Concomitant medication, comorbidity and survival in patients with breast cancer.

Between 30% and 70% of patients with breast cancer have pre-existing chronic conditions, and more than half are on long-term non-cancer medication at the time of diagnosis. Preliminary epidemiological evidence suggests that some non-cancer medications may affect breast cancer risk, recurrence, and survival. In this nationwide cohort study, we assessed the association between medication use at breast cancer diagnosis and survival. We included 235,368 French women with newly diagnosed non-metastatic breast cancer. In analyzes of 288 medications, we identified eight medications positively associated with either overall survival or disease-free survival: rabeprazole, alverine, atenolol, simvastatin, rosuvastatin, estriol (vaginal or transmucosal), nomegestrol, and hypromellose; and eight medications negatively associated with overall survival or disease-free survival: ferrous fumarate, prednisolone, carbimazole, pristinamycin, oxazepam, alprazolam, hydroxyzine, and mianserin. Full results are available online from an interactive platform ( https://adrenaline.curie.fr ). This resource provides hypotheses for drugs that may naturally influence breast cancer evolution.

Long Terms Follow-Up of the Randomized MetaspHER Study Comparing Intravenous Versus Subcutaneous Trastuzumab in Patients' With HER2-Positive Metastatic Breast Cancer.

INTRODUCTION: The subcutaneous (H-SC) formulation of trastuzumab was demonstrated to be as effective and safe as intravenous (H-IV) and highly preferred by patients in early breast cancer. The present randomized MetaspHER trial (NCT01810393) has been the first study assessing patient's preference in metastatic setting and we report the final analysis with long term follow-up. METHODS: Patients with HER2-positive metastatic breast cancer who completed a first line chemotherapy with trastuzumab and achieved a long terms response lasting more than 3 years were randomized to receive 3 cycles of 600 mg fixed-dose H-SC, followed by 3 cycles of standard H-IV, or the reverse sequence. The primary endpoint was overall preference for H-SC or H-IV at cycle 6 and was previously reported. Secondary endpoints included safety over 1 year of treatment and with 4 additional years follow up. Overall survival (OS) and progression free survival (PFS) were assessed in this final analysis. RESULTS: A total of 113 patients were randomized and treated and the median follow-up duration was 45.4 months (range: 0.8-48.8). After the cross over period all patients excepted 2 pursued the H-SC. During the 18 cycles overall treatment period, at least 1 adverse event (AE), 1 AE of grade ≥3, and 1 serious adverse events (SAE) were respectively reported among 104 patients (92.0%), 23 patients (20.4%), and 16 patients (14.2%), respectively. Also, 10 patients (8.9%) experienced at least 1 cardiac event, including 4 patients (3.5%) with ejection fraction decreased. Beyond cycle 18 no significant additional safety concern emerged. PFS and OS rates at months 42 were 74.8% (64.7%-82.4%) and 94.9% (88.2%-97.9%), respectively. No factor appeared related to the survival outcome excepted the complete response status at baseline. CONCLUSION: The safety was consistent with the known H-IV and H-SC profiles without any safety concern raised over a prolonged exposure to H-SC.

Contraception in breast cancer survivors from the FEERIC case-control study (performed on behalf of the Seintinelles research network).

OBJECTIVE: To compare the prevalence of contraception in breast cancer (BC) patients at risk of unintentional pregnancy (i.e. not currently pregnant or trying to get pregnant) and matched controls. STUDY DESIGN: The FEERIC study (Fertility, Pregnancy, Contraception after BC in France) is a prospective, multicenter case-control study, including localized BC patients aged 18-43 years, matched for age and parity to cancer-free volunteer controls in a 1:2 ratio. Data were collected through online questionnaires completed on the Seintinelles research platform. RESULTS: In a population of 1278 women at risk of unintentional pregnancy, the prevalence of contraception at study inclusion did not differ significantly between cases (340/431, 78.9%) and controls (666/847, 78.6%, p = 0.97). Contrarily, the contraceptive methods used were significantly different, with a higher proportion of copper IUD use in BC survivors (59.5% versus 25.0% in controls p < 0.001). For patients at risk of unintentional pregnancy, receiving information about chemotherapy-induced ovary damage at BC diagnosis (OR = 2.47 95%CI [ 1.39-4.37] and anti-HER2 treatment (OR = 2.46, 95% CI [ 1.14-6.16]) were significantly associated with the use of a contraception in multivariate analysis. CONCLUSION: In this large French study, BC survivors had a prevalence of contraception use similar to that for matched controls, though almost one in five women at risk of unintentional pregnancy did not use contraception. Dedicated consultations at cancer care centers could further improve access to information and contraception counseling.

Pregnancy, fertility concerns and fertility preservation procedures in a national study of French breast cancer survivors.

RESEARCH QUESTION: What are the real-life oncofertility practices in young women diagnosed with breast cancer? DESIGN: The FEERIC (FErtility, prEgnancy, contRaceptIon after breast Cancer in France) study is a web-based cohort study launched with the French collaborative research platform Seintinelles. The current work is based on the enrolment self-administered questionnaire of 517 patients with prior breast cancer diagnosis, free from relapse and aged 18 to 43 years at inclusion (from 12 March 2018 to 27 June 2019). RESULTS: Median age at breast cancer diagnosis was 33.6 years and 424 patients (82.0%) received chemotherapy. Overall, 236 (45.6%) patients were offered specialized oncofertility counselling, 181 patients underwent at least one fertility preservation procedure (FPP); 125 (24.2%) underwent one or more FPP with material preservation (oocytes n = 108, 20.9%; embryos n = 31, 6.0%; ovarian cryopreservation n = 6, 1.2%) and 78 patients received gonadotrophin-releasing hormone agonists (15.1%). With a median follow-up of 26.9 months after the end of treatments, 133 pregnancies had occurred in 85 patients (16.4%), including 20 unplanned pregnancies (15.0%). Most of the pregnancies were natural conceptions (n = 113, 87.6%), while 16 (12.4%) required medical interventions. For the planned pregnancies, median time to the occurrence of an ongoing pregnancy was 3 months. Patients who had an unplanned pregnancy reported lower rates of information on the consequences of the treatments on fertility (P = 0.036) at diagnosis. CONCLUSIONS: Most of the patients were not offered proper specialized oncofertility counselling at the time of breast cancer diagnosis. Naturally conceived pregnancies after breast cancer were much more frequent than pregnancies resulting from the use of cryopreserved gametes. Adequate contraceptive counselling seems as important as information about fertility and might prevent unplanned pregnancies.

Negative Relationship between Post-Treatment Stromal Tumor-Infiltrating Lymphocyte (TIL) and Survival in Triple-Negative Breast Cancer Patients Treated with Dose-Dense Dose-Intense NeoAdjuvant Chemotherapy.

Background: Patients with triple-negative breast cancers (TNBC) have a poor prognosis unless a pathological complete response (pCR) is achieved after neoadjuvant chemotherapy (NAC). Few studies have analyzed changes in TIL levels following dose-dense dose-intense (dd-di) NAC. Patients and methods: From 2009 to 2018, 117 patients with TNBC received dd-di NAC at our institution. We aimed to identify factors associated with pre- and post-NAC TIL levels, and oncological outcomes relapse-free survival (RFS), and overall survival (OS). Results: Median pre-NAC and post-NAC TIL levels were 15% and 3%, respectively. Change in TIL levels with treatment was significantly correlated with metabolic response (SUV) and pCR. High post-NAC TIL levels were associated with a weak metabolic response after two cycles of NAC, with the presence of residual disease and nodal involvement at NAC completion. In multivariate analyses, high post-NAC TIL levels independently predicted poor RFS and poor OS (HR = 1.4 per 10% increment, 95%CI (1.1; 1.9) p = 0.014 and HR = 1.8 per 10% increment 95%CI (1.3−2.3), p < 0.0001, respectively). Conclusion: Our results suggest that TNBC patients with TIL enrichment after NAC are at higher risk of relapse. These patients are potential candidates for adjuvant treatment, such as immunotherapy, in clinical trials.

Intraoperative Radiotherapy for Breast Cancer in Elderly Women.

PURPOSE: To evaluate outcomes and postoperative toxicities after intraoperative radiotherapy (IORT) in elderly women. POPULATION: Women older than 65 years, with infiltrating ductal breast cancer ≤3 cm, expressing estrogen receptor (ER+) without Her2 overexpression, and with negative axillary nodes. TREATMENT: Treatment consisted of partial mastectomy with a sentinel lymph node biopsy (SLNB) procedure; in case of positive SLNB, IORT was cancelled. IORT consisted in a total dose of 20 Gy in 1 fraction delivered at the surface of the applicator with the Intrabeam® technique. RESULTS: IORT was planned to be administered to a total of 225 patients but was cancelled for 34 patients during surgery. Thus 191 patients were analyzed; mean age was 76 years, with 57 patients (30%) >80 years. Despite inclusion criteria, 15 had lobular carcinoma and 7 were triple negative. With a median follow-up of 40 months, we observed only 1 local recurrence, located in the skin over the initial tumor. The 5-year local relapse rate was 1.7%. A wound healing delay (>15 days) was observed in 21 patients (11%). Sixty-six patients (35%) had postoperative complications, mainly grade 2, resolving within a few days. Two patients needed surgical drainage for local abscesses. Long-term (>1 year) cosmetic outcome was evaluated in 120 patients and was judged excellent or good in 102 (91%). CONCLUSION: IORT can be safely given to elderly women, with a good local control rate and without major toxicities.

[Non-genetic indications for risk reducing mastectomies: Guidelines of the National College of French Gynecologists and Obstetricians (CNGOF)]. / Indications des mastectomies de réduction de risque en dehors du risque avéré de prédisposition héréditaire : recommandations du Collège national des gynécologues et obstétriciens français (CNGOF).

OBJECTIVE: To determine the value of performing a risk-reducting mastectomy (RRM) in the absence of a deleterious variant of a breast cancer susceptibility gene, in 4 clinical situations at risk of breast cancer. DESIGN: The CNGOF Commission of Senology, composed of 26 experts, developed these recommendations. A policy of declaration and monitoring of links of interest was applied throughout the process of making the recommendations. Similarly, the development of these recommendations did not benefit from any funding from a company marketing a health product. The Commission of Senology adhered to the AGREE II (Advancing guideline development, reporting and evaluation in healthcare) criteria and followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) method to assess the quality of the evidence on which the recommendations were based. The potential drawbacks of making recommendations in the presence of poor quality or insufficient evidence were highlighted. METHODS: The Commission of Senology considered 8 questions on 4 topics, focusing on histological, familial (no identified genetic abnormality), radiological (of unrecognized cancer), and radiation (history of Hodgkin's disease) risk. For each situation, it was determined whether performing RRM compared with surveillance would decrease the risk of developing breast cancer and/or increase survival. RESULTS: The Commission of Senology synthesis and application of the GRADE method resulted in 11 recommendations, 6 with a high level of evidence (GRADE 1±) and 5 with a low level of evidence (GRADE 2±). CONCLUSION: There was significant agreement among the Commission of Senology members on recommendations to improve practice for performing or not performing RRM in the clinical setting.

Ten-Year Outcomes of Hypofractionated Postmastectomy Radiation Therapy of 26 Gy in 6 Fractions.

PURPOSE: To investigate the efficacy and long-term side effects of hypofractionated postmastectomy radiation therapy (HFRT-PM) of 26 Gy in 6 fractions over 5 weeks. METHODS AND MATERIALS: We retrospectively reviewed characteristics and outcomes of patients with stage I to III breast cancer treated with HFRT-PM between 2000 and 2009. Treatment provided 4 fractions of 4 Gy (days 1, 3, 15, 17) and then 2 fractions of 5 Gy (days 29 and 31) over 5 weeks. The treatment techniques were applied by using 3-dimensional conformal radiation therapy of the chest wall with regional nodal volume if required. RESULTS: We identified 454 patients with a median follow-up of 10.6 years (range, 0.5-22.9). Regional nodal irradiation was done in 84.1% of patients. At 10 years, the cumulative incidence of locoregional relapse was 15.1%. In multivariate analysis, regional lymph node involvement (≥4 nodes) was associated with worse locoregional control (hazard ratio, 1.68; 95% confidence interval, 1.06-2.67; P = .03) and overall survival (hazard ratio, 2.16; 95% confidence interval, 1.59-2.95; P < .001). The toxicities were acceptable. The incidence of cardiac disorders (3.3%), and symptomatic lung fibrosis (1.5%) was low during follow-up. At 10 years, the cumulative rate of arm lymphedema was 9.5% and considered severe in 20 patients (4.4%). CONCLUSIONS: The long-term results of this study show that HFRT-PM of 26 Gy in 6 fractions over 5 weeks seems safe, but locoregional recurrence seems slightly higher than that observed in the literature, highlighting the need for long-term follow-up and for randomized trials for hypofractionated radiation therapy postmastectomy.

Final results of the double-blind placebo-controlled randomized phase 2 LOTUS trial of first-line ipatasertib plus paclitaxel for inoperable locally advanced/metastatic triple-negative breast cancer.

PURPOSE: In LOTUS (NCT02162719), adding the oral AKT inhibitor ipatasertib to first-line paclitaxel for locally advanced/metastatic triple-negative breast cancer (aTNBC) improved progression-free survival (PFS; primary endpoint), with an enhanced effect in patients with PIK3CA/AKT1/PTEN-altered tumors (FoundationOne next-generation sequencing [NGS] assay). We report final overall survival (OS) results. METHODS: Eligible patients had measurable previously untreated aTNBC. Patients were stratified by prior (neo)adjuvant therapy, chemotherapy-free interval, and tumor immunohistochemistry PTEN status, and were randomized 1:1 to paclitaxel 80 mg/m2 (days 1, 8, 15) plus ipatasertib 400 mg or placebo (days 1-21) every 28 days until disease progression or unacceptable toxicity. OS (intent-to-treat [ITT], immunohistochemistry PTEN-low, and PI3K/AKT pathway-activated [NGS PIK3CA/AKT1/PTEN-altered] populations) was a secondary endpoint. RESULTS: Median follow-up was 19.0 versus 16.0 months in the ipatasertib-paclitaxel versus placebo-paclitaxel arms, respectively. In the ITT population (n = 124), median OS was numerically longer with ipatasertib-paclitaxel than placebo-paclitaxel (hazard ratio 0.80, 95% CI 0.50-1.28; median 25.8 vs 16.9 months, respectively; 1-year OS 83% vs 68%). Likewise, median OS favored ipatasertib-paclitaxel in the PTEN-low (n = 48; 23.1 vs 15.8 months; hazard ratio 0.83) and PIK3CA/AKT1/PTEN-altered (n = 42; 25.8 vs 22.1 months; hazard ratio 1.13) subgroups. The ipatasertib-paclitaxel safety profile was unchanged. CONCLUSIONS: Final OS results show a numerical trend favoring ipatasertib-paclitaxel and median OS exceeding 2 years with ipatasertib-paclitaxel. Overall, results are consistent with the reported PFS benefit; interpretation within biomarker-defined subgroups is complicated by small sample sizes and TNBC heterogeneity.

Nonpalpable breast lesions: impact of a second-opinion review at a breast unit on BI-RADS classification.

OBJECTIVE: To compare BI-RADS classification, management, and outcome of nonpalpable breast lesions assessed both by community practices and by a multidisciplinary tumor board (MTB) at a breast unit. METHODS: All nonpalpable lesions that were first assigned a BI-RADS score by community practices and then reassessed by an MTB at a single breast unit from 2009 to 2017 were retrospectively reviewed. Inter-review agreement was assessed with Cohen's kappa statistic. Changes in biopsy recommendation were calculated. The percentage of additional tumor lesions detected by the MTB was obtained. The sensitivity, AUC, and cancer rates for BI-RADS category 3, 4, and 5 lesions were computed for both reviews. RESULTS: A total of 1909 nonpalpable lesions in 1732 patients were included. For BI-RADS scores in the whole cohort, a fair agreement was found (κ = 0.40 [0.36-0.45]) between the two reviews. Agreement was higher when considering only mammography combined with ultrasound (κ = 0.53 [0.44-0.62]), masses (κ = 0.50 [0.44-0.56]), and architectural distortion (κ = 0.44 [0.11-0.78]). Changes in biopsy recommendation occurred in 589 cases (31%). Ninety of 345 additional biopsies revealed high-risk or malignant lesions. Overall, the MTB identified 27% additional high-risk and malignant lesions compared to community practices. The BI-RADS classification AUCs for detecting malignant lesions were 0.66 (0.63-0.69) for community practices and 0.76 (0.75-0.78) for the MTB (p < 0.001). CONCLUSION: Agreement between community practices and MTB reviews for BI-RADS classification in nonpalpable lesions is only fair. MTB review improves diagnostic performances of breast imaging and patient management. KEY POINTS: • The inter-review agreement for BI-RADS classification between community practices and the multidisciplinary board was only fair (κ = 0.40). • Disagreements resulted in changes of biopsy recommendation in 31% of the lesions. • The multidisciplinary board identified 27% additional high-risk and malignant lesions compared to community practices.

Prospective Multicenter Study Validate a Prediction Model for Surgery Uptake Among Women with Atypical Breast Lesions.

BACKGROUND: Diagnosis of atypical breast lesions (ABLs) leads to unnecessary surgery in 75-90% of women. We have previously developed a model including age, complete radiological target excision after biopsy, and focus size that predicts the probability of cancer at surgery. The present study aimed to validate this model in a prospective multicenter setting. - METHODS: Women with a recently diagnosed ABL on image-guided biopsy were recruited in 18 centers, before wire-guided localized excisional lumpectomy. Primary outcome was the negative predictive value (NPV) of the model. RESULTS: The NOMAT model could be used in 287 of the 300 patients included (195 with ADH). At surgery, 12 invasive (all grade 1), and 43 in situ carcinomas were identified (all ABL: 55/287, 19%; ADH only: 49/195, 25%). The area under the receiving operating characteristics curve of the model was 0.64 (95% CI 0.58-0.69) for all ABL, and 0.63 for ADH only (95% CI 0.56-0.70). For the pre-specified threshold of 20% predicted probability of cancer, NPV was 82% (77-87%) for all ABL, and 77% (95% CI 71-83%) for patients with ADH. At a 10% threshold, NPV was 89% (84-94%) for all ABL, and 85% (95% CI 78--92%) for the ADH. At this threshold, 58% of the whole ABL population (and 54% of ADH patients) could have avoided surgery with only 2 missed invasive cancers. CONCLUSION: The NOMAT model could be useful to avoid unnecessary surgery among women with ABL, including for patients with ADH. CLINICAL TRIAL REGISTRATION: NCT02523612.

Efficacy of Circulating Tumor Cell Count-Driven vs Clinician-Driven First-line Therapy Choice in Hormone Receptor-Positive, ERBB2-Negative Metastatic Breast Cancer: The STIC CTC Randomized Clinical Trial.

IMPORTANCE: The choice between chemotherapy and endocrine therapy as first-line treatment for hormone receptor-positive, ERBB2 (also known as HER2)-negative metastatic breast cancer is usually based on the presence of clinical features associated with a poor prognosis. In this setting, a high circulating tumor cell (CTC) count (≥5 CTCs/7.5 mL) is a strong adverse prognostic factor for overall survival and progression-free survival (PFS). OBJECTIVE: To compare the efficacy of a clinician-driven treatment choice vs a CTC-driven choice for first-line treatment. INTERVENTIONS: In the CTC arm, patients received chemotherapy or endocrine therapy according to the CTC count (chemotherapy if ≥5 CTCs/7.5 mL; endocrine therapy if <5 CTCs/7.5 mL), whereas in the control arm, the choice was left to the investigator. DESIGN, SETTING, AND PARTICIPANTS: In the STIC CTC randomized, open-label, noninferiority phase 3 trial, participants were randomized to a clinician-driven choice of first-line treatment or a CTC count-driven first-line treatment choice. Eligible participants were premenopausal and postmenopausal women 18 years or older diagnosed with hormone receptor-positive, ERBB2-negative metastatic breast cancer. Data were collected at 17 French cancer centers from February 1, 2012, to July 28, 2016, and analyzed June 2019 to October 2019. MAIN OUTCOME AND MEASURES: The primary end point was the investigator-assessed PFS in the per-protocol population, with a noninferiority margin of 1.25 for the 90% CI of the hazard ratio. RESULTS: Among the 755 women in the per-protocol population, the median (range) age was 63 (30-88) years [64 (30-88) years for the 377 patients allocated to the CTC arm and 63 (31-87) years for the 378 patients allocated to the standard arm]; 138 (37%) and 103 (27%) received chemotherapy, respectively. Median PFS was 15.5 months (95% CI, 12.7-17.3) in the CTC arm and 13.9 months (95% CI, 12.2-16.3) in the standard arm. The primary end point was met, with a hazard ratio of 0.94 (90% CI, 0.81-1.09). CONCLUSIONS AND RELEVANCE: This randomized clinical trial found that the CTC count may be a reliable biomarker method for guiding the choice between chemotherapy and endocrine therapy as the first-line treatment in hormone receptor-positive, ERBB2-negative metastatic breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01710605.

Prognostic Impact of Stromal Immune Infiltration before and after Neoadjuvant Chemotherapy (NAC) in Triple Negative Inflammatory Breast Cancers (TNIBC) Treated with Dose-Dense Dose-Intense NAC.

Inflammatory breast cancers are very aggressive, and among them, triple negative breast cancer (TNBC) has the worst prognosis. While many studies have investigated the association between tumor-infiltrating lymphocytes (TIL) before neoadjuvant chemotherapy (NAC) and outcome in TNBC, the impact of post-NAC TIL and TIL variation in triple negative inflammatory breast cancer (TNIBC) outcome is unknown. Between January 2010 to December 2018, all patients with TNIBC seen at the breast disease unit (Saint-Louis Hospital) were treated with dose-dense dose-intense NAC. The main objective of the study was to determine factors associated with event-free survival (EFS), particularly pathological complete response (pCR), pre- and post-NAC TIL, delta TIL and post-NAC lymphovascular invasion (LVI). After univariate analysis, post-NAC LVI (HR 2.06; CI 1.13-3.74; p = 0.02), high post-NAC TIL (HR 1.81; CI 1.07-3.06; p = 0.03) and positive delta TIL (HR 2.20; CI 1.36-3.52; p = 0.001) were significantly associated with impaired EFS. After multivariate analysis, only a positive TIL variation remained negatively associated with EFS (HR 1.88; CI 1.05-3.35; p = 0.01). TNIBC patients treated with intensive NAC who present TIL enrichment after NAC have a high risk of relapse, which could be used as a prognostic marker in TNIBC and could help to choose adjuvant post-NAC treatment.

[Prospects in senology]. / Perspectives en sénologie.

Le traitement médical des cancers du sein s'est considérablement enrichi ces dernières années z Les indications thérapeutiques ont été affinées grâce à la classification moléculaire des cancers. La chimiothérapie restera encore pour quelques années indispensable notamment pour les cancers du sein triple négatif et surexprimant le récepteur 2 du facteur de croissance épidermique humain. De nouvelles molécules sont en développement pour contourner les mécanismes de résistance à l'hormonothérapie et en association pour en augmenter l'efficacité. L'avenir est aux thérapies ciblées qui visent les anomalies moléculaires de chaque cancer pour chaque patiente.

Actionability of HER2-amplified circulating tumor cells in HER2-negative metastatic breast cancer: the CirCe T-DM1 trial.

BACKGROUND: In this prospective phase 2 trial, we assessed the efficacy of trastuzumab-emtansine (T-DM1) in HER2-negative metastatic breast cancer (MBC) patients with HER2-positive CTC. METHODS: Main inclusion criteria for screening were as follows: women with HER2-negative MBC treated with ≥ 2 prior lines of chemotherapy and measurable disease. CTC with a HER2/CEP17 ratio of ≥ 2.2 by fluorescent in situ hybridization (CellSearch) were considered to be HER2-amplified (HER2amp). Patients with ≥ 1 HER2amp CTC were eligible for the treatment phase (T-DM1 monotherapy). The primary endpoint was the overall response rate. RESULTS: In 154 screened patients, ≥ 1 and ≥ 5 CTC/7.5 ml of blood were detected in N = 118 (78.7%) and N = 86 (57.3%) patients, respectively. ≥1 HER2amp CTC was found in 14 patients (9.1% of patients with ≥ 1 CTC/7.5 ml). Among 11 patients treated with T-DM1, one achieved a confirmed partial response. Four patients had a stable disease as best response. Median PFS was 4.8 months while median OS was 9.5 months. CONCLUSIONS: CTC with HER2 amplification can be detected in a limited subset of HER2-negative MBC patients. Treatment with T-DM1 achieved a partial response in only one patient. TRIAL REGISTRATION: NCT01975142, Registered 03 November 2013.

High expression of apoptosis protein (Api-5) in chemoresistant triple-negative breast cancers: an innovative target.

Anti-apoptotic protein-5 (API-5) is a survival protein interacting with the protein acinus, preventing its cleavage by caspase-3 and thus inhibiting apoptosis. We studied the effect of targeting API-5 in chemoresistant triple negative breast cancers (TNBCs), to reverse chemoresistance. 78 TNBC biopsies from patients with different responses to chemotherapy were analysed for API-5 expression before any treatment. Further studies on API-5 expression and inhibition were performed on patient-derived TNBC xenografts, one highly sensitive to chemotherapies (XBC-S) and the other resistant to most tested drugs (XBC-R). In situ assessments of necrosis, cell proliferation, angiogenesis, and apoptosis in response to anti-API-5 peptide were performed on the TNBC xenografts. Clinical analyses of the 78 TNBC biopsies revealed that API-5 was more markedly expressed in endothelial cells before any treatment among patients with chemoresistant TNBC, and this was associated with greater micro-vessel density. A transcriptomic analysis of xenografted tumors showed an involvement of anti-apoptotic genes in the XBC-R model, and API-5 expression was higher in XBC-R endothelial cells. API-5 expression was also correlated with hypoxic stress conditions both in vitro and in vivo. 28 days of anti-API-5 peptide efficiently inhibited the XBC-R xenograft via caspase-3 apoptosis. This inhibition was associated with major inhibition of angiogenesis associated with necrosis and apoptosis. API-5 protein could be a valid therapeutic target in chemoresistant metastatic TNBC.

6 months versus 12 months of adjuvant trastuzumab in early breast cancer (PHARE): final analysis of a multicentre, open-label, phase 3 randomised trial.

BACKGROUND: In 2013, the interim analysis of the Protocol for Herceptin as Adjuvant therapy with Reduced Exposure (PHARE) trial could not show that 6 months of adjuvant trastuzumab was non-inferior to 12 months. Here, we report the planned final analysis based on the prespecified number of occurring events. METHODS: PHARE is an open-label, phase 3, non-inferiority randomised trial of patients with HER2-positive early breast cancer comparing 6 months versus 12 months of trastuzumab treatment concomitant with or following standard neoadjuvant or adjuvant chemotherapy. The study was undertaken in 156 centres in France. Eligible patients were women aged 18 years or older with non-metastatic, operable, histologically confirmed adenocarcinoma of the breast and either positive axillary nodes or negative axillary nodes but a tumour of at least 10 mm. Participants must have received at least four cycles of a chemotherapy for this breast cancer and have started receiving adjuvant trastuzumab-treatment. Eligible patients were randomly assigned to either 6 months or 12 months of trastuzumab therapy duration between the third and sixth months of adjuvant trastuzumab. The randomisation was stratified by concomitant or sequential treatment with chemotherapy, oestrogen receptor status, and centre. The primary objective was non-inferiority in the intention-to-treat population in the 6-month group in terms of disease-free survival with a prespecified hazard margin of 1·15. This trial is registered with ClinicalTrials.gov, number NCT00381901. FINDINGS: 3384 patients were enrolled and randomly assigned to either 12 months (n=1691) or 6 months (n=1693) of adjuvant trastuzumab. One patient in the 12-month group and three patients in the 6-month group were excluded, so 1690 patients in each group were included in the intention-to-treat analysis. At a median follow-up of 7·5 years (IQR 5·3-8·8), 704 events relevant to disease-free survival were observed (345 [20·4%] in the 12-month group and 359 [21·2%] in the 6-month group). The adjusted hazard ratio for disease-free survival in the 12-month group versus the 6-month group was 1·08 (95% CI 0·93-1·25; p=0·39). The non-inferiority margin was included in the 95% CI. No differences in effects pertaining to trastuzumab duration were found in any of the subgroups. After the completion of trastuzumab treatment, rare adverse events occurred over time and the safety analysis remained similar to the previously published report. In particular, we found no change in the cardiac safety comparison, and only three additional cases in which the left ventricular ejection fraction decreased to less than 50% have been reported in the 12-month group. INTERPRETATION: The PHARE study did not show the non-inferiority of 6 months versus 12 months of adjuvant trastuzumab. Hence, adjuvant trastuzumab standard duration should remain 12 months. FUNDING: The French National Cancer Institute.