Patterns of Distant Failure by Intrinsic Breast Cancer Subtype in Premenopausal Women Treated With Neoadjuvant Chemotherapy

Purpose

To identify patterns of distant failure (DF) in premenopausal women receiving neoadjuvant chemotherapy (NAC) for breast cancer.

Incidence of Brain Metastases in Women Treated With Neoadjuvant Chemotherapy for Breast Cancer: Implications for Screening

PurposePatients with metastatic breast cancer may develop brain metastases. Our study identified high-risk patients to refine selection criteria for BM screening approaches.PatientsWe reviewed breast cancer patients treated with neoadjuvant chemotherapy (NAC) at a single university center between 2005 and 2019.MethodsCompeting risks analysis was performed with the Fine and Gray model to analyze the cumulative incidence of BM and loco-regional recurrence. Overall survival (OS) and progression-free survival (PFS) were calculated using Kaplan-Meier and log-rank tests. Multivariable analysis was performed with Cox proportional hazards regression to identify factors predictive for development of BM. Statistical significance was determined as a 2-sided P value of <.05.ResultsIn total, 112 patients experienced distant failure (DF) and 49 patients developed BM. Twenty patients with BM (41%) presented with symptoms requiring craniotomy +/- whole brain radiation treatment. Patients with BM were significantly more likely to have local (P < .01) and regional (P < .01) failure. On multivariable analysis, age <40 years (P = .011), presence of lung metastases (P < .0001), and residual nodal disease with >4 lymph nodes positive after NAC (P = .024) all predicted for increased likelihood of BM. Patients with these criteria had higher likelihoods of having BM (P = .013) and worse PFS (P = .044). On multivariable analysis for OS, presence of lung metastases was the most significant predictor of poor outcome (P < .0001).ConclusionWe propose a study of screening brain MRI for young (<40 years) patients with breast cancer receiving NAC and patients who develop metastatic disease post-NAC, especially those with lung involvement.     

Prognostic Value of Chemotherapy-Induced Amenorrhea in Breast Cancer: a Meta-Analysis

Background: There is still a great deal of controversy with regard to the prognostic role of chemotherapyinducedamenorrhea (CIA) in breast cancer patients. To confirm whether CIA can serve as a useful factor inpredicting clinical effects of systemic adjuvant chemotherapy, we performed this meta-analysis. Materials andMethods: Relevant studies were identified using PubMed, and Embase databases. Eligible study results werepooled and summary hazard ratios (HRs) with corresponding confidence intervals (CIs) were calculated. Subgroupanalyses and an assessment of publication bias were also conducted. Results: A total of 8,333 patients from 11published studies were identified through searching the databases. The pooled HRs for disease-free survival(DFS) suggested that CIA was associated with a significant reduction in the risk of recurrence, especially inpatients with hormone receptor-positive lesions (overall HR=0.65, 95%CI 0.53-0.80, I2= 41.3%). When the fivestudies reporting the HR for overall survival (OS) were pooled (n=4193), a favorable trend was found (HR=0.69,95%CI 0.52-0.91, I2= 51.6%). No publication bias was observed in this study. Conclusions: This meta-analysissuggests that CIA predicts a better outcome in premenopausal hormone receptor-positive breast cancer patients.     

Metastatic Colorectal Cancer with Severe Liver Dysfunction Successfully Treated Using FOLFOX Therapy

Introduction

The liver is the most frequent site of metastases from colorectal cancer (CRC), and extensive liver metastases often cause severe secondary liver dysfunction. However, whether chemotherapy for metastatic CRC with severe liver dysfunction offers any clinical benefit is unclear since patients in this setting are typically excluded from clinical trials.

Discussion

We report herein a case of metastatic sigmoid colon cancer with severe liver dysfunction that was successfully treated using infusional 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX). FOLFOX was effective and well tolerated in the present case, and subsequent addition of bevacizumab to FOLFOX after disease progression was similarly feasible.     

Chemotherapy-Induced Neutropenia and Outcome in Patients With Metastatic Castration-Resistant Prostate Cancer Treated With First-Line Docetaxel

Background

Neutropenia is a common side effect associated with docetaxel use. We retrospectively investigated the association between chemotherapy-induced neutropenia and survival in metastatic castration-resistant prostate cancer (mCRPC) patients receiving first-line docetaxel.

Cost-Effectiveness of Zoledronic Acid Plus Endocrine Therapy in Premenopausal Women With Hormone-Responsive Early Breast Cancer

PurposeThe aim of this study was to estimate the cost-effectiveness of adding zoledronic acid 4 mg intravenously every 6 months to endocrine therapy in premenopausal women with hormone receptor—positive early breast cancer from a US health care system perspective.Materials and MethodsA Markov model was developed to predict disease progression, mortality, and costs of breast cancer care for premenopausal women with hormone receptor—positive early breast cancer receiving up to 3 years of (1) endocrine therapy (goserelin plus tamoxifen or anastrozole); or (2) endocrine therapy plus zoledronic acid. Model parameters were obtained from ABCSG-12 (Austrian Breast and Colorectal Cancer Study Group Trial-12) and the literature. The incremental cost per quality-adjusted life year (QALY) gained with zoledronic acid was calculated under 2 scenarios: (1) benefits of zoledronic acid persist to maximum (7 years) follow-up in ABCSG-12 (“trial benefits”) or (2) benefits persist until death (“lifetime benefits”).ResultsAdding zoledronic acid to endocrine therapy was projected to yield a gain of 0.41 life years (LYs) and 0.43 QALYs assuming trial benefits and 1.34 LYs and 1.41 QALYs assuming lifetime benefits. Assuming trial benefits, the incremental cost per QALY gained with zoledronic acid was $9300. Assuming lifetime benefits, zoledronic acid was estimated to increase QALYs and reduce costs. Cost per QALY gained was ≤ $56,000 in all deterministic sensitivity analyses and was ≤ $50,000 in 94% and 97% of probabilistic sensitivity analyses for trial and lifetime benefits scenarios, respectively.ConclusionAdding zoledronic acid to endocrine therapy in premenopausal women with hormone receptor—positive early breast cancer is cost-effective from a US health care system perspective.     

Prospective Study Evaluating Changes in Bone Quality in Premenopausal Women With Breast Cancer Undergoing Adjuvant Chemotherapy

BackgroundOvarian suppression from chemotherapy results in bone loss in premenopausal women with breast cancer (BC). Less is known about bone microarchitecture changes. We used high-resolution peripheral quantitative computed tomography (HR-pQCT) to measure volumetric bone density and trabecular and cortical microarchitecture in this population.Materials and MethodsThe primary endpoint was to assess changes in cortical thickness and trabecular bone density by HR-pQCT. Premenopausal women with stage I to III BC undergoing adjuvant chemotherapy underwent a bone mineral density (BMD) dual energy x-ray absorptiometry scan and HR-pQCT (voxel size, 82 microns) at baseline and 12 months. Paired t tests were used to observe the change over time in bone microarchitecture and areal and volumetric density.ResultsEighteen patients were evaluated, of which 12 patients had baseline and matched 12-month imaging. The mean age was 45.2 years (range, 35-51 years), 17 (94%) patients had hormone receptor-positive BC, and 16 (89%) initiated tamoxifen. At 12 months, there was a significant decrease in femoral neck (P < .05) and lumbar spine and total hip (P < .01) BMD. Changes detected by HR-pQCT at 12 months included significant decreases in cortical thickness and area at the tibia (P < .05), and total and cortical volumetric BMD at the radius and tibia (P < .01), as well as an increase in tibial trabecular area (P < .05).ConclusionPremenopausal women undergoing chemotherapy experience BMD decline and trabecular and cortical bone microarchitecture deterioration. In this population, future efforts should focus on therapy-induced bone loss and optimizing bone density-related management.     

MicroRNA Signature in Metastatic Colorectal Cancer Patients Treated With Anti-EGFR Monoclonal Antibodies

BackgroundTo investigate whether microRNAs are predictive of sensitivity to anti–epidermal growth factor receptor (EGFR) monoclonal antibodies in patients with metastatic colorectal cancer (mCRC).MethodsA total of 183 mCRC cases from 2 independent cohorts (cohort 1: 74 cases; validation cohort: 109 cases) treated with cetuximab or panitumumab were included in the study. MiRNA arrays were analyzed using Agilent's miRNA platform.ResultsThe study identified the cluster Let-7c/miR-99a/miR-125b as a signature associated with an outcome different from that of anti-EGFR therapies. In the first cohort, patients with high-intensity signatures had a significantly longer progression-free survival (PFS) (6.1 vs. 2.3 mo; P = .02) and longer overall survival (OS) ( 29.8 vs. 7.0 mo, P = .08) than patients with low-intensity signatures. In the validation cohort, patients with high signature had significantly longer PFS and OS than individuals with low-intensity signatures (PFS 7.8 vs. 4.3 mo, P = .02; OS 12.8 vs. 7.5 mo, P = .02). In the KRAS wild-type population (n = 120), high-intensity signature patients had a significantly longer PFS (7.8 vs. 4.6 mo, P = .016) and longer OS (16.1 vs. 10.9 mo, P = .09) than low-signature individuals, with no difference in KRAS mutated patients.ConclusionThe MiR-99a/Let-7c/miR-125b signature may improve the selection of patients with KRAS wild-type mCRC as good candidates for anti-EGFR therapy.     

The Role of Intestinal Microbiota in Metastatic Colorectal Cancer Patients Treated With Capecitabine

BackgroundPrevious pre-clinical research has indicated that the intestinal microbiota can potentiate anti-tumour efficacy of capecitabine and that capecitabine treatment impacts intestinal microbiota composition and diversity. Using a longitudinal design, this study explores the associations between the intestinal microbiota and treatment response in patients with metastatic colorectal cancer (mCRC) during capecitabine treatment.Patients and MethodsPatients with mCRC treated with capecitabine were prospectively enrolled in a multicentre cohort study. Patients collected a faecal sample and completed a questionnaire before, during, and after three cycles of capecitabine. Several clinical characteristics, including tumour response, toxicity and antibiotic use were recorded. Intestinal microbiota were analysed by amplicon sequencing of the 16S rRNA V4 gene-region.ResultsThirty-three patients were included. After three cycles of capecitabine, six patients (18%) achieved a partial response, 25 (76%) showed stable disease, and one (3%) experienced progressive disease. Of the 90 faecal samples were collected. Microbial diversity (α-diversity), community structure (β-diversity), and bacterial abundance on phylum and genus level were not significantly different between responders and non-responders and were not significantly affected by three cycles of capecitabine.ConclusionThis is the first clinical study with longitudinal intestinal microbiota sampling in mCRC patients that explores the role of the intestinal microbiota during treatment with capecitabine. Intestinal microbiota composition and diversity before, during, and after three cycles of capecitabine were not associated with response in this study population. Capecitabine did not induce significant changes in the microbiota composition and diversity during the treatment period. Individual effects of antibiotics during capecitabine treatment were observed.     

Circulating Sex Steroids and Breast Cancer Risk in Premenopausal Women

Evidence from both laboratory and epidemiologic studies indicate a key role of hormones in the etiology of breast cancer. In epidemiologic studies, indirect data, including the consistent associations observed between reproductive factors and breast cancer risk, support an important contribution of hormones to risk. Recently, the associations between circulating hormones in premenopausal women and subsequent risk of breast cancer have been evaluated. To date, both positive and null associations have been observed for estrogens and inverse and null associations for progesterone with breast cancer risk. For estrogens, the relationships may vary by menstrual cycle phase (e.g., follicular versus luteal phase), although this requires confirmation. Few studies have evaluated estrogen metabolites in relation to breast cancer risk; hence, no conclusions can yet be drawn. Findings for the largely adrenal-derived dehydroepiandrosterone (DHEA) and DHEA sulfate also are inconsistent and may vary by age. However, relatively consistent positive associations have been observed between testosterone (or free testosterone) levels and breast cancer risk; these associations are of similar magnitude to those confirmed among postmenopausal women. In this review, we summarize current evidence and identify gaps and inconsistencies that need to be addressed in future studies of sex steroids and premenopausal breast cancer risk.     

A Phase 1B Study of Dulanermin in Combination With Modified FOLFOX6 Plus Bevacizumab in Patients With Metastatic Colorectal Cancer

ObjectivesThe study objectives were to evaluate the safety, tolerability, and preliminary efficacy of multiple doses of dulanermin in combination with modified FOLFOX6 and bevacizumab in previously untreated patients with locally advanced, recurrent, or metastatic colorectal cancer.Patients and MethodsA total of 23 patients received dulanermin at dosages of 4.5 or 9 mg/kg/d given on days 1 to 3 of each 14-day cycle along with standard dosing of modified FOLFOX6 plus bevacizumab. Dose-limiting toxicities, adverse events (AEs), maximum tolerated dose, and response according to Response Evaluation Criteria in Solid Tumors were assessed.ResultsIn the first cohort (3 patients given dulanermin at 4.5 mg/kg/d) and second cohort (6 patients given dulanermin at 9 mg/kg/day), no dose-limiting toxicities were observed. The subsequent 14 patients were treated with a dulanermin dosage of 9 mg/kg/d. Patients (N = 23) received 2 to 42 cycles of dulanermin (median 15). The most common grade 3 or 4 AEs were neutropenia (39%), hypertension (17%), peripheral neuropathy (17%), hand-foot syndrome (13%), and pulmonary embolism (13%). Three patients (13%) discontinued the study because of serious AEs. Overall, a best response of partial response was observed in 13 patients (57%) (9 confirmed, 4 unconfirmed), stable disease was observed in 7 patients (30%), and disease progression was observed in 3 patients (13%). The median progression-free survival was 9.9 months (95% confidence interval, 7.0-12.7).ConclusionsOverall, the addition of dulanermin to first-line FOLFOX plus bevacizumab was well tolerated in patients with advanced colorectal cancer, with similar AEs that would be expected from FOLFOX plus bevacizumab. A randomized study is required to assess the clinical efficacy of dulanermin in this patient population.     

Neutropenia as a Predictive Factor in Metastatic Colorectal Cancer Treated With TAS-102

Background

TAS-102 significantly improves overall survival in patients with metastatic colorectal cancer. The most common treatment-related adverse event of TAS-102 is bone marrow suppression, which leads to neutropenia. The potential predictive value of neutropenia caused by cytotoxic drugs has been reported in various types of cancer.

Duration of Signs and Survival in Premenopausal Women with Breast Cancer

CONDENSED: Among 550 women reporting a lump as the first sign of breast cancer, those with this sign for 6-29 months compared to those with 1-6 months, had bigger tumors and more frequent axillary node involvement. Overall survival, however, was not significantly different in these two groups. BACKGROUND: The relationship of delay in diagnosis of breast cancer to survival is uncertain. METHODS: We evaluated the relationship of patient-reported duration of signs of breast cancer to survival in participants in a clinical trial of adjuvant hormonal therapy in Vietnam and China. RESULTS: Among 550 women reporting a lump as the first sign of breast cancer and information on when this appeared, the median duration of this sign before diagnosis was 6 months. Comparing two groups of patients with durations of lumps 1-6 months and 6-29 months, the group with longer duration of lumps had larger tumors clinically and pathologically (p = 0.0006, and p = 0.004), more frequent axillary node involvement (p = 0.008), and shorter but not statistically different disease-free and overall survival from the time of diagnosis (p = 0.09 and 0.35, respectively). CONCLUSIONS: Breast cancer evolves slowly in the detectable period of its natural history. The impact of delays in diagnosis of less than 6 months is likely to be very limited; delays more than 6 months appear to have some, but marginal impact on survival.     

Effectiveness of Adjuvant Ovarian Function Suppression in Premenopausal Women With Early Breast Cancer: A Multicenter Cohort Study

BackgroundOvarian function suppression (OFS) with tamoxifen or aromatase inhibitors (AIs) improves disease-free survival in premenopausal women with breast cancer, mostly in those at higher risk of recurrence. However, its real-world use and impact remain poorly understood.Patients and MethodsThis is a multicenter retrospective cohort study of premenopausal women with stage I to III hormone receptor-positive breast cancer diagnosed from 2006 to 2015 that aimed to look at the uptake and effectiveness of the addition of OFS to backbone endocrine therapy (tamoxifen or AI). To deal with confounding, we used both multivariate modeling and propensity score matching.ResultsOf 1717 eligible patients, 17.1% were treated with OFS. There was a substantial increase of use of OFS over time, especially from 2014 onward (16% vs. 25% after 2014), particularly for the combination with AI (0.4% vs. 8% after 2014). In a multivariate model, only younger age and year of diagnosis ≥ 2014 were associated with OFS utilization (both P < .001). With a median follow-up of 38 months (P25-P75, 19.6-66.4 months), patients receiving OFS had a better overall survival than those not receiving OFS (adjusted hazard ratio, 0.44; 95% confidence interval, 0.19-0.96; absolute benefit at 5 years, 2.1% [95.3% vs. 93.2% in those not receiving OFS]). A similar benefit was identified using propensity score matching.ConclusionsIn the real-world setting, there was an increase in the use of OFS after 2014. After 2014, one-quarter of premenopausal women received adjuvant OFS, of which more than 30% received it in combination with an AI. In this study, the use of adjuvant OFS was associated with an overall survival benefit.     

Prognostic Effect of Adenosine-related Genetic Variants in Metastatic Colorectal Cancer Treated With Bevacizumab-based Chemotherapy

Background

Adenosine has an immunosuppressive and angiogenic modulation of the tumor microenvironment. The present study explored the efficacy of single nucleotide polymorphisms (SNPs) in adenosine-related molecules for patients with metastatic colorectal cancer treated with bevacizumab-based chemotherapy.

Cost Effectiveness Analysis of Pharmacokinetically-Guided 5-Fluorouracil in FOLFOX Chemotherapy for Metastatic Colorectal Cancer

BackgroundDosing chemotherapy based on BSA results in marked interindividual variability in drug exposure. A randomized trial showed increased OS and decreased toxicity with PK-guided compared with BSA-based 5-FU dosing in patients with mCRC. The objective of this study was to compare the cost effectiveness of PK-based 5-FU dosing with BSA-based 5-FU dosing in patients with mCRC receiving FOLFOX (5-FU, leucovorin, and oxaliplatin).Materials and MethodsWe developed a Markov model to evaluate the cost effectiveness of PK FOLFOX compared with BSA FOLFOX. Progression risks and cause-specific mortality were extrapolated from the fitted survival models. Costs for administration and management of adverse events were estimated based on 2013 Medicare reimbursement rates and average sale prices.ResultsPK FOLFOX provided 2.03 QALYs at a cost of $50,205 compared with BSA FOLFOX, which provided 1.46 QALYs at a cost of $37,173. The incremental cost-effectiveness ratio (ICER) was $22,695 per QALY. The ICER remained < $50,000 per QALY in all univariate and multivariate sensitivity analyses.ConclusionAt a $50,000 per QALY threshold, PK FOLFOX is cost effective for mCRC. Because of the cost effectiveness profile and OS advantage with PK FOLFOX, it should be evaluated further in comparative effectiveness studies.