Search

Objective To analyze data from a large group of patients enrolled in the International Breast Cancer Study Group (IBCSG) Trial in order to provide information about the prognostic significance of medially located primary breast cancers. [ABSTRACT FROM AUTHOR]

BACKGROUND: Poly(adenosine diphosphate-ribose) polymerase inhibitors target cancers with defects in homologous recombination repair by synthetic lethality. New therapies are needed to reduce recurrence in patients with BRCA1 or BRCA2 germline mutation-associated early breast cancer. METHODS: We conducted a phase 3, double-blind, randomized trial involving patients with human epidermal growth factor receptor 2 (HER2)-negative early breast cancer with BRCA1 or BRCA2 germline pathogenic or likely pathogenic variants and high-risk clinicopathological factors who had received local treatment and neoadjuvant or adjuvant chemotherapy. Patients were randomly assigned (in a 1:1 ratio) to 1 year of oral olaparib or placebo. The primary end point was invasive disease-free survival. RESULTS: A total of 1836 patients underwent randomization. At a prespecified event-driven interim analysis with a median follow-up of 2.5 years, the 3-year invasive disease-free survival was 85.9% in the olaparib group and 77.1% in the placebo group (difference, 8.8 percentage points; 95% confidence interval [CI], 4.5 to 13.0; hazard ratio for invasive disease or death, 0.58; 99.5% CI, 0.41 to 0.82; P<0.001). The 3-year distant disease-free survival was 87.5% in the olaparib group and 80.4% in the placebo group (difference, 7.1 percentage points; 95% CI, 3.0 to 11.1; hazard ratio for distant disease or death, 0.57; 99.5% CI, 0.39 to 0.83; P<0.001). Olaparib was associated with fewer deaths than placebo (59 and 86, respectively) (hazard ratio, 0.68; 99% CI, 0.44 to 1.05; P = 0.02); however, the between-group difference was not significant at an interim-analysis boundary of a P value of less than 0.01. Safety data were consistent with known side effects of olaparib, with no excess serious adverse events or adverse events of special interest. CONCLUSIONS: Among patients with high-risk, HER2-negative early breast cancer and germline BRCA1 or BRCA2 pathogenic or likely pathogenic variants, adjuvant olaparib after completion of local treatment and neoadjuvant or adjuvant chemotherapy was associated with significantly longer survival free of invasive or distant disease than was placebo. Olaparib had limited effects on global patient-reported quality of life. (Funded by the National Cancer Institute and AstraZeneca; OlympiA ClinicalTrials.gov number, NCT02032823.). [ABSTRACT FROM AUTHOR]

Background Design, conduct, and analysis of randomized clinical trials (RCTs) with time to event end points rely on a variety of assumptions regarding event rates (hazard rates), proportionality of treatment effects (proportional hazards), and differences in intensity and type of events over time and between subgroups. Design and methods In this article, we use the experience of the recently reported Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) RCT, which enrolled 8381 patients with human epidermal growth factor 2-positive early breast cancer between June 2007 and July 2011, to highlight how routinely applied statistical assumptions can impact RCT result reporting. Results and conclusions We conclude that (i) futility stopping rules are important to protect patient safety, but stopping early for efficacy can be misleading as short-term results may not imply long-term efficacy, (ii) biologically important differences between subgroups may drive clinically different treatment effects and should be taken into account, e.g. by pre-specifying primary subgroup analyses and restricting end points to events which are known to be affected by the targeted therapies, (iii) the usual focus on the Cox model may be misleading if we do not carefully consider non-proportionality of the hazards. The results of the accelerated failure time model illustrate that giving more weight to later events (as in the log rank test) can affect conclusions, (iv) the assumption that accruing additional events will always ensure gain in power needs to be challenged. Changes in hazard rates and hazard ratios over time should be considered, and (v) required family-wise control of type 1 error ≤ 5% in clinical trials with multiple experimental arms discourages investigations designed to answer more than one question. Trial Registration clinicaltrials.gov Identifier NCT00490139. [ABSTRACT FROM AUTHOR]

Background: Late cardiotoxic effects of doxorubicin are increasingly a problem for patients who survive childhood cancer. Cardiotoxicity is often progressive, and some patients have disabling symptoms. Our objective was to identify risk factors for late cardiotoxicity. Methods: We examined echocardiograms from 120 children and adults who had received cumulative doses of 244 to 550 mg of doxorubicin per square meter of body-surface area for the treatment of acute lymphoblastic leukemia or osteogenic sarcoma in childhood, a mean of 8.1 years earlier. Measurements of blood pressure and left ventricular function, contractility (measured as the stress-velocity index), end-diastolic posterior-wall thickness, end-diastolic dimension, mass, and afterload (measured as end-systolic wall stress) were compared with sex-specific values from a cohort of 296 normal subjects. Results: All echocardiographic measurements were abnormal at follow-up a minimum of two years after the end of therapy, with more frequent and severe abnormalities in female patients. In a multivariate analysis, female sex and a higher cumulative dose of doxorubicin were associated with depressed contractility (P < or = 0.001), and there was an interaction between these two variables. Independent and significant associations were found between a higher rate of administration of doxorubicin and increased afterload (P < or = 0.001), left ventricular dilatation, and depressed left ventricular function; between a higher cumulative dose and depressed left ventricular function (P < or = 0.001); between a younger age at diagnosis and reduced left-ventricular-wall thickness and mass and increased afterload; and between a longer time since the completion of doxorubicin therapy and reduced left-ventricular-wall thickness and increased afterload (P < or = 0.001). Conclusions: Female sex and a higher rate of administration of doxorubicin were independent risk factors for cardiac abnormalities after treatment with doxorubicin for childhood cancer; the prevalence and severity of abnormalities increased with longer follow-up. [ABSTRACT FROM AUTHOR]

Background: Adjuvant therapy for early breast cancer is effective but may be toxic. Our aim was to investigate the impact of the presence, timing, and duration of adjuvant chemotherapy on patients' perceptions of their quality of life (QL).Methods: International Breast Cancer Study Group trial VI assessed adjuvant chemotherapy in 1475 premenopausal and perimenopausal patients, and trial VII assessed adjuvant tamoxifen or chemoendocrine therapy in 1212 postmenopausal patients with node-positive breast cancer. Patients were asked to complete a QL questionnaire-single-item linear analogue self-assessment scales measured physical wellbeing, mood, appetite, and perceived adjustment/coping. QL was assessed in this way at the beginning of treatment, 2 months after the start of treatment, every 3 months, and at 1 and 6 months after recurrence.Findings: Baseline QL scores decreased as the number of involved axillary nodes increased (for example, mean mood score: 66.1 for women with one positive node, 66.4 for two to four positive nodes, 61.3 for five to nine positive nodes, and 59.1 for ten or more positive nodes; p = 0.008 for trends), and were lower in patients with oestrogen-receptor-negative than in patients with oestrogen-receptor-positive tumours (61.4 vs 66.3, p = 0.0009). All treatment groups showed substantial improvement in QL scores during adjuvant therapy. Patterns of QL scores reflected presence, duration, and timing of cytotoxic treatment. Longer initial cytotoxic therapy delayed improvement in QL scores. Later cytotoxic therapy had transient adverse effects. Anticipation of future therapy also affected QL scores.Interpretation: Overall, chemotherapy had a measurable adverse effect on QL, but this effect was transient and minor compared with patients' adaptation/coping after diagnosis and surgery. This finding should encourage patients and doctors to choose appropriate adjuvant therapy with less concern for initial toxicity. [ABSTRACT FROM AUTHOR]

Background: Adjuvant tamoxifen for early breast cancer provides an improvement in relapse-free (RFS) and overall survival (OS), especially for older women. We carried out a meta-analysis to find out whether the benefit of adding chemotherapy to tamoxifen outweighs its costs in terms of toxic effects for postmenopausal patients.Methods: The meta-analysis of quality-adjusted survival was based on data from 3920 patients aged 50 years or older with node-positive breast cancer randomly assigned in nine trials that compared combination chemotherapy plus tamoxifen with tamoxifen alone. The nine trials were included in the worldwide overview conducted by the early breast cancer trialists' collaborative group (EBCTCG). The quality-adjusted time without symptoms or toxicity (Q-TWiST) method was used to provide treatment comparisons incorporating differences in quality of life associated with subjective toxic effects of treatment and symptoms of disease relapse.Findings: Within 7 years of follow-up the modest benefit of increased RFS and OS for patients who received chemotherapy just balanced the costs in terms of acute toxic side-effects. Chemotherapy-treated patients gained an average of 5.4 months of RFS and 2 months of OS (neither statistically significant), but had to receive cytotoxic treatment for between 2 and 24 months to achieve these gains. No values of preference weights for time spent undergoing chemotherapy and time after relapse gave significantly more Q-TWiST with chemotherapy plus tamoxifen than with tamoxifen alone.Interpretation: Within 7 years of follow-up, adjuvant chemoendocrine therapy did not provide more quality-adjusted survival time than tamoxifen alone for women aged 50 years or older with node-positive breast cancer. Better selection and administration of chemotherapy regimen, different scheduling of chemotherapy and tamoxifen, and appropriate use of patient and tumour characteristics may increase the therapeutic advantage of the combination. [ABSTRACT FROM AUTHOR]

Introduction Patients with isolated local and regional recurrences (ILRR) of breast cancer (BC) have a high risk of developing distant metastasis and dying from BC. We investigated the impact of chemotherapy (C) on disease-free survival (DFS) and overall survival (OS) after ILRR. Methods Patients with resected ILRR were stratified according to prior chemotherapy (yes vs. no), ER and/or PgR status of the recurrent tumor (both negative vs. either positive), and location of recurrence (breast vs. scar/chest wall vs. lymph nodes). Radiation, hormone and HER2 directed therapies were delineated in the protocol. Participants were randomly assigned to receive C or none. Multidrug C for at least 4 courses was recommended. Drug selection was at the discretion of the investigator. Slow accrual led to premature closure of the trial before achieving the planned sample size of 265. Results The trial accrued 162 patients (C, 85; control, 77) from 2002-2010. The groups were balanced in regard to the characteristics listed in the table below. At a median follow up of 4.9 years, there were 24 (28%) DFS events and 9 (11%) deaths in the C group compared with 34 (44%) DFS events and 21 (27%) deaths in the control group, corresponding to a 5-year DFS of 69% vs. 57%, [DFS HR (C/control) = 0.59, 95% CI (0.35, 0.99)], p =0.046] and a 5-year OS of 88% vs. 76%, [OS HR (C/control) = 0.41, 95% CI (0.19, 0.89)], p =0.02]. The results remained significant for both DFS and OS in multivariable Cox proportional hazards modeling controlling for ILRR location, disease-free interval, ER status and prior adjuvant chemotherapy. Adjuvant C was particularly effective for women with ER- negative ILRR: 5-year DFS 67% vs. 35%, [DFS HR (C/control) = 0.32, 95% CI (0.14, 0.73)], p =0.007] and OS 79% vs. 69%, [OS HR (C/control) = 0.43, 95% CI (0.15, 1.24)], p =0.12]. Results for the ER-positive ILRR cohort were: 5-year DFS 70% vs. 69%, [DFS HR (C/control) = 0.94, 95% CI (0.47, 1.89)], p =0.87] and OS 94% vs. 80%, [OS HR (C/control) = 0.40, 95% CI (0.12, 1.28)], p =0.12]. Conclusion Adjuvant chemotherapy should be recommended for patients with completely resected isolated loco-regional recurrences of breast cancer, in particular, if the recurrence is not sensitive to endocrine therapy. [ABSTRACT FROM AUTHOR]

Introduction: The risk of developing distant metastasis is elevated in patients (pts) who experience isolated locoregional recurrences (ILRR) after initial breast cancer treatment. Surgical resection of ILRR, radiation therapy (RT), and adjuvant hormonal therapy are common practice strategies. However, the role of chemotherapy (C) is unknown. Pts with complete excision of an ILRR were randomly assigned to C or no C. We report treatments, estrogen (ER) and progesterone receptor (PR) status in primary tumors and ILRR, incidence of second-ILRR failure events, and deaths. Methods: 162 pts were enrolled in IBCSG 27-02, BIG 1-02, NSABP B-37. RT was recommended but not required if a completion/salvage mastectomy was performed after an ipsilateral breast tumor recurrence. Hormonal therapy was required for ER+ and/or PR+ tumors and anti-HER2 therapy was given at investigator discretion. Stratification criteria were hormone receptor status of recurrence, site of recurrence (breast, mastectomy scar/chest, regional lymph nodes), and use of prior C. Results: Primary surgery was breast conserving: 98 (60%) and mastectomy: 64 (40%). Types of nodal surgery for primary cancer included sentinel node resection: 20 (12%), axillary node (AN) sampling: 37 (23%), AN dissection: 88 (54%), more extensive nodal surgery: 6 (4%), and no nodal surgery: 8 (5%). The sites of first ILRR were breast: 88 (54%), mastectomy scar/chest wall: 53 (33%), and regional lymph nodes: 21 (13%), and were similarly distributed by treatment arms. Of the 98 pts who originally had a lumpectomy, 92 (94%) received RT. Among these 92, ILRR were in-breast: 83 (90%), chest wall: 1 (1 %), and regional node: 8 (9%). Salvage mastectomy was performed in 76/98 (78%) with prior lumpectomy. Of the other 22 pts, 17 had repeat lumpectomies and 5 had AN resection. Of the 64 who originally had mastectomy, 52 (81%) recurred in the scar/chest wall, 12 (19%) in the regional nodes and 15 pts (23%) received post-mastectomy RT, 4 of whom had regional nodal recurrences. Of the 143 pts who had ER status reported for the primary tumor, 21 (15%) had a different ER status reported for the ILRR (table). PR expression was discordant in 35 (26%) of the patients with known values. Average time from surgery for ILRR to surgery for second ILRR was 1.6 yrs (range: 0.08 -4.8). The average pt age for second LRR was 58.9 yrs versus 54.6 yrs for those who developed distant failures. At median follow up of 4.9 yrs, 15 pts developed a second ILRR (10 local, 5 regional), 7 (47%) of whom have died. Of the 37 (23%) pts who developed a distant failure 19 (51%) have died. Conclusions Similar to the effect observed in distant failure rates, a second ILRR following multimodality therapy for an ILRR is a strong prognostic indicator of subsequent death in this population. [ABSTRACT FROM AUTHOR]

BACKGROUND: Disease-free survival (DFS) is often a primary endpoint of randomized trials of adjuvant therapies for breast cancer, but long-term follow-up of DFS and especially overall survival (OS) remain important. When the primary DFS results favor the experimental arm, patients (pts) assigned to the control group may select the option to crossover to receive the experimental treatment via protocol amendment. Such "selective crossover" disturbs the integrity of the randomized comparison for any efficacy endpoints that rely on further follow-up. Selective crossover, which is motivated by positive results having been observed in the current trial, is distinct from so-called "unplanned crossover," which refers to non-adherence to protocol. In this abstract, we discuss the consequences of selective crossover for trials evaluating adjuvant trastuzumab, using the HERA (HERceptin Adjuvant) trial as an example, and present a variety of alternative analysis approaches. METHODS: HERA enrolled 5102 women with HER2-positive early breast cancer who had completed all surgery and (neo)adjuvant chemotherapy to compare 1 or 2 years of trastuzumab treatment vs observation. After a positive first interim analysis at 1y median follow-up (MFU) showed that 1 year of trastuzumab significantly improved DFS vs observation [MJ Piccart-Gebhart et al; NEJM 2005], event-free patients in the observation group were offered crossover to receive trastuzumab. 885 (52%) of the 1698 pts in the observation group selectively crossed over to trastuzumab. RESULTS: Previously reported intention-to-treat (ITT) analysis of HERA at 4y MFU showed a decreasing effectiveness of trastuzumab with respect to DFS compared with those at 2y MFU [L Gianni et al, Lancet Oncol 2011; I Smith et al, Lancet 2007]. In addition, the ITT analysis of OS at 4y MFU showed little effect of trastuzumab, while the analysis artificially censoring follow-up in the observation group at the time of selective crossover showed a substantial OS advantage for trastuzumab. The dependent censored analysis of OS is clearly biased in favor of trastuzumab because data for pts who remain event-free can be censored at the time of crossover, while data for the sicker pts in the observation group (those who relapsed) cannot be censored due to crossover. The issues related to the ITT and dependent censored analyses will be reviewed and discussed. Alternative analytic approaches designed to estimate the treatment effect that would have been observed had there been no selective crossover will be presented. The methods include the inverse probability of censoring weighted (IPCW) approach, and randomization-based estimators under the accelerated failure time model. HERA data to about 8y MFU (available fall 2012) will be used to illustrate approaches. CONCLUSION: Alternative methods addressing selective crossover are required to estimate the trastuzumab effect for updated analyses of DFS and OS for HERA, and for any other large randomized trial with positive interim results. [ABSTRACT FROM AUTHOR]

Background: The SOFT and TEXT randomized phase 3 trials address two primary questions for endocrine treatment of premenopausal women with hormone receptor-positive breast cancer. 1) In combination with ovarian function suppression (OFS), does an aromatase inhibitor (exemestane, E) improve outcome compared with tamoxifen (T)? 2) Does addition of OFS to T improve outcome compared with T alone? Trial Designs: SOFT compares 5y of T to OFS+T or OFS+E. OFS can be GnRH analog (triptorelin) x 5y, oophorectomy or ovarian irradiation. Median age was 43y (11% <35y); 35% had N+ disease. Prior neo/adjuvant chemotherapy (CT) given in 53%. TEXT compares 5y of OFS+T to OFS+E. Patients were enrolled prior to CT (if planned). Median age was 43y (9% <35y); 48% had N+ disease. Adjuvant CT was planned in 60%. Major Eligibility Criteria * - Premenopausal, confirmed by estradiol levels * - ER ≥10% and/or PgR ≥10% * - Invasive early breast cancer Specific Aims: Evaluate the role of aromatase inhibitors and the addition of OFS to T in this population. Statistical Methods (amended 2011): The primary analysis will be intention-to-treat of all randomized patients. The primary endpoint, invasive disease-free survival (DFS), is defined as time from randomization to invasive local, regional, or distant relapse, contralateral breast cancer, appearance of a second non-breast malignancy, or death. DFS will be compared using a 2-sided stratified logrank test with an overall experiment-wise alpha level equal to at most 0.05. In the original protocol, anticipated 5y DFS was 67% with T alone, 74% with OFS+T, and 79.8% with OFS+E, and required a total of 396 DFS events in TEXT and 783 DFS events in SOFT to reach 80% power. Because the enrolled population had more favorable characteristics and the event rates were lower than anticipated (2%/yr vs 8%/yr), the revised analysis plan is 'time-driven' rather than 'event-driven.' The comparison of OFS+E to OFS+T across both trials (n = 4717) is planned at median follow- up (MFU) >5y. The estimated power to detect a 20%, 25%, or 30% reduction in the hazard with OFS+E vs OFS+T is 63%, 84%, and 95%, respectively. The comparison of OFS+T to T alone is planned at 5y MFU (SOFT, n=2045). The estimated power to detect a 20%, 25%, 30%, or 33.5% reduction in the hazard is 34%, 52%, 69%, and 80%, respectively. Accruals SOFT Target: 3000; Final: 3066 TEXT Target: 2639; Final: 2672 Enrollment 2003-2011; primary analyses expected late 2013/early 2014. Related Research Quality of Life (QL) component evaluates QL, menopausal symptoms and sexual impairment. TEXT Translational Research investigates patient and tumor features that may contribute to treatment effectiveness and side effects. TEXT-Bone investigates changes in bone mineral density and the role of serial serum markers of bone remodeling as predictors of bone side effects. Co-SOFT evaluates changes in cognitive function during the first year. SOFT-EST evaluates estrogen levels during the first 4y of GnRH analogue and whether there is a suboptimally estrogen-suppressed subgroup. North American Pharmacogenetics study investigates whether genetic variations that affect T and E metabolism influence efficacy. [ABSTRACT FROM AUTHOR]

Combined chemotherapy for early breast cancer with cyclophosphamide, methotrexate, and fluorouracil has low associated mortality, but related deaths were seen among women aged 65 years or older in International Breast Cancer Study Group trials. [ABSTRACT FROM AUTHOR]

Editorial. Discusses a study reported by Muss, et al, in the May 5, 1994 issue of the `New England Journal of Medicine,' which correlated responses to adjuvant chemotherapy with the expression of c-erbB-2 in biopsy specimens from 442 patients randomly selected from a larger trial.

Background: One year (yr) of trastuzumab (T) significantly improves disease-free (DFS) and overall survival (OS) in patients with HER2-positive early breast cancer (EBC) and is considered the standard of care. HERA is the only randomized trial investigating whether longer duration of T can further improve efficacy outcome. Materials and Methods: HERA (BIG 01-01) is an international, multicenter, phase III randomized trial involving 5102 women with HER2-positive EBC. Pts were randomized, after completion of primary therapy [surgery, chemotherapy and radiotherapy as indicated], to T every 3 weeks for 1 yr , 2 years (yrs), or observation. This landmark efficacy analysis compares the outcome of pts randomized to either 2 yrs or 1 yr of T who were disease-free at 1 yr after randomization (N = 1553 for 2 yrs, and N=1552 for 1 yr). The primary endpoint is DFS and secondary endpoints are OS and time to distant recurrence (TTDR). Updated efficacy analyses of the T arms vs. observation at 8-yrs of median follow-up (FU) are also presented. Results: On 12 April 2012 HERA reached the target number of 725 DFS events needed for 80% power to detect a true hazard ratio (HR) of 0.80 for the comparison of 2 yrs vs. 1 yr of T. The unadjusted HR for an event in the 2-yr vs. 1-yr T arms was 0.99 (95% CI 0.85-1.14; p = 0.86). OS in the two arms was comparable [HR=1.05 (95% CI 0.86-1.28; p = 0.63)]. TTDR results were similar . The primary cardiac endpoint* was comparable (1.0% vs. 0.8% for 2-yr and 1-yr arms, respectively), but the secondary cardiac endpoint** was higher in the 2-yr arm (7.2% vs. 4.1%). Importantly , the durable benefit in DFS and OS for both 1 yr and 2 yrs of T compared with observation remains stable at 8 yrs of median FU. Subgroup analyses including by hormone receptor status will be available for the meeting. Conclusions: These results confirm that 1 yr of adjuvant T remains the standard of care for HER2-positive EBC pts. It is also reassuring that the significant improvement in DFS and OS persists over time and that the incidence of cardiac endpoints remains low at a median FU of 8 yrs. * NYHA class III or IV, confirmed by a cardiologist, and LVEF < 50% and 10% below baseline, OR cardiac death. ** LVEF < 50% and ≥10% below baseline confirmed by repeat assessment, excluding patients with a primary cardiac endpoint. [ABSTRACT FROM AUTHOR]

Background: Invasive lobular carcinoma (ILC) is mostly hormone receptor-positive (ER+) and associated with higher risk of late relapse (> 5 years after diagnosis) when compared to invasive ductal carcinoma (IDC). In this analysis we investigate the magnitude of benefit of endocrine treatment (tamoxifen [tam] or letrozole [let]) and the patterns of relapse over time in patients with ILC (classical subtype) or IDC enrolled in the monotherapy arms of BIG 1-98 study (12-year update). Material and methods: BIG 1-98 was a randomized, phase III study that compared five years of tam or let (monotherapy arms), or their sequences in post-menopausal women with ER+ early BC. There were 4922 patients enrolled in the monotherapy arms of BIG 1-98. This analysis includes patients who had centrally-reviewed histology data (n = 4080) and classified as IDC and ILC (n = 3660). Centrally-defined ER, PgR, Ki-67 were used to defined ER+ subtypes (n = 2923). ER+ subtypes were defined as Luminal A (ER+ and/or PR+ HER2-- and Ki67<14%) or Luminal B (ER+ and/or PR+, HER2-- and Ki6714%) for both ILC and IDC. Follow-up in the tam arm was censored at the time of selective crossover for women who chose to switch to let. Results: In the IDC subset, 1436 (44%) and 1163 (36%) were classified as Luminal A and Luminal B, while in the ILC subset 237 (59%) and 87 (22%) were classified as Luminal A and Luminal B, respectively. The 5-year DFS and OS estimates (±SE) for IDC and ILC are described in the table. I n multivariate models for DFS adjusted for classic clinicopathological features, significant interactions between treatment and histology (ILC or IDC), (p = 0.01) and treatment and subgroups (Luminal B or A), (p = 0.01) were observed. The DFS HRs for let vs tam were 0.51 (95% CI, 0.33 to 0.79) for ILC Luminal A and 0.35 (95% CI, 0.21 to 0.56) for ILC Luminal B. The DFS HRs for let vs tam were 0.93 (95% CI, 0.74 to 1.77) for IDC-Luminal A and 0.64 (95% CI, 0.52 to 0.78) and IDC-Luminal B. In the models for OS, the data suggest that the effect of letrozole varies by histology (interaction p = 0.053). The OS HRs for let vs tam was 0.39 (95% CI, 0.23 to 0.68) for ILC and 0.70 (95% CI, 0.57 to 0.86) for IDC. The hazards of DFS and OS events increased between 30 and 60 months after diagnosis among ILC pts treated with tam. In contrast, comparable hazard rates were observed for ILC pts treated with let and IDC pts treated with either let or tam. Conclusions: The magnitude of benefit of adjuvant let varies by histology and ER-subgroup. Greater reduction in risk of a DFS event is noted in women with Luminal B for both IDC and ILC. There is a trend for OS favoring let in women with ILC. ILC pts treated with let have similar patterns of relapse over time when compared to IDC. The biologic underpinnings of these observations should be explored. [ABSTRACT FROM AUTHOR]

Background: Rates and risk factors of local, axillary and supraclavicular recurrences can guide patient selection and target for postmastectomy radiotherapy (PMRT). Patients and methods: Local, axillary and supraclavicular recurrences were evaluated in 8106 patients enrolled in 13 randomized trials. Patients received chemotherapy and/or endocrine therapy and mastectomy without radiotherapy. Median follow-up was 15.2 years. Results: Ten-year cumulative incidence for chest wall recurrence of >15% was seen in patients aged <40 years (16.1%), with ≥4 positive nodes (16.5%) or 0-7 uninvolved nodes (15.1%); for supraclavicular failures >10%: ≥4 positive nodes (10.2%); for axillary failures of >5%: aged <40 years (5.1%), unknown primary tumor size (5.2%), 0-7 uninvolved nodes (5.2%). In patients with 1-3 positive nodes, 10-year cumulative incidence for chest wall recurrence of >15% were age <40, peritumoral vessel invasion or 0-7 uninvolved nodes. Age, number of positive nodes and number of uninvolved nodes were significant parameters for each locoregional relapse site. Conclusion: PMRT to the chest wall and supraclavicular fossa is supported in patients with ≥4 positive nodes. With 1-3 positive nodes, chest wall PMRT may be considered in patients aged <40 years, with 0-7 uninvolved nodes or with vascular invasion. The findings do not support PMRT to the dissected axilla. [ABSTRACT FROM AUTHOR]

Background: The role of adjuvant dose-intensive chemotherapy and its efficacy according to baseline features has not yet been established. Patients and methods: Three hundred and forty-four patients were randomized to receive seven courses of standard-dose chemotherapy (SD-CT) or three cycles of dose-intensive epirubicin and cyclophosphamide (epirubicin 200 mg/m2 plus cyclophosphamide 4 mg/m2 with filgrastim and progenitor cell support). All patients were assigned tamoxifen at the completion of chemotherapy. The primary end point was disease-free survival (DFS). This paper updates the results and explores patterns of recurrence according to predicting baseline features. Results: At 8.3-years median follow-up, patients assigned DI-EC had a significantly better DFS compared with those assigned SD-CT [8-year DFS percent 47% and 37%, respectively, hazard ratio (HR) 0.76; 95% confidence interval 0.58–1.00; P = 0.05]. Only patients with estrogen receptor (ER)-positive disease benefited from the DI-EC (HR 0.61; 95% confidence interval 0.39, 0.95; P = 0.03). Conclusions: After prolonged follow-up, DI-EC significantly improved DFS, but the effect was observed only in patients with ER-positive disease, leading to the hypothesis that efficacy of DI-EC may relate to its endocrine effects. Further studies designed to confirm the importance of endocrine responsiveness in patients treated with dose-intensive chemotherapy are encouraged. [ABSTRACT FROM AUTHOR]

Background: Dual anti-human epidermal growth factor receptor 2 (HER2) blockade has improved the outcomes of patients with early and metastatic HER2-positive breast cancer. Here we present the final 10-year analysis of the ALTTO trial., Patients and Methods: The ALTTO trial (NCT00490139) is a prospective randomized, phase III, open-label, multicenter study that investigated the role of adjuvant chemotherapy and trastuzumab alone, in combination or sequentially with lapatinib. The primary endpoint was disease-free survival (DFS) and secondary endpoints included overall survival (OS), time to distant recurrence and safety., Results: Overall, 6281 patients with HER2-positive early breast cancer were included in the final efficacy analysis in three treatment groups: trastuzumab (T), lapatinib + trastuzumab (L + T) and trastuzumab followed by lapatinib (T→L). Baseline characteristics were well balanced between groups. At a median follow-up of 9.8 years, the addition of lapatinib to trastuzumab and chemotherapy did not significantly improve DFS nor OS. The 10-year DFS was 77% in T, 79% in L + T and 79% in T→L, and the 10-year OS was 87%, 89% and 89%, respectively. The incidence of any cardiac event was low and similar in the three treatment groups., Conclusions: With a longer follow-up, no significant improvement was observed in DFS in patients treated with dual anti-HER2 blockade with lapatinib + trastuzumab compared to trastuzumab alone. The 10-year survival rates for the combination group are consistent with other studies that have explored dual anti-HER2 therapy., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety., Patients and Methods: One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015., Results: With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI -0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome., Conclusion: With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Late recurrences in postmenopausal women with hormone receptor-positive breast cancers remain an important challenge. Avoidance or delayed development of resistance represents the main objective in extended endocrine therapy (ET). In animal models, resistance was reversed with restoration of circulating estrogen levels during interruption of letrozole treatment. This phase III, randomized, open-label Study of Letrozole Extension (SOLE) studied the effect of extended intermittent letrozole treatment in comparison with continuous letrozole. In parallel, the SOLE estrogen substudy (SOLE-EST) analyzed the levels of estrogen during the interruption of treatment., Patients and Methods: SOLE enrolled 4884 postmenopausal women with hormone receptor-positive, lymph node-positive, operable breast cancer between December 2007 and October 2012 and among them, 104 patients were enrolled in SOLE-EST. They must have undergone local treatment and have completed 4-6 years of adjuvant ET. Patients were randomized between continuous letrozole (2.5 mg/day orally for 5 years) and intermittent letrozole treatment (2.5 mg/day for 9 months followed by a 3-month interruption in years 1-4 and then 2.5 mg/day during all of year 5)., Results: Intention-to-treat population included 4851 women in SOLE (n = 2425 in the intermittent and n = 2426 in the continuous letrozole groups) and 103 women in SOLE-EST (n = 78 in the intermittent and n = 25 in the continuous letrozole groups). After a median follow-up of 84 months, 7-year disease-free survival (DFS) was 81.4% in the intermittent group and 81.5% in the continuous group (hazard ratio: 1.03, 95% confidence interval: 0.91-1.17). Reported adverse events were similar in both groups. Circulating estrogen recovery was demonstrated within 6 weeks after the stop of letrozole treatment., Conclusions: Extended adjuvant ET by intermittent administration of letrozole did not improve DFS compared with continuous use, despite the recovery of circulating estrogen levels. The similar DFS coupled with previously reported quality-of-life advantages suggest intermittent extended treatment is a valid option for patients who require or prefer a treatment interruption., Competing Interests: Disclosure GJ reported receiving contracted research support from Novartis within the submitted work; personal fees from Daiichi Sankyo and Abbvie; non-financial support from Medimmune and Merck KGaA; personal fees and non-financial support from Lilly, Amgen, Bristol Myers Squibb (BMS), AstraZeneca; and grants, personal fees and non-financial support from Novartis, Roche, and Pfizer from outside submitted work. PK reported receiving non-financial support from PFS Genomics; and honoraria from Prelude Dx and Roche (all outside the submitted work). PN reported receiving institutional payments or non-financial support from Novartis, Pfizer, Lilly, Amgen, and Roche. ES reported receiving advisory fees and a traveling grant from Pfizer, Genomic Health, Lilly, and Novartis. CK reported receiving consulting or advisory fees from Roche, Pfizer, AstraZeneca, and Daiichi-Sankyo. SL reported receiving salary from GBG Forschungs GmbH; consulting fees (to institution) from BMS, Roche, Puma, Seattle Genetics, AstraZeneca, Novartis, Lilly, Pfizer, Daiichi, EirGenix, and Samsung; contracted research support from Austrian Breast & Colorectal Study Group, AstraZeneca, Amgen, Celgene, Daiichi, Immunomedics, NSABP Foundation, Novartis, Pfizer, and Roche. KK reported receiving honoraria from Taiho Pharmaceutical, Eisai, and Chugai Pharmaceutical. CM reported receiving honoraria from Novartis. SOR reported receiving honoraria from Novartis. TR reported receiving consulting fees/honoraria from Roche–Genentech, Novartis, Lilly, AstraZeneca, and Pfizer. GV reported receiving consulting or advisory fees from Novartis, Roche-Genentech, MSD Oncology, Pfizer, and AstraZeneca. RDG reported receiving research funding (to institution) from Novartis, Pfizer, Ipsen, Merck, Celgene, Ferring, Roche, and AstraZeneca to partially support his salary. SL reported receiving research funding (to institution) from Novartis, BMS, Merck, Roche–Genentech, Puma Biotechnology, Pfizer, Eli Lilly, Nektar Therapeutics, AstraZeneca, and Seattle Genetics; serving as a consultant (not compensated) for Seattle Genetics, Pfizer, Novartis, BMS, Merck, AstraZeneca, and Roche–Genentech; serving as a consultant (paid to institution) for Aduro Biotech, Novartis, GlaxoSmithKline, Roche–Genentech, Puma Biotechnology, AstraZeneca, Silverback Therapeutics, and G1 Therapeutics; serving as a Scientific Advisory Board Member of Akamara Therapeutics; and receiving support from the National Breast Cancer Foundation of Australia Endowed Chair and the Breast Cancer Research Foundation, New York. MMR reported receiving research funding (to institution) from Novartis, Pfizer, AstraZeneca, Ipsen, TerSera, Pierre Fabre, Merck, Roche, BMS, and Bayer, consulting fees (to institution) from BMS, Ipsen; and consulting fees/honoraria from BMS, Tolmar Pharmaceuticals. MC reported receiving research funding (to institution) from Roche. All other authors have declared no conflicts of interest., (Copyright © 2021 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Background: Recent breast cancer treatment guidelines recommend that higher-risk premenopausal patients should receive ovarian function suppression (OFS) as part of adjuvant endocrine therapy. If chemotherapy is also given, it is uncertain whether to select concurrent or sequential OFS initiation., Design and Methods: We analyzed 1872 patients enrolled in the randomized phase III TEXT and SOFT trials who received adjuvant chemotherapy for hormone receptor-positive, HER2-negative breast cancer and upon randomization to an OFS-containing adjuvant endocrine therapy, initiated gonadotropin-releasing-hormone-agonist triptorelin. Breast cancer-free interval (BCFI) was compared between patients who received OFS concurrently with chemotherapy in TEXT (n = 1242) versus sequentially post-chemotherapy in SOFT (n = 630). Because timing of trial enrollment relative to adjuvant chemotherapy differed, we implemented landmark analysis re-defining BCFI beginning 1 year after final dose of chemotherapy (median, 15.5 and 8.1 months from enrollment to landmark in TEXT and SOFT, respectively). As a non-randomized treatment comparison, we implemented comparative-effectiveness propensity score methodology with weighted Cox modeling., Results: Distributions of several clinico-pathologic characteristics differed between groups. Patients who were premenopausal post-chemotherapy in SOFT were younger on average. The median duration of adjuvant chemotherapy was 18 weeks in both groups. There were 231 (12%) BC events after post-landmark median follow-up of about 5 years. Concurrent use of triptorelin with chemotherapy was not associated with a significant difference in post-landmark BCFI compared with sequential triptorelin post-chemotherapy, either in the overall population (HR = 1.11, 95% CI 0.72-1.72; P = 0.72; 4-year BCFI 89% in both groups), or in the subgroup of 692 women <40 years at diagnosis (HR = 1.13, 95% CI 0.69-1.84) who are less likely to develop chemotherapy-induced amenorrhea., Conclusion: Based on comparative-effectiveness modeling of TEXT and SOFT after about 5 years median follow-up, with limited statistical power especially for the subgroup <40 years, neither detrimental nor beneficial effect of concurrent administration of OFS with chemotherapy on the efficacy of adjuvant therapy that includes chemotherapy was detected., Clinicaltrials.gov: NCT00066690 and NCT00066703., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: We investigated the outcomes of postmenopausal women with hormone receptor-positive, early breast cancer with special histotypes (mucinous, tubular, or cribriform) enrolled in the monotherapy cohort of the BIG 1-98 trial., Patients and Methods: The intention-to-treat BIG 1-98 monotherapy cohort (5 years of therapy with tamoxifen or letrozole) included 4922 women, of whom 4091 had central pathology review. Histotype groups were defined as: mucinous (N = 100), tubular/cribriform (N = 83), ductal (N = 3257), and other (N = 651). Of 183 women with either mucinous or tubular/cribriform tumors, 96 were randomly assigned to letrozole and 87 to tamoxifen. Outcomes assessed were disease-free survival (DFS), overall survival (OS), breast cancer-free interval (BCFI), and distant recurrence-free interval (DRFI). Median follow-up in the analytic cohort was 8.1 years., Results: Women with tubular/cribriform breast cancer had the best outcomes for all end points compared with the other three histotypes, and had less breast cancer recurrence (97.5% 5-year BCFI) than those with mucinous (93.5%), ductal (88.9%), or other (89.9%) histotypes. Patients with mucinous or tubular/cribriform carcinoma had better DRFI (5-year rates 97.8% and 98.8%, respectively) than those with ductal (90.9%) or other (92.1%) carcinomas. Within the subgroup of women with special histotypes, we observed a nonsignificant increase in the hazard of breast cancer recurrence with letrozole [hazard (letrozole versus tamoxifen): 3.31, 95% confidence interval 0.94-11.7; P = 0.06]., Conclusions: Women with mucinous or tubular/cribriform breast cancer have better outcomes than those with other histotypes, although the observation is based on a limited number of events. In postmenopausal women with these histotypes, the magnitude of the letrozole advantage compared with tamoxifen may not be as large in patients with mucinous or tubular/cribriform disease., Clinicaltrialsgov: NCT00004205., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The 14th St Gallen International Breast Cancer Conference (2015) reviewed substantial new evidence on locoregional and systemic therapies for early breast cancer. Further experience has supported the adequacy of tumor margins defined as 'no ink on invasive tumor or DCIS' and the safety of omitting axillary dissection in specific cohorts. Radiotherapy trials support irradiation of regional nodes in node-positive disease. Considering subdivisions within luminal disease, the Panel was more concerned with indications for the use of specific therapies, rather than surrogate identification of intrinsic subtypes as measured by multiparameter molecular tests. For the treatment of HER2-positive disease in patients with node-negative cancers up to 1 cm, the Panel endorsed a simplified regimen comprising paclitaxel and trastuzumab without anthracycline as adjuvant therapy. For premenopausal patients with endocrine responsive disease, the Panel endorsed the role of ovarian function suppression with either tamoxifen or exemestane for patients at higher risk. The Panel noted the value of an LHRH agonist given during chemotherapy for premenopausal women with ER-negative disease in protecting against premature ovarian failure and preserving fertility. The Panel noted increasing evidence for the prognostic value of commonly used multiparameter molecular markers, some of which also carried prognostic information for late relapse. The Panel noted that the results of such tests, where available, were frequently used to assist decisions about the inclusion of cytotoxic chemotherapy in the treatment of patients with luminal disease, but noted that threshold values had not been established for this purpose for any of these tests. Multiparameter molecular assays are expensive and therefore unavailable in much of the world. The majority of new breast cancer cases and breast cancer deaths now occur in less developed regions of the world. In these areas, less expensive pathology tests may provide valuable information. The Panel recommendations on treatment are not intended to apply to all patients, but rather to establish norms appropriate for the majority. Again, economic considerations may require that less expensive and only marginally less effective therapies may be necessary in less resourced areas. Panel recommendations do not imply unanimous agreement among Panel members. Indeed, very few of the 200 questions received 100% agreement from the Panel. In the text below, wording is intended to convey the strength of Panel support for each recommendation, while details of Panel voting on each question are available in supplementary Appendix S2, available at Annals of Oncology online., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)