Ductal carcinoma in situ (DCIS) now represents 20-25% of all 'breast cancers' consequent upon detection by population-based breast cancer screening programmes. Currently, all DCIS lesions are ...treated, and treatment comprises either mastectomy or breast-conserving surgery supplemented with radiotherapy. However, most DCIS lesions remain indolent. Difficulty in discerning harmless lesions from potentially invasive ones can lead to overtreatment of this condition in many patients. To counter overtreatment and to transform clinical practice, a global, comprehensive and multidisciplinary collaboration is required. Here we review the incidence of DCIS, the perception of risk for developing invasive breast cancer, the current treatment options and the known molecular aspects of progression. Further research is needed to gain new insights for improved diagnosis and management of DCIS, and this is integrated in the PRECISION (PREvent ductal Carcinoma In Situ Invasive Overtreatment Now) initiative. This international effort will seek to determine which DCISs require treatment and prevent the consequences of overtreatment on the lives of many women affected by DCIS.
IMPORTANCE: Metformin, a biguanide commonly used to treat type 2 diabetes, has been associated with potential beneficial effects across breast cancer subtypes in observational and preclinical ...studies. OBJECTIVE: To determine whether the administration of adjuvant metformin (vs placebo) to patients with breast cancer without diabetes improves outcomes. DESIGN, SETTING, AND PARTICIPANTS: MA.32, a phase 3 randomized, placebo-controlled, double-blind trial, conducted in Canada, Switzerland, US, and UK, enrolled 3649 patients with high-risk nonmetastatic breast cancer receiving standard therapy between August 2010 and March 2013, with follow-up to October 2020. INTERVENTIONS: Patients were randomized (stratified for hormone receptor estrogen receptor and/or progesterone receptor {ER/PgR} status, positive vs negative; body mass index, ≤30 vs >30; human epidermal growth factor receptor 2 ERBB2, formerly HER2 or HER2/neu, positive vs negative; and any vs no chemotherapy) to 850 mg of oral metformin twice a day (n = 1824) or oral placebo twice a day (n = 1825) for 5 years. MAIN OUTCOMES AND MEASURES: The primary outcome was invasive disease–free survival in hormone receptor–positive breast cancer. Of the 8 secondary outcomes, overall survival, distant relapse–free survival, and breast cancer–free interval were analyzed. RESULTS: Of the 3649 randomized patients (mean age, 52.4 years; 3643 women 99.8%), all (100%) were included in analyses. After a second interim analysis, futility was declared for patients who were ER/PgR−, so the primary analysis was conducted for 2533 patients who were ER/PgR+. The median duration of follow-up in the ER/PgR+ group was 96.2 months (range, 0.2-121 months). Invasive disease–free survival events occurred in 465 patients who were ER/PgR+. The incidence rates for invasive disease–free survival events were 2.78 per 100 patient-years in the metformin group vs 2.74 per 100 patient-years in the placebo group (hazard ratio HR, 1.01; 95% CI, 0.84-1.21; P = .93), and the incidence rates for death were 1.46 per 100 patient-years in the metformin group vs 1.32 per 100 patient-years in the placebo group (HR, 1.10; 95% CI, 0.86-1.41; P = .47). Among patients who were ER/PgR−, followed up for a median of 94.1 months, incidence of invasive disease–free survival events was 3.58 vs 3.60 per 100 patient-years, respectively (HR, 1.01; 95% CI, 0.79-1.30; P = .92). None of the 3 secondary outcomes analyzed in the ER/PgR+ group had statistically significant differences. Grade 3 nonhematological toxic events occurred more frequently in patients taking metformin than in patients taking placebo (21.5% vs 17.5%, respectively, P = .003). The most common grade 3 or higher adverse events in the metformin vs placebo groups were hypertension (2.4% vs 1.9%), irregular menses (1.5% vs 1.4%), and diarrhea (1.9% vs 7.0%). CONCLUSIONS AND RELEVANCE: Among patients with high-risk operable breast cancer without diabetes, the addition of metformin vs placebo to standard breast cancer treatment did not significantly improve invasive disease–free survival. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01101438
With current advances in neoadjuvant systemic therapy (NST) and improved breast imaging, the potential of nonoperative therapy for invasive breast cancer has emerged as a viable option when utilizing ...meticulous image-guided percutaneous biopsy to document pathologic complete response. Feasibility clinical trials utilizing this approach are being performed by teams of investigators from single and multicenter/cooperative groups around the world. Imaging alone after NST lacks sufficient sensitivity and specificity in predicting pCR and therefore cannot be utilized for clinical selection of patients for omission of surgery. Imaging with adequate sampling after NST of the residual lesions (or around the remaining clip if a complete radiologic response occurs) appears to be essential in selecting patients with pCR to lower the false-negative rates based on initial reported feasibility studies to identify pCR without surgery that range from 5 to 49%. In this manuscript, recently completed, ongoing, and planned clinical feasibility trials and a new omission of surgery trial are described. Drastic rethinking of all diagnostic and therapeutic management strategies that are ordinarily utilized for patients who receive standard breast cancer surgery is required. A roadmap of essential questions and issues that will have to be resolved as the field of nonoperative breast cancer management advances is described in detail.
Deregulation of key PI3K/AKT pathway genes may contribute to endocrine resistance in breast cancer (BC). PIK3CA is the most frequently mutated gene in luminal BC (35%); however, the effect of ...mutations in helical versus kinase domains remains controversial. We hypothesize that improved outcomes occur in patients with estrogen receptor–positive (ER positive) BC receiving endocrine therapy and possessing PIK3CA mutations.
DNA was extracted from 4,540 formalin-fixed paraffin-embedded BC samples from the Exemestane Versus Tamoxifen-Exemestane pathology study. Mutational analyses were performed for 25 mutations (PIK3CAx10, AKT1x1, KRASx5, HRASx3, NRASx2 and BRAFx4).
PIK3CA mutations were frequent (39.8%), whereas RAS/RAF mutations were rare (1%). In univariable analyses PIK3CA mutations were associated with significantly improved 5-year distant relapse-free survival (DRFS; HR, 0.76; 95% CI, 0.63 to 0.91; P = .003). However, a multivariable analysis correcting for known clinical and biologic prognostic factors failed to demonstrate that PIK3CA mutation status is an independent prognostic marker for DRFS (HR, 0.92; 95% CI, 0.75 to 1.12; P = .4012). PIK3CA mutations were more frequent in low-risk luminal BCs (e.g., grade 1 nodev 3, node-negative v -positive), confounding the relationship between mutations and outcome.
PIK3CA mutations are present in approximately 40% of luminal BCs but are not an independent predictor of outcome in the context of endocrine therapy, whereas RAS/RAF mutations are rare inluminal BC. A complex relationship between low-risk cancers and PIK3CA mutations was identified. Although the PI3K/AKT pathway remains a viable therapeutic target as the result of ahigh mutation frequency, PIK3CA mutations do not seem to affect residual risk following treatment with endocrine therapy.
Previous reports identifying discordance between multiparameter tests at the individual patient level have been largely attributed to methodological shortcomings of multiple in silico studies. ...Comparisons between tests, when performed using actual diagnostic assays, have been predicted to demonstrate high degrees of concordance. OPTIMA prelim compared predicted risk stratification and subtype classification of different multiparameter tests performed directly on the same population.
Three hundred thirteen women with early breast cancer were randomized to standard (chemotherapy and endocrine therapy) or test-directed (chemotherapy if Oncotype DX recurrence score >25) treatment. Risk stratification was also determined with Prosigna (PAM50), MammaPrint, MammaTyper, NexCourse Breast (IHC4-AQUA), and conventional IHC4 (IHC4). Subtype classification was provided by Blueprint, MammaTyper, and Prosigna.
Oncotype DX predicted a higher proportion of tumors as low risk (82.1%, 95% confidence interval CI = 77.8% to 86.4%) than were predicted low/intermediate risk using Prosigna (65.5%, 95% CI = 60.1% to 70.9%), IHC4 (72.0%, 95% CI = 66.5% to 77.5%), MammaPrint (61.4%, 95% CI = 55.9% to 66.9%), or NexCourse Breast (61.6%, 95% CI = 55.8% to 67.4%). Strikingly, the five tests showed only modest agreement when dichotomizing results between high vs low/intermediate risk. Only 119 (39.4%) tumors were classified uniformly as either low/intermediate risk or high risk, and 183 (60.6%) were assigned to different risk categories by different tests, although 94 (31.1%) showed agreement between four of five tests. All three subtype tests assigned 59.5% to 62.4% of tumors to luminal A subtype, but only 121 (40.1%) were classified as luminal A by all three tests and only 58 (19.2%) were uniformly assigned as nonluminal A. Discordant subtyping was observed in 123 (40.7%) tumors.
Existing evidence on the comparative prognostic information provided by different tests suggests that current multiparameter tests provide broadly equivalent risk information for the population of women with estrogen receptor (ER)-positive breast cancers. However, for the individual patient, tests may provide differing risk categorization and subtype information.
Purpose Phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha ( PIK3CA) mutations are frequently observed in primary breast cancer. We evaluated their prognostic relevance by ...performing a pooled analysis of individual patient data. Patients and Methods Associations between PIK3CA status and clinicopathologic characteristics were tested by applying Cox regression models adjusted for age, tumor size, nodes, grade, estrogen receptor (ER) status, human epidermal growth factor receptor 2 (HER2) status, treatment, and study. Invasive disease-free survival (IDFS) was the primary end point; distant disease-free survival (DDFS) and overall survival (OS) were also assessed, overall and by breast cancer subtypes. Results Data from 10,319 patients from 19 studies were included (median OS follow-up, 6.9 years); 1,787 patients (17%) received chemotherapy, 4,036 (39%) received endocrine monotherapy, 3,583 (35%) received both, and 913 (9%) received none or their treatment was unknown. PIK3CA mutations occurred in 32% of patients, with significant associations with ER positivity, increasing age, lower grade, and smaller size (all P < .001). Prevalence of PIK3CA mutations was 18%, 22%, and 37% in the ER-negative/HER2-negative, HER2-positive, and ER-positive/HER2-negative subtypes, respectively. In univariable analysis, PIK3CA mutations were associated with better IDFS (HR, 0.77; 95% CI, 0.71 to 0.84; P < .001), with evidence for a stronger effect in the first years of follow-up (0 to 5 years: HR, 0.73; 95% CI, 0.66 to 0.81; P < .001; 5 to 10 years: HR, 0.82; 95% CI, 0.68 to 0.99; P = .037); > 10 years: (HR, 1.15; 95% CI, 0.84 to 1.58; P = .38; P heterogeneity = .02). In multivariable analysis, PIK3CA genotype remained significant for improved IDFS ( P = .043), but not for the DDFS and OS end points. Conclusion In this large pooled analysis, PIK3CA mutations were significantly associated with a better IDFS, DDFS, and OS, but had a lesser prognostic effect after adjustment for other prognostic factors.
Summary Background The role and dose of anticoagulants in thromboprophylaxis for patients with cancer receiving chemotherapy through central venous catheters (CVCs) is controversial. We therefore ...assessed whether warfarin reduces catheter-related thrombosis compared with no warfarin and whether the dose of warfarin determines the thromboprophylactic effect. Methods In 68 clinical centres in the UK, we randomly assigned 1590 patients aged at least 16 years with cancer who were receiving chemotherapy through CVCs to no warfarin, fixed-dose warfarin 1 mg per day, or dose-adjusted warfarin per day to maintain an international normalised ratio between 1·5 and 2·0. Clinicians who were certain of the benefit of warfarin randomly assigned patients to fixed-dose or dose-adjusted warfarin groups. The primary outcome was the rate of radiologically proven, symptomatic catheter-related thrombosis. Analysis was by intention to treat. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN 50312145. Findings Compared with no warfarin (n=404), warfarin (n=408; 324 79% on fixed-dose and 84 21% on dose-adjusted) did not reduce the rate of catheter-related thromboses (24 6% vs 24 6%; relative risk 0·99, 95% CI 0·57–1·72, p=0·98). However, compared with fixed-dose warfarin (n=471), dose-adjusted warfarin (n=473) was superior in the prevention of catheter-related thromboses (13 3% vs 34 7%; 0·38, 0·20–0·71, p=0·002). Major bleeding events were rare; an excess was noted with warfarin compared with no warfarin (7 vs 1, p=0·07) and with dose-adjusted warfarin compared with fixed-dose warfarin (16 vs 7, p=0·09). A combined endpoint of thromboses and major bleeding showed no difference between comparisons. We did not note a survival benefit in either comparison. Interpretation The findings show that prophylactic warfarin compared with no warfarin is not associated with a reduction in symptomatic catheter-related or other thromboses in patients with cancer and therefore we should consider newer treatments. Funding Medical Research Council and Cancer Research UK.
The Breast Cancer Index (BCI) HOXB13/IL17BR (H/I) ratio predicts benefit from extended endocrine therapy in hormone receptor-positive (HR+) early-stage breast cancer. Here, we report the final ...analysis of the Trans-aTTom study examining BCI (H/I)'s predictive performance.
BCI results were available for 2,445 aTTom trial patients. The primary endpoint of recurrence-free interval (RFI) and secondary endpoints of disease-free interval (DFI) and disease-free survival (DFS) were examined using Cox proportional hazards regression and log-rank test.
Final analysis of the overall study population (N = 2,445) did not show a significant improvement in RFI with extended tamoxifen HR, 0.90; 95% confidence interval (CI), 0.69-1.16; P = 0.401. Both the overall study population and N0 group were underpowered due to the low event rate in the N0 group. In a pre-planned analysis of the N+ subset (N = 789), BCI (H/I)-High patients derived significant benefit from extended tamoxifen (9.7% absolute benefit: HR, 0.33; 95% CI, 0.14-0.75; P = 0.016), whereas BCI (H/I)-Low patients did not (-1.2% absolute benefit; HR, 1.11; 95% CI, 0.76-1.64; P = 0.581). A significant treatment-to-biomarker interaction was demonstrated on the basis of RFI, DFI, and DFS (P = 0.037, 0.040, and 0.025, respectively). BCI (H/I)-High patients remained predictive of benefit from extended tamoxifen in the N+/HER2- subgroup (9.4% absolute benefit: HR, 0.35; 95% CI, 0.15-0.81; P = 0.047). A three-way interaction evaluating BCI (H/I), treatment, and HER2 status was not statistically significant (P = 0.849).
Novel findings demonstrate that BCI (H/I) significantly predicts benefit from extended tamoxifen in HR+ N+ patients with HER2- disease. Moreover, BCI (H/I) demonstrates significant treatment to biomarker interaction across survival outcomes.
Novel human epidermal growth factor receptor 2 (HER2)-directed antibody-drug conjugates have demonstrated efficacy in HER2-low expressing breast cancers, which are currently defined as those with ...immunohistochemistry (IHC) scores of 1+ or 2+ with a negative in situ hybridization assay. However, current HER2 testing methods are designed to identify HER2-amplified tumors with high expression levels. The true definition of HER2-low expressing breast cancers remains controversial. Using quantitative molecular analysis of breast cancers based on RNA expression, the dynamic range of HER2 expression exceeds that detected by in situ IHC approaches. Erb-B2 receptor tyrosine kinase 2 (ERBB2) mRNA expression levels across IHC groups using patient samples derived from the Tamoxifen Exemestane Adjuvant Multicenter Trial were investigated. The standardized mean differences in ERBB2 mRNA scores in log base 2 are 0.47 (95% CI, 0.36-0.57), 0.58 (95% CI, 0.26-0.70), and 0.32 (95% CI, -0.12 to 0.75) when comparing IHC 0+ without staining versus IHC 0+ with some staining, IHC 0+ with some staining versus IHC 1+, and IHC 1+ versus IHC 2+/fluorescence in situ hybridization-negative, respectively. The results showed immunohistochemical methods have a comparatively limited dynamic range for measuring HER2 protein expression. The range of expression based on RNA abundance suggests a molecular method defining HER2-low cancers may better serve the treatment decision needs of this group. Indeed, the validity of RNA abundance to identify HER2-low cancers and predict treatment response needs to be further evaluated by prospective clinical trials.
JCO
Metformin has been associated with lower cancer risk in epidemiologic and preclinical research. In the MA.32 randomized adjuvant breast cancer trial, metformin (
placebo) did not affect invasive ...disease-free or overall survival. Here, we report metformin effects on the risk of new cancer. Between 2010 and 2013, 3,649 patients with breast cancer younger than 75 years without diabetes with high-risk T1-3, N0-3 M0 breast cancer (any estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2) were randomly assigned to metformin 850 mg orally twice a day or placebo twice a day for 5 years. New primary invasive cancers (outside the ipsilateral breast) developing as a first event were identified. Time to events was described by the competing risks method; two-sided likelihood ratio tests adjusting for age, BMI, smoking, and alcohol intake were used to compare metformin versus placebo arms. A total of 184 patients developed new invasive cancers: 102 metformin and 82 placebo, hazard ratio (HR), 1.25; 95% CI, 0.94 to 1.68;
= .13. These included 48 contralateral invasive breast cancers (27 metformin
21 placebo), HR, 1.29; 95% CI, 0.72 to 2.27;
= .40 and 136 new nonbreast primary cancers (75 metformin
61 placebo), HR, 1.24; 95% CI, 0.88 to 1.74;
= .21. Metformin did not reduce the risk of new cancer development in these nondiabetic patients with breast cancer.
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