p4EBP1 staining predicts outcome in ER-positive endocrine-resistant metastatic breast cancer patients treated with everolimus and exemestane.

BACKGROUND: To identify patients most likely to respond to everolimus, a mammalian target of rapamycin (mTOR) inhibitor, a prospective biomarker study was conducted in hormone receptor-positive endocrine-resistant metastatic breast cancer patients treated with exemestane-everolimus therapy. METHODS: Metastatic tumor biopsies were processed for immunohistochemical staining (p4EBP1, PTEN, pAKT, LKB1, and pS6K). ESR1, PIK3CA and AKT1 gene mutations were detected by NGS. The primary endpoint was the association between the p4EBP1 expression and clinical benefit rate (CBR) at 6 months of everolimus plus exemestane treatment. RESULTS: Of 150 patients included, 107 were evaluable for the primary endpoint. p4EBP1 staining above the median (Allred score ≥6) was associated with a higher CBR at 6 months (62% versus 40% in high-p4EBP1 versus low-p4EBP1, χ2 test, p = 0.026) and a longer progression-free survival (PFS) (median PFS of 9.2 versus 5.8 months in high-p4EBP1 versus low-p4EBP1; p = 0.02). When tested with other biomarkers, only p4EBP1 remained a significant predictive marker of PFS in multivariate analysis (hazard ratio, 0.591; p = 0.01). CONCLUSIONS: This study identified a subset of patients with hormone receptor-positive endocrine-resistant metastatic breast cancer and poor outcome who would derive less benefit from everolimus and exemestane. p4EBP1 may be a useful predictive biomarker in routine clinical practice. CLINICAL TRIAL REGISTRATION: NCT02444390.

A phase III randomized trial of weight loss to reduce cancer-related fatigue among overweight and obese breast cancer patients: MEDEA Study design.

BACKGROUND: Elevated body mass index (BMI) represents a risk factor for cancer-related fatigue (CRF). Weight loss interventions are feasible and safe in cancer survivors, leading to improved cardio-metabolic and quality of life (QOL) outcomes and modulating inflammatory biomarkers. Randomized data are lacking showing that a lifestyle intervention aimed at weight loss, combining improved diet, exercise, and motivational counseling, reduces CRF. Motivating to Exercise and Diet, and Educating to healthy behaviors After breast cancer (MEDEA) is a multi-center, randomized controlled trial evaluating the impact of weight loss on CRF in overweight or obese survivors of breast cancer. Herein, we described the MEDEA methodology. METHODS: Patients (N = 220) with stage I-III breast cancer and BMI ≥ 25 kg/m2, within 12 months of primary treatment, and able to walk ≥ 400 m are eligible to enroll. Participants are randomized 1:1 to health education alone vs. a personalized telephone-based weight loss intervention plus health education. Both arms receive a health education program focusing on healthy living. Patients in the intervention arm are paired with an individual lifestyle coach, who delivers the intervention through 24 semi-structured telephone calls over 1 year. Intervention goals include weight loss ≥ 10% of baseline, caloric restriction of 500-1000 Kcal/day, and increased physical activity (PA) to 150 (initial phase) and 225-300 min/week (maintenance phase). The intervention is based on the social cognitive theory and is adapted from the Breast Cancer Weight Loss trial (BWEL, A011401). The primary endpoint is the difference in self-reported CRF (EORTC QLQ-C30) between arms. Secondary endpoints include the following: QOL (EORTC QLQ-C30, -BR45, -FA12), anxiety, and depression (HADS); weight and BMI, dietary habits and quality, PA, and sleep; health care costs (hospital-admissions, all-drug consumption, sick leaves) and cost-effectiveness (cost per quality-adjusted life-year); and patient motivation and satisfaction. The primary analysis of MEDEA will compare self-reported CRF at 12 months post-randomization between arms, with 80.0% power (two-sided α = 0.05) to detect a standardized effect size of 0.40. DISCUSSION: MEDEA will test the impact of a weight loss intervention on CRF among overweight or obese BC survivors, potentially providing additional management strategies and contributing to establish weight loss support as a new standard of clinical care. TRIAL REGISTRATION: ClinicalTrials.gov NCT04304924.

Dynamics of Long-Term Patient-Reported Quality of Life and Health Behaviors After Adjuvant Breast Cancer Chemotherapy.

PURPOSE: We aimed to characterize long-term quality of life (QOL) trajectories among patients with breast cancer treated with adjuvant chemotherapy and to identify related patterns of health behaviors. METHODS: Female stage I-III breast cancer patients receiving chemotherapy in CANTO (CANcer TOxicity; ClinicalTrials.gov identifier: NCT01993498) were included. Trajectories of QOL (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 Summary Score) and associations with trajectory group membership were identified by iterative estimations of group-based trajectory models and multivariable multinomial logistic regression, respectively. RESULTS: Four trajectory groups were identified (N = 4,131): excellent (51.7%), very good (31.7%), deteriorating (10.0%), and poor (6.6%) QOL. The deteriorating trajectory group reported fairly good baseline QOL (mean [95% CI], 78.3/100 [76.2 to 80.5]), which significantly worsened at year-1 (58.1/100 [56.4 to 59.9]) and never recovered to pretreatment values through year-4 (61.1/100 [59.0 to 63.3]) postdiagnosis. Healthy behaviors were associated with better performing trajectory groups. Obesity (adjusted odds ratio [aOR] v lean, 1.51 [95% CI, 1.28 to 1.79]; P < .0001) and current smoking (aOR v never, 1.52 [95% CI, 1.27 to 1.82]; P < .0001) at diagnosis were associated with membership to the deteriorating group, which was also characterized by a higher prevalence of patients with excess body weight and insufficient physical activity through year-4 and by frequent exposure to tobacco smoking during chemotherapy. Additional factors associated with membership to the deteriorating group included younger age (aOR, 1-year decrement 1.01 [95% CI, 1.01 to 1.02]; P = .043), comorbidities (aOR v no, 1.22 [95% CI, 1.06 to 1.40]; P = .005), lower income (aOR v wealthier households, 1.21 [95% CI, 1.07 to 1.37]; P = .002), and endocrine therapy (aOR v no, 1.14 [95% CI, 1.01 to 1.30]; P = .047). CONCLUSION: This latent-class analysis identified some patients with upfront poor QOL and a high-risk cluster with severe, persistent postchemotherapy QOL deterioration. Screening relevant patient-level characteristics may inform tailored interventions to mitigate the detrimental impact of chemotherapy and preserve QOL, including early addressal of behavioral concerns and provision of healthy lifestyle support programs.

Long-Term Longitudinal Patterns of Patient-Reported Fatigue After Breast Cancer: A Group-Based Trajectory Analysis.

PURPOSE: Fatigue is recognized as one of the most burdensome and long-lasting adverse effects of cancer and cancer treatment. We aimed to characterize long-term fatigue trajectories among breast cancer survivors. METHODS: We performed a detailed longitudinal analysis of fatigue using a large ongoing national prospective clinical study (CANcer TOxicity, ClinicalTrials.gov identifier: NCT01993498) of patients with stage I-III breast cancer treated from 2012 to 2015. Fatigue was assessed at diagnosis and year 1, 2, and 4 postdiagnosis. Baseline clinical, sociodemographic, behavioral, tumor-related, and treatment-related characteristics were available. Trajectories of fatigue and risk factors of trajectory-group membership were identified by iterative estimates of group-based trajectory models. RESULTS: Three trajectory groups were identified for severe global fatigue (n = 4,173). Twenty-one percent of patients were in the high-risk group, having risk estimates of severe global fatigue of 94.8% (95% CI, 86.6 to 100.0) at diagnosis and 64.6% (95% CI, 59.2 to 70.1) at year 4; 19% of patients clustered in the deteriorating group with risk estimates of severe global fatigue of 13.8% (95% CI, 6.7 to 20.9) at diagnosis and 64.5% (95% CI, 57.3 to 71.8) at year 4; 60% were in the low-risk group with risk estimates of 3.6% (95% CI, 2.5 to 4.7) at diagnosis and 9.6% (95% CI, 7.5 to 11.7) at year 4. The distinct dimensions of fatigue clustered in different trajectory groups than those identified by severe global fatigue, being differentially affected by sociodemographic, clinical, and treatment-related factors. CONCLUSION: Our findings highlight the multidimensional nature of cancer-related fatigue and the complexity of its risk factors. This study helps to identify patients with increased risk of severe fatigue and to inform personalized interventions to ameliorate this problem.

Wound healing and catheter thrombosis after implantable venous access device placement in 266 breast cancers treated with bevacizumab therapy.

The aim of this study was to determine, in a population with metastatic breast cancer treated with bevacizumab therapy, the incidence of wound dehiscence after placement of an implantable venous access device (VAD) and to study the risk of catheter thrombosis. This study enrolled all VADs placed by 14 anesthetists between 1 January 2007 and 31 December 2009: 273 VADs in patients treated with bevacizumab therapy and 4196 VADs in patients not treated with bevacizumab therapy. In the bevacizumab therapy group, 13 cases of wound dehiscence occurred in 12 patients requiring removal of the VAD (4.76%). All cases of dehiscence occurred when bevacizumab therapy was initiated less than 7 days after VAD placement. Bevacizumab therapy was initiated less than 7 days after VAD placement in 150 cases (13 of 150: 8.6%). The risk of dehiscence was the same from 0 to 7 days. In parallel, the VAD wound dehiscence rate in patients not receiving bevacizumab therapy was eight of 4197 cases (0.19%) (Fisher's test significant, P<0.001). No risk factors of dehiscence were identified: anesthetists, learning curves, and irradiated patients. VAD thrombosis occurred in four patients (1.5%). In parallel, VAD thrombosis occurred in 51 of 4197 patients (1.2%) not receiving bevacizumab therapy (Fisher's test not significant; P=0.43). Bevacizumab therapy was permanently discontinued in five patients related to wound dehiscence and in one patient due to extensive skin necrosis. These data suggest the need to observe an interval of at least 7 days between VAD placement and initiation of bevacizumab therapy to avoid the risk of a wound dehiscence requiring chest wall port explant. The risk of VAD thrombosis does not require any particular primary prevention.

A genomic and transcriptomic approach for a differential diagnosis between primary and secondary ovarian carcinomas in patients with a previous history of breast cancer.

BACKGROUND: The distinction between primary and secondary ovarian tumors may be challenging for pathologists. The purpose of the present work was to develop genomic and transcriptomic tools to further refine the pathological diagnosis of ovarian tumors after a previous history of breast cancer. METHODS: Sixteen paired breast-ovary tumors from patients with a former diagnosis of breast cancer were collected. The genomic profiles of paired tumors were analyzed using the Affymetrix GeneChip Mapping 50 K Xba Array or Genome-Wide Human SNP Array 6.0 (for one pair), and the data were normalized with ITALICS (ITerative and Alternative normaLIzation and Copy number calling for affymetrix Snp arrays) algorithm or Partek Genomic Suite, respectively. The transcriptome of paired samples was analyzed using Affymetrix GeneChip Human Genome U133 Plus 2.0 Arrays, and the data were normalized with gc-Robust Multi-array Average (gcRMA) algorithm. A hierarchical clustering of these samples was performed, combined with a dataset of well-identified primary and secondary ovarian tumors. RESULTS: In 12 of the 16 paired tumors analyzed, the comparison of genomic profiles confirmed the pathological diagnosis of primary ovarian tumor (n = 5) or metastasis of breast cancer (n = 7). Among four cases with uncertain pathological diagnosis, genomic profiles were clearly distinct between the ovarian and breast tumors in two pairs, thus indicating primary ovarian carcinomas, and showed common patterns in the two others, indicating metastases from breast cancer. In all pairs, the result of the transcriptomic analysis was concordant with that of the genomic analysis. CONCLUSIONS: In patients with ovarian carcinoma and a previous history of breast cancer, SNP array analysis can be used to distinguish primary and secondary ovarian tumors. Transcriptomic analysis may be used when primary breast tissue specimen is not available.

Onapristone Extended Release: Safety Evaluation from Phase I-II Studies with an Emphasis on Hepatotoxicity.

INTRODUCTION: Antiprogestins have demonstrated promising activity against breast and gynecological cancers, but liver-related safety concerns limited the advancement of this therapeutic class. Onapristone is a full progesterone receptor antagonist originally developed as an oral contraceptive and later evaluated in phase II studies for metastatic breast cancer. Because of liver enzyme elevations identified during clinical studies, further development was halted. Evaluation of antiprogestin pharmacology and pharmacokinetic data suggested that liver enzyme elevations might be related to off-target or metabolic effects associated with clinical drug exposure. OBJECTIVE: We explored whether the use of a pharmaceutic strategy targeting efficacious systemic dose concentrations, but with diminished peak serum concentrations and/or total drug exposure would mitigate hepatotoxicity. Twice-daily dosing of an extended-release formulation of onapristone was developed and clinically evaluated in light of renewed interest in antiprogestin therapy for treating progesterone receptor-positive breast and gynecologic cancers. The hepatotoxic potential of extended-release onapristone was assessed from two phase I-II studies involving patients with breast, ovarian, endometrial, and prostate cancer. RESULTS: Among the 88 patients in two phase I-II studies in progesterone receptor-positive malignancies treated with extended-release onapristone, elevated alanine aminotransferase/aspartate aminotransferase levels were found in 20% of patients with liver metastases compared with 6.3% without metastases. Of five patients with grade 3 or higher alanine aminotransferase elevations with or without bilirubin elevations (four with breast cancer and one with endometrial cancer), four were assessed as unrelated to extended-release onapristone by the safety data review committee. Furthermore, while the fifth patient's liver enzyme elevations were considered possibly drug related by the study investigator, they were adjudicated as unlikely to be related (< 25% likelihood) by a subsequent independent hepatologist. CONCLUSIONS: These results suggest that the extended-release formulation by reducing drug exposure may be associated with a reduced risk of hepatotoxicity, and supports the continued clinical evaluation of extended-release onapristone for treating progesterone receptor-positive cancers.

Changes in weight, physical and psychosocial patient-reported outcomes among obese women receiving treatment for early-stage breast cancer: A nationwide clinical study.

BACKGROUND: Evidence on how weight loss correlates to health-related quality-of-life (HRQOL) among obese breast cancer (BC) patients is limited. We aimed to evaluate associations between weight changes and HRQOL. METHODS: We included 993 obese women with stage I-II-III BC from CANTO, a multicenter, prospective cohort collecting longitudinal, objectively-assessed anthropometric measures and HRQOL data (NCT01993498). Associations between weight changes (±5% between diagnosis and post-treatment [shortly after completion of surgery, adjuvant chemo- or radiation-therapy]) and patient-reported HRQOL (EORTC QLQ-C30/B23) were comprehensively evaluated. Changes in HRQOL and odds of severely impaired HRQOL were assessed using multivariable generalized estimating equations and logistic regression, respectively. RESULTS: 14.1% women gained weight, 67.3% remained stable and 18.6% lost weight. Significant decreases in functional status and exacerbation of symptoms were observed overall post-treatment. Compared to gaining weight or remaining stable, obese women who lost weight experienced less of a decline in HRQOL, reporting better physical function (mean change [95%CI] for gain, stability and loss: -12.9 [-16.5,-9.3], -6.9 [-8.2,-5.5] and -6.2 [-8.7,-3.7]; pinteraction[weight-change-by-time] = 0.006), less dyspnea (+18.9 [+12.3,+25.6], +9.2 [+6.5,+11.9] and +3.2 [-1.0,+7.3]; pinteraction = 0.0003), and fewer breast symptoms (+22.1 [+16.8,+27.3], +18.0 [+15.7,+20.3] and +13.4 [+9.0,+17.2]; pinteraction = 0.044). Weight loss was also significantly associated with reduced odds of severe pain compared with weight gain (OR [95%CI] = 0.51 [0.31-0.86], p = 0.011) or stability (OR [95%CI] = 0.62 [0.41-0.95], p = 0.029). No associations between weight loss and worsening of other physical or psychosocial parameters were found. CONCLUSIONS: This large contemporary study suggests that weight loss among obese BC patients during early survivorship was associated with better patient-reported outcomes, without evidence of worsened functionality or symptomatology in any domain of HRQOL.

Serum Detection of Nonadherence to Adjuvant Tamoxifen and Breast Cancer Recurrence Risk.

PURPOSE: Nonadherence to long-term treatments is often under-recognized by physicians and there is no gold standard for its assessment. In breast cancer, nonadherence to tamoxifen therapy after surgery constitutes a major obstacle to optimal outcomes. We sought to evaluate the rate of biochemical nonadherence to adjuvant tamoxifen using serum assessment and to examine its effects on short-term, distant disease-free survival (DDFS). PATIENTS AND METHODS: We studied 1,177 premenopausal women enrolled in a large prospective study (CANTO/NCT01993498). Definition of biochemical nonadherence was based on a tamoxifen serum level < 60 ng/mL, assessed 1 year after prescription. Self-reported nonadherence to tamoxifen therapy was collected at the same time through semistructured interviews. Survival analyses were conducted using an inverse probability weighted Cox proportional hazards model, using a propensity score based on age, staging, surgery, chemotherapy, and center size. RESULTS: Serum assessment of tamoxifen identified 16.0% of patients (n = 188) below the set adherence threshold. Patient-reported rate of nonadherence was lower (12.3%). Of 188 patients who did not adhere to the tamoxifen prescription, 55% self-reported adherence to tamoxifen. After a median follow-up of 24.2 months since tamoxifen serum assessment, patients who were biochemically nonadherent had significantly shorter DDFS (for distant recurrence or death, adjusted hazard ratio, 2.31; 95% CI, 1.05 to 5.06; P = .036), with 89.5% of patients alive without distant recurrence at 3 years in the nonadherent cohort versus 95.4% in the adherent cohort. CONCLUSION: Therapeutic drug monitoring may be a useful method to promptly identify patients who do not take adjuvant tamoxifen as prescribed and are at risk for poorer outcomes. Targeted interventions facilitating patient adherence are needed and have the potential to improve short-term breast cancer outcomes.

Concurrent capecitabine and whole-brain radiotherapy for treatment of brain metastases in breast cancer patients.

Preclinical data have demonstrated that ionizing radiation acts synergistically with capecitabine. This report retrospectively assessed the use of capecitabine concurrently with whole-brain radiotherapy (WBRT) in patients with brain metastases from breast cancer. From January 2003 to March 2005, five breast cancer patients with brain metastases were referred for WBRT with concurrent capecitabine. Median age was 44 years (range: 38-53). The median dose of capecitabine was 1,000 mg/m(2) twice daily for 14 days (day1-14). Treatment cycles were repeated every 21 days, concurrently with WBRT (30 Gy, 3 Gy per fraction, 5 days per week). Median survival after starting WBRT plus capecitabine was 6.5 months (range 1-34 months). One patient achieved a complete response. Two patients achieved partial response, including one with local control lasting until most recent follow-up. One patient had stable disease. The remaining patient was not assessable for response because of early death. Most commonly reported adverse events were nausea (n = 2) and headache (n = 2), always grade 1. Other toxicities were grade 3 hand/foot syndrome (n = 1), moderate anemia requiring transfusion and dose reduction of capecitabine (n = 1), and grade 1 mucositis (n = 1). Although promising, these preliminary data warrant further assessment of capecitabine-based chemoradiation in brain metastases from breast cancer and need to be further validated in the setting of a clinical trial.

Assessment of the efficacy of successive endocrine therapies in hormone receptor-positive and HER2-negative metastatic breast cancer: a real-life multicentre national study.

BACKGROUND: For luminal metastatic breast cancer (MBC), endocrine therapy (ET) is the recommended initial treatment before chemotherapy. Our objective was to evaluate the efficacy of multiple ET lines in a real-life study. METHODS: The Breast Cancer Epidemiological Strategy and Medical Economics (ESME) project analysed data from all patients with systemic treatment for MBC initiated between 2008 and 2014 in one of the 18 French Comprehensive Cancer Centres. The primary end-point was the successive progression-free survival (PFS) evaluation. RESULTS: The ESME research programme included 9921 patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 (HER2) negative (HER2-) MBC. Before any chemotherapy, 4195 (43.4%), 1252 (29.8%) and 279 (6.6%) patients received one, two or three ET ± targeted therapy, respectively. The median PFS for first-, second- and third-line ET ± targeted therapy was 11.5 (95% confidence interval [CI], 10.8-12.1), 5.8 (95% CI, 5.3-6.1) and 5.5 (95% CI, 4.6-6.3) months, respectively. In a multivariate analysis, time from diagnosis to metastatic recurrence (P < 0.0001), presence of symptoms at metastatic relapse (P = 0.01), number of metastatic sites (P = 0.0003) and their localisation (P < 0.0001) were prognostic factors for PFS1. Duration of previous PFS was the only prognostic factor for subsequent PFS (10% threshold). Ten percent of the patients showed long-term response to ET, with a total treatment duration before chemotherapy ≥43.6 months. CONCLUSIONS: Median PFS in our HR+/HER2- real-life cohort is similar to median first-line PFS reported in clinical trials, regardless of ET used as second- and third-line treatment. Despite the international consensus on early initiation of ET, the latter is not prescribed in most of the cases. Patients with a low tumour burden may achieve prolonged response on ET.

Phase I study of onapristone, a type I antiprogestin, in female patients with previously treated recurrent or metastatic progesterone receptor-expressing cancers.

INTRODUCTION: Onapristone is a type I progesterone receptor (PR) antagonist, which prevents PR- mediated DNA transcription. Onapristone is active in multiple preclinical models and two prior studies demonstrated promising activity in patients with breast cancer. We conducted a study of extended release (ER) Onapristone to determine a recommended dose and explore the role of transcriptionally-activated PR (APR), detected as an aggregated subnuclear distribution pattern, as a predictive biomarker. METHODS: An open-label, multicenter, randomized, parallel-group, phase 1 study (target n = 60; NCT02052128) included female patients ≥18 years with PRpos tumors. APR analysis was performed on archival tumor tissue. Patients were randomized to five cohorts of extended release (ER) onapristone tablets 10, 20, 30, 40 or 50 mg BID, or immediate release 100 mg QD until progressive disease or intolerability. Primary endpoint was to identify the recommended phase 2 dose. Secondary endpoints included safety, clinical benefit and pharmacokinetics. RESULTS: The phase 1 dose escalation component of the study is complete (n = 52). Tumor diagnosis included: endometrial carcinoma 12; breast cancer 20; ovarian cancer 13; other 7. Median age was 64 (36-84). No dose limiting toxicity was observed with reported liver function test elevation related only to liver metastases. The RP2D was 50 mg ER BID. Median therapy duration was 8 weeks (range 2-44), and 9 patients had clinical benefit ≥24 weeks, including 2 patients with APRpos endometrial carcinoma. CONCLUSION: Clinical benefit with excellent tolerance was seen in heavily pretreated patients with endometrial, ovarian and breast cancer. The data support the development of Onapristone in endometrial endometrioid cancer. Onapristone should also be evaluated in ovarian and breast cancers along with APR immunohistochemistry validation.

[Systemic neoadjuvant therapy of luminal breast cancer in 2016]. / Les traitements médicaux néoadjuvants des cancers du sein luminaux en 2016.

Neoadjuvant systemic therapies have been extensively evaluated in luminal breast cancer. Conventional cytotoxic chemotherapy increases breast conservation rate, albeit with a low level of complete pathological response of uncertain clinical significance. Endocrine therapies allow similar clinical results with much less side effects. Biological criteria of response to endocrine therapies are still being defined. The neoadjuvant setting must be used for early development of new compounds and to further document biological mechanisms of sensitivity and resistance to treatments.

Costs associated with Eribulin treatment for patients with metastatic breast cancer in a comprehensive cancer center in France.

BACKGROUND: There is no standard recommendation for metastatic breast cancer treatment (MBC) after two chemotherapy regimens. Eribulin (Halaven®) has shown a significant improvement in overall survival (OS) in this setting. Its use may however be hampered by its cost, which is up to three times the cost of other standard drugs. We report the clinical outcomes and health care costs of a large series of consecutive MBC patients treated with Eribulin. METHODS: A monocentric retrospective study was conducted at Institut Curie over 1 year (August 2012 to August 2013). Data from patient's medical records were extracted to estimate treatment and outcome patterns, and direct medical costs until the end of treatment were measured. Factors affecting cost variability were identified by multiple linear regressions and factors linked to OS by a multivariate Cox model. RESULTS: We included 87 MBC patients. The median OS was 10.7 months (95%CI = 8.0-13.3). By multivariate Cox analysis, independent factors of poor prognosis were an Eastern Cooperative Oncology Group (ECOG) performance status of 3, a number of metastatic sites ≥ 4 and the need for hospitalization. Per-patient costs during whole treatment were €18,694 [CI 95%: 16,028-21,360], and €2581 [CI 95%: 2226-3038] per month. Eribulin administration contributed to 79% of per-patient costs. CONCLUSIONS: Innovative and expensive drugs often appear to be the main cost drivers in cancer treatment, particularly for MBC. There is an urgent need to assess clinical practice benefits.

Intra-tumor genetic heterogeneity and alternative driver genetic alterations in breast cancers with heterogeneous HER2 gene amplification.

BACKGROUND: HER2 is overexpressed and amplified in approximately 15% of invasive breast cancers, and is the molecular target and predictive marker of response to anti-HER2 agents. In a subset of these cases, heterogeneous distribution of HER2 gene amplification can be found, which creates clinically challenging scenarios. Currently, breast cancers with HER2 amplification/overexpression in just over 10% of cancer cells are considered HER2-positive for clinical purposes; however, it is unclear as to whether the HER2-negative components of such tumors would be driven by distinct genetic alterations. Here we sought to characterize the pathologic and genetic features of the HER2-positive and HER2-negative components of breast cancers with heterogeneous HER2 gene amplification and to define the repertoire of potential driver genetic alterations in the HER2-negative components of these cases. RESULTS: We separately analyzed the HER2-negative and HER2-positive components of 12 HER2 heterogeneous breast cancers using gene copy number profiling and massively parallel sequencing, and identified potential driver genetic alterations restricted to the HER2-negative cells in each case. In vitro experiments provided functional evidence to suggest that BRF2 and DSN1 overexpression/amplification, and the HER2 I767M mutation may be alterations that compensate for the lack of HER2 amplification in the HER2-negative components of HER2 heterogeneous breast cancers. CONCLUSIONS: Our results indicate that even driver genetic alterations, such as HER2 gene amplification, can be heterogeneously distributed within a cancer, and that the HER2-negative components are likely driven by genetic alterations not present in the HER2-positive components, including BRF2 and DSN1 amplification and HER2 somatic mutations.

[Brain metastases in breast cancer. Epidemiology and natural history. The Institut Curie experience]. / Métastases cérébrales dans les cancers du sein. Épidémiologie et histoire naturelle. Expérience de l'Institut Curie à travers deux études : les patientes HER2- de moins de 65 ans et les patientes de plus de 65 ans.

Breast cancer is the second cause for brain metastases. Their incidence is rising, partly due to the therapeutic improvements which alter the natural history of breast cancer. Predictive factors for brain metastases have been identified: HER2 oncogene overexpression, lack of expression of hormone receptors, young age and triple negative status. Brain metastases prognosis remains poor with a median survival shorter than 1 year, except for solitary lesions treated by surgery or radiosurgery. We have analysed two series of data from Institut Curie (Paris and Saint-Cloud). In women younger than 65 years, with HER2 negative breast carcinoma, median survival was 7.1 months. In women older than 65 years, median survival was 4 months.

High-dose adjuvant chemotherapy for breast cancer: state of the art.

To date, seven randomised trials of high-dose chemotherapy for high-risk breast cancer have been published, both in Europe and in the US. We will not comment on the discredited Bezwoda trials. The main inclusion criteria for entry into these trials was an involvement of 4 or more axillary lymph nodes. Only two of these trials showed a trend in event-free survival favouring the high-dose arm. However, many differences in the designs of the trials were observed and general conclusions cannot be drawn as yet. The number of randomised patients spanned from 78 to 885, the scheduling and the drug combination of high-dose regimens varied notably and finally the issue of the contamination of the grafts by tumour cells still needs to be correctly addressed. We certainly are only at the end of the beginning.