The association of isolated tumor cells and micrometastases in regional lymph nodes with the clinical outcome of breast cancer is unclear.
We identified all patients in The Netherlands who underwent ...a sentinel-node biopsy for breast cancer before 2006 and had breast cancer with favorable primary-tumor characteristics and isolated tumor cells or micrometastases in the regional lymph nodes. Patients with node-negative disease were randomly selected from the years 2000 and 2001. The primary end point was disease-free survival.
We identified 856 patients with node-negative disease who had not received systemic adjuvant therapy (the node-negative, no-adjuvant-therapy cohort), 856 patients with isolated tumor cells or micrometastases who had not received systemic adjuvant therapy (the node-positive, no-adjuvant-therapy cohort), and 995 patients with isolated tumor cells or micrometastases who had received such treatment (the node-positive, adjuvant-therapy cohort). The median follow-up was 5.1 years. The adjusted hazard ratio for disease events among patients with isolated tumor cells who did not receive systemic therapy, as compared with women with node-negative disease, was 1.50 (95% confidence interval CI, 1.15 to 1.94); among patients with micrometastases, the adjusted hazard ratio was 1.56 (95% CI, 1.15 to 2.13). Among patients with isolated tumor cells or micrometastases, the adjusted hazard ratio was 0.57 (95% CI, 0.45 to 0.73) in the node-positive, adjuvant-therapy cohort, as compared with the node-positive, no-adjuvant-therapy cohort.
Isolated tumor cells or micrometastases in regional lymph nodes were associated with a reduced 5-year rate of disease-free survival among women with favorable early-stage breast cancer who did not receive adjuvant therapy. In patients with isolated tumor cells or micrometastases who received adjuvant therapy, disease-free survival was improved.
Abstract Context Cancer pain has a severe impact on quality of life and is associated with numerous psychosocial responses. Recent studies suggest that treatment of cancer pain has improved during ...the last decade. Objectives The aim of this review was to examine the present status of pain prevalence and pain severity in patients with cancer. Methods A systematic search of the literature published between September 2005 and January 2014 was performed using the databases PubMed, Medline, Embase, CINAHL, and Cochrane. Articles in English or Dutch that reported on the prevalence of cancer pain in an adult population were included. Titles and abstracts were screened by two authors independently, after which full texts were evaluated and assessed on methodological quality. Study details and pain characteristics were extracted from the articles with adequate study quality. Prevalence rates were pooled with meta-analysis; meta-regression was performed to explore determinants of pain prevalence. Results Of 4117 titles, 122 studies were selected for the meta-analyses on pain (117 studies, n = 63,533) and pain severity (52 studies, n = 32,261). Pain prevalence rates were 39.3% after curative treatment; 55.0% during anticancer treatment; and 66.4% in advanced, metastatic, or terminal disease. Moderate to severe pain (numerical rating scale score ≥5) was reported by 38.0% of all patients. Conclusion Despite increased attention on assessment and management, pain continues to be a prevalent symptom in patients with cancer. In the upcoming decade, we need to overcome barriers toward effective pain treatment and develop and implement interventions to optimally manage pain in patients with cancer.
Activation of the PI3K/AKT/mTOR pathway occurs frequently in breast cancer that is resistant to endocrine therapy. Approved mTOR inhibitors effectively inhibit cell growth and proliferation but ...elicit AKT phosphorylation via a feedback activation pathway, potentially leading to resistance to mTOR inhibitors. We evaluated the efficacy and safety of buparlisib plus fulvestrant in patients with advanced breast cancer who were pretreated with endocrine therapy and mTOR inhibitors.
BELLE-3 was a randomised, double-blind, placebo-controlled, multicentre, phase 3 study. Postmenopausal women aged 18 years or older with histologically or cytologically confirmed hormone-receptor-positive, HER2-negative, locally advanced or metastatic breast cancer, who had relapsed on or after endocrine therapy and mTOR inhibitors, were recruited from 200 trial centres in 22 countries. Eligible patients were randomly assigned (2:1) via interactive response technology (block size of six) to receive oral buparlisib (100 mg per day) or matching placebo starting on day 1 of cycle 1, plus intramuscular fulvestrant (500 mg) on days 1 and 15 of cycle 1 and on day 1 of subsequent 28-day cycles. Randomisation was stratified by visceral disease status. The primary endpoint was progression-free survival by local investigator assessment as per the Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 in the full analysis population (all randomised patients, by intention-to-treat). Safety was analysed in all patients who received at least one dose of treatment and at least one post-baseline safety assessment. This study is registered with ClinicalTrials.gov, number NCT01633060, and is ongoing but no longer enrolling patients.
Between Jan 15, 2013, and March 31, 2016, 432 patients were randomly assigned to the buparlisib (n=289) or placebo (n=143) groups. Median progression-free survival was significantly longer in the buparlisib versus placebo group (3·9 months 95% CI 2·8–4·2 vs 1·8 months 1·5–2·8; hazard ratio HR 0·67, 95% CI 0·53–0·84, one-sided p=0·00030). The most frequent grade 3–4 adverse events in the buparlisib versus placebo group were elevated alanine aminotransferase (63 22% of 288 patients vs four 3% of 140), elevated aspartate aminotransferase (51 18% vs four 3%), hyperglycaemia (35 12% vs none), hypertension (16 6% vs six 4%), and fatigue (ten 3% vs two 1%). Serious adverse events were reported in 64 (22%) of 288 patients in the buparlisib group versus 23 (16%) of 140 in the placebo group; the most frequent serious adverse events (affecting ≥2% of patients) were elevated aspartate aminotransferase (six 2% vs none), dyspnoea (six 2% vs one 1%), and pleural effusion (six 2% vs none). On-treatment deaths occurred in ten (3%) of 288 patients in the buparlisib group and in six (4%) of 140 in the placebo group; most deaths were due to metastatic breast cancer, and two were considered treatment-related (cardiac failure n=1 in the buparlisib group and unknown reason n=1 in the placebo group).
The safety profile of buparlisib plus fulvestrant does not support its further development in this setting. Nonetheless, the efficacy of buparlisib supports the rationale for the use of PI3K inhibitors plus endocrine therapy in patients with PIK3CA mutations.
Novartis Pharmaceuticals Corporation.
Contrary to the situation in early breast cancer, little is known about the prognostic relevance of the hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) in metastatic breast ...cancer. The objectives of this study were to present survival estimates and to determine the prognostic impact of breast cancer subtypes based on HR and HER2 status in a recent cohort of metastatic breast cancer patients, which is representative of current clinical practice. Patients diagnosed with metastatic breast cancer between 2007 and 2009 were included. Information regarding patient and tumor characteristics and treatment was collected. Patients were categorized in four subtypes based on the HR and HER2 status of the primary tumor: HR positive (+)/HER2 negative (−), HR+/HER2+, HR−/HER2+ and triple negative (TN). Survival was estimated using the Kaplan–Meier method. Cox proportional hazards model was used to determine the prognostic impact of breast cancer subtype, adjusted for possible confounders. Median follow-up was 21.8 months for the 815 metastatic breast cancer patients included; 66 % of patients had the HR+/HER2− subtype, 8 % the HR−/HER2+ subtype, 15 % the TN subtype and 11 % the HR+/HER2+ subtype. The longest survival was observed for the HR+/HER2+ subtype (median 34.4 months), compared to 24.8 months for the HR+/HER2− subtype, 19.8 months for the HR−/HER2+ subtype and 8.8 months for the TN subtype (
P
< 0.0001). In the multivariate analysis, subtype was an independent prognostic factor, as were initial site of metastases and metastatic-free interval. The HR+/HER2+ subtype was associated with the longest survival after diagnosis of distant metastases.
Background
The Khorana score is a validated tool to identify cancer patients at higher risk of venous thromboembolism (VTE).
Objective
We compared its predictive performance to that of the clinical ...PROTECHT and the polygenic 5‐SNP scores in patients who participated in the Dutch CPCT‐02 study.
Patients/methods
Data on VTE and its risk factors were retrospectively collected for 2729 patients with advanced stage solid tumors planned for systemic cancer treatment. Patients were followed for 6 months. Overall discriminatory performance of the scores was evaluated by time‐dependent c‐indices. The scores were additionally evaluated dichotomously in competing risk models.
Results
A total of 160 (5.9%) patients developed VTE during follow‐up. Time‐dependent c‐indices at 6 months for the Khorana, PROTECHT, and 5‐SNP scores were 0.57 (95% confidence interval CI: 0.55–0.60), 0.60 (95% CI: 0.57–0.62), and 0.54 (95% CI: 0.51–0.57), respectively. The dichotomous scores classified 9.6%, 16.8%, and 9.5% as high‐risk, respectively. VTE risk was about 2‐fold higher among high‐risk patients than low‐risk patients for the Khorana (subdistribution hazard ratio SHR 1.9, 95% CI: 1.3–3.0), PROTECHT (SHR 2.1, 95% CI: 1.5–3.0), and 5‐SNP scores (SHR 1.7, 95% CI: 1.03–2.8). The sensitivity at 6 months was 16.6% (95% CI: 10.5–22.7), 28.9% (95% CI: 21.5–36.3), and 14.9% (95% CI: 8.5‐21.2), respectively.
Conclusions
Performance of the PROTECHT or 5‐SNP score was not superior to that of the Khorana score. The majority of cancer patients who developed VTE during 6‐month follow‐up were not identified by these scores. Future directions for studies on cancer‐associated VTE prediction may include combined clinical‐genetic scores.
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.
We determined the characteristics and prognosis of interval breast cancers (IC) at screen-film (SFM) and full-field digital (FFDM) screening mammography. The study population consisted of 417,746 ...consecutive screening mammograms (302,699 SFM screens and 115,047 FFDM screens), obtained between 2000 and 2011. During 2-year follow-up, we collected breast imaging reports, surgical reports, and pathology results. A total of 800 ICs had been diagnosed in the screened population, of which 288 detected in the first year (early ICs) and 512 in the second year (late ICs) after a negative screen. 31.3 % of early IC’s and 19.1 % of late IC’s, respectively, were visible in retrospect on the latest previous screens, but had been missed during screening (
P
< 0.001). Missed invasive ICs were larger (28.5 mm vs. 23.9 mm,
P
= 0.003) and showed a higher fraction of T3+cancers (16.9 vs. 8.5 %,
P
= 0.02) than true ICs (i.e., not visible at the latest screen). A higher portion of missed than true ICs underwent mastectomy (44.7 vs. 30.8 %,
P
= 0.002). We found no differences in mammographic and tumor characteristics for early ICs, detected either after SFM or FFDM. Late ICs following FFDM were more often true ICs than missed ICs (69.0 vs. 57.6 %,
P
= 0.03) and more often receptor triple negative (
P
= 0.02), compared to late ICs at SFM. Interval cancer subgroups showed comparable overall survival. Interval cancer subgroups show distinctive mammographic and tumor characteristics but a comparable overall survival.
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