systematic review and meta-analysis.

BACKGROUND: The cardiovascular risk of angiogenesis inhibitors is not well-quantified. We hypothesized that, compared to direct vascular endothelial growth factor (VEGF) inhibitors (anti-VEGF antibodies or decoy receptors), small molecule agents have higher risk due to their less specific mechanism. METHODS: We searched the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials for phase III randomised controlled trials comparing angiogenesis inhibitor-based therapy to other systemic therapy. Outcomes evaluated were hypertension, severe hypertension, cardiac dysfunction, congestive heart failure, cardiac ischemia, arterial thromboembolism, venous thromboembolism, and fatal cardiovascular events. Data were pooled using Mantel-Haenszel random effects method to generate odds ratios (OR). RESULTS: We identified 77 studies meeting inclusion criteria. Compared to routine care, angiogenesis inhibitors were associated with a higher risk of hypertension (OR 5.28 [4.53-6.15], number needed to harm [NNH] 6), severe hypertension (OR 5.59 [4.67-6.69], NNH 17), cardiac ischemia (OR 2.83 [1.72-4.65], NNH 85) and cardiac dysfunction (OR 1.35 [1.06-1.70], NNH 139). VEGF inhibitors were associated with an increased risk of arterial thromboembolism (OR 1.52 [1.17-1.98], NNH 141). No significant interaction was observed between the two drug subgroups for any outcomes. We identified no significant increase in the risk of the other outcomes evaluated. CONCLUSION: Angiogenesis inhibitors increase the risk of hypertension, arterial thromboembolism, cardiac ischemia and cardiac dysfunction. There was no significant difference in cardiovascular risk between direct VEGF inhibitors and small molecule agents.

Prognostic role of neutrophil-to-lymphocyte ratio in breast cancer: a systematic review and meta-analysis.

BACKGROUND: The presence of a high neutrophil-to-lymphocyte ratio (NLR) has been associated with increased mortality in several malignancies. Here, we quantify the effect of NLR on survival in patients with breast cancer, and examine the effect of clinicopathologic factors on its prognostic value. METHODS: A systematic search of electronic databases was conducted to identify publications exploring the association of blood NLR (measured pre treatment) and overall survival (OS) and disease-free survival (DFS) among patients with breast cancer. Data from studies reporting a hazard ratio (HR) and 95% confidence interval (CI) or a P value were pooled in a meta-analysis. Pooled HRs were computed and weighted using generic inverse variance. Meta-regression was performed to evaluate the influence of clinicopathologic factors such as age, disease stage, tumor grade, nodal involvement, receptor status, and NLR cutoff on the HR for OS and DFS. All statistical tests were two-sided. RESULTS: Fifteen studies comprising a total of 8563 patients were included. The studies used different cutoff values to classify high NLR (range 1.9-5.0). The median cutoff value for high NLR used in these studies was 3.0 amongst 13 studies reporting a HR for OS, and 2.5 in 10 studies reporting DFS outcomes. NLR greater than the cutoff value was associated with worse OS (HR 2.56, 95% CI = 1.96-3.35; P < 0.001) and DFS (HR 1.74, 95% CI = 1.47-2.07; P < 0.001). This association was similar in studies including only early-stage disease and those comprising patients with both early-stage and metastatic disease. Estrogen receptor (ER) and HER-2 appeared to modify the effect of NLR on DFS, because NLR had greater prognostic value for DFS in ER-negative and HER2-negative breast cancer. No subgroup showed an influence on the association between NLR and OS. CONCLUSIONS: High NLR is associated with an adverse OS and DFS in patients with breast cancer with a greater effect on disease-specific outcome in ER and HER2-negative disease. NLR is an easily accessible prognostic marker, and its addition to established risk prediction models warrants further investigation.

The Role of the 21-Gene Recurrence Score in Breast Cancer Treatment.

Several multi-gene assays have been developed to predict the risk of recurrence in patients with estrogen receptor-positive early breast cancer and in whom endocrine therapy is planned. The 21-gene assay is widely used and its prognostic value has been retrospectively validated, showing significant differences in the risk of distant recurrence for patients at high versus low risk. Its role in predicting chemotherapy benefit has also been established, showing a clear benefit for high-risk patients and minimal benefit in those at low risk. These findings have been prospectively investigated in TAILORx (Trial Assigning Individualized Options for Treatment), where available data from the low-risk cohort confirms the prognostic value of this diagnostic test. The prognostic utility of the 21-gene assay increases when combined with clinicopathologic variables, and data from integrated models suggest that its use should be limited to patients with tumor characteristics suggestive of potential chemotherapy benefit. Furthermore, the 21-gene assay has been shown to impact clinical decision making in a cost-effective manner, although direct evidence of benefit from modified treatment recommendations is yet to be proven. The prognostic value of this test has also been shown in populations with node-positive or locally advanced disease treated with neoadjuvant chemotherapy, and ongoing trials aim to prospectively validate these findings.