Genomics to select treatment for patients with metastatic breast cancer.

Cancer progression is driven in part by genomic alterations1. The genomic characterization of cancers has shown interpatient heterogeneity regarding driver alterations2, leading to the concept that generation of genomic profiling in patients with cancer could allow the selection of effective therapies3,4. Although DNA sequencing has been implemented in practice, it remains unclear how to use its results. A total of 1,462 patients with HER2-non-overexpressing metastatic breast cancer were enroled to receive genomic profiling in the SAFIR02-BREAST trial. Two hundred and thirty-eight of these patients were randomized in two trials (nos. NCT02299999 and NCT03386162) comparing the efficacy of maintenance treatment5 with a targeted therapy matched to genomic alteration. Targeted therapies matched to genomics improves progression-free survival when genomic alterations are classified as level I/II according to the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT)6 (adjusted hazards ratio (HR): 0.41, 90% confidence interval (CI): 0.27-0.61, P < 0.001), but not when alterations are unselected using ESCAT (adjusted HR: 0.77, 95% CI: 0.56-1.06, P = 0.109). No improvement in progression-free survival was observed in the targeted therapies arm (unadjusted HR: 1.15, 95% CI: 0.76-1.75) for patients presenting with ESCAT alteration beyond level I/II. Patients with germline BRCA1/2 mutations (n = 49) derived high benefit from olaparib (gBRCA1: HR = 0.36, 90% CI: 0.14-0.89; gBRCA2: HR = 0.37, 90% CI: 0.17-0.78). This trial provides evidence that the treatment decision led by genomics should be driven by a framework of target actionability in patients with metastatic breast cancer.

Real-World Impact of Adjuvant Anti-HER2 Treatment on Characteristics and Outcomes of Women With HER2-Positive Metastatic Breast Cancer in the ESME Program.

BACKGROUND: Although adjuvant cancer treatments increase cure rates, they may induce clonal selection and tumor resistance. Information still lacks as whether (neo)adjuvant anti-HER2 treatments impact the patterns of recurrence and outcomes of HER2-positive (HER2+) metastatic breast cancer (MBC). We aimed to assess this in the large multicenter ESME real-world database. PATIENTS AND METHODS: We examined the characteristics and outcomes (overall survival (OS) and progression-free survival under first-line treatment (PFS1)) of HER2+ patients with MBC from the French ESME program with recurrent disease, as a function of the previous receipt of adjuvant trastuzumab. Multivariable analyses used Cox models adjusted for baseline demographic, prognostic factors, adjuvant treatment received, and disease-free interval. RESULTS: Two thousand one hundred and forty-three patients who entered the ESME cohort between 2008 and 2017 had a recurrent HER2+ MBC. Among them, 56% had received (neo)adjuvant trastuzumab and 2.5% another anti-HER2 in this setting. Patients pre-exposed to trastuzumab were younger, had a lower disease-free interval, more HR-negative disease and more metastatic sites. While the crude median OS appeared inferior in patients exposed to adjuvant trastuzumab, as compared to those who did not (37.2 (95%CI 34.4-40.3) versus 53.5 months (95% CI: 47.6-60.1)), this difference disappeared in the multivariable model (HR = 1.05, 95%CI 0.91-1.22). The same figures were observed for PFS1. CONCLUSIONS: Among patients with relapsed HER2+ MBC, the receipt of adjuvant trastuzumab did not independently predict for worse outcomes when adjusted to other prognostic factors.

Impact of web application support versus standard management on adherence with adjuvant hormone therapy in patients treated for breast cancer: the WEBAPPAC study.

BACKGROUND: Non-metastatic breast cancer treatment is mainly based on surgery, with or without chemotherapy, radiotherapy and/or hormone therapy. To reduce the risk of hormone receptor positive (HR+) disease recurrence, hormone therapy is prescribed for at least 5 years. It may induce adverse drug reactions (ADRs) as joint pain, sexual dysfunction, weight increase, fatigue, mood disorders and vasomotor symptoms. Around 30-40% of patients withhold hormone therapy within 5 years after initiation. Based on encouraging results of mobile health in patient follow-up, we developed a web-application addressed for breast cancer patients initiating adjuvant hormonal therapy and aimed to assess its impact on hormone therapy adherence, ADRs management, and health-related quality of life. METHODS: The WEBAPPAC trial is a randomized, open-label, prospective, single-center phase 3 study aiming to assess the interest of a web-application support as compared to standard management among breast cancer patients initiating hormone therapy. The main endpoint is the proportion of patients with hormone therapy adherence failure within 18 months after treatment start, in each arm. Eligible patients will be 1:1 randomized between the WEBAPPAC web-application support (experimental arm,) or standard support (control arm), with stratification on type of hormone therapy (Aromatase inhibitor or Tamoxifen). We plan to enroll 438 patients overall. Failure to hormone therapy will be assessed using the Morisky 8-item self-questionnaire (MMSA8), patient adherence logbook, and medical consultations. Secondary outcomes include hormone therapy adherence at 6 months, pain (Visual Analogue Scale and Brief Pain Inventory), quality of life (EORTC QLQ-C30 and BR23 self-questionnaires), anxiety and depression (Hospital and Depression Scale), and return to work and/or daily activities. The user experience with the WEBAPPAC web-application will be assessed using the System Usability Scale (SUS) questionnaire. DISCUSSION: Hormone therapy discontinuation or adherence failure in breast cancer patients may be indirectly related to an increased risk of recurrence. A better control of medication adherence, through the detection of side effects and some proposed actions trying to reduce them, appears therefore essential to limit the risk of disease recurrence. The WEBAPPAC web-application thus aims better monitoring and allowing higher level of responsiveness in case of ADRs, thus improving treatment adherence. TRIAL REGISTRATION: NCT04554927, registered September 18, 2020. PROTOCOL VERSION: Version 2.1 dated from December 21, 2021.

The TRIPLEX study: use of patient-derived tumor organoids as an innovative tool for precision medicine in triple-negative breast cancer.

BACKGROUND: Triple negative breast cancers (TNBC) account for approximately 15% of all breast cancers and are associated with a shorter median survival mainly due to locally advanced tumor and high risk of metastasis. The current neoadjuvant treatment for TNBC consists of a regimen of immune checkpoint blocker and chemotherapy (chemo-ICB). Despite the frequent use of this combination for TNBC treatment, moderate results are observed and its clinical benefit in TNBC remains difficult to predict. Patient-derived tumor organoids (PDTO) are 3D in vitro cellular structures obtained from patient's tumor samples. More and more evidence suggest that these models could predict the response of the tumor from which they are derived. PDTO may thus be used as a tool to predict chemo-ICB efficacy in TNBC patients. METHOD: The TRIPLEX study is a single-center observational study conducted to investigate the feasibility of generating PDTO from TNBC and to evaluate their ability to predict clinical response. PDTO will be obtained after the dissociation of biopsies and embedding into extra cellular matrix. PDTO will be cultured in a medium supplemented with growth factors and signal pathway inhibitors. Molecular and histological analyses will be performed on established PDTO lines to validate their phenotypic proximity with the original tumor. Response of PDTO to chemo-ICB will be assessed using co-cultures with autologous immune cells collected from patient blood samples. PDTO response will finally be compared with the response of the patient to evaluate the predictive potential of the model. DISCUSSION: This study will allow to assess the feasibility of using PDTO as predictive tools for the evaluation of the response of TNBC patients to treatments. In the event that PDTO could faithfully predict patient response in clinically relevant time frames, a prospective clinical trial could be designed to use PDTO to guide clinical decision. This study will also permit the establishment of a living biobank of TNBC PDTO usable for future innovative strategies evaluation. TRIAL REGISTRATION: The clinical trial (version 1.2) has been validated by local research ethic committee on December 30th 2021 and registered at ClinicalTrials.gov with the identifier NCT05404321 on June 3rd 2022, version 1.2.

HELENA: HER2-Low as a prEdictive factor of response to Neoadjuvant chemotherapy in eArly breast cancer.

BACKGROUND: HER2 expression has a prognostic and predictive impact in early-stage breast cancer (BC). HER2 positive BC (immunohistochemistry (IHC) score 3 + or 2 + with in situ hybridization (ISH) amplification) are treated with HER2 targeted therapies. The concept of HER2-low BC (IHC score 1 + or 2 + without ISH amplification) is drawing attention as anti-HER2 treatment has recently shown efficacy in this subgroup. We aimed to explore the response to neoadjuvant chemotherapy (NAC) in HER2-low early BC according to the HER2 score (1 + or 2 + without amplification). METHODS: We conducted a retrospective study in two French comprehensive cancer centers. All patients with HER2-low BC treated with NAC from January 2014 to December 2020 were included. The primary objective was to analyze the pathological complete response (pCR) rate to NAC using the Sataloff or RCB system, according to the HER2 score. Secondary objectives were to assess disease free survival (DFS), overall survival (OS) and to explore the immune environment through the Neutrophil-to-Lymphocyte Ratio (NLR), according to HER2 expression. Univariate and multivariate analyses were performed. RESULTS: We included 237 tumors for 229 patients. Of these, 160 (67.5%) tumors were HER2 1 + , 77 (32.5%) were HER2 2 + , and 152 (64.1%) were hormone receptor (HR) positive. The median age was 53.9 years. No differences in tumor characteristics were observed between HER2 1 + and HER2 2 + subgroups. pCR was achieved in 38 tumors (17%), without any difference between HER2 1 + and HER2 2 + subgroups (p = 0.77). DFS and OS were significantly different between HER2 1 + and HER2 2 + patients (HR = 0.41,CI95%[0.17;0.97] p = 0.037 and HR = 0.31,CI95%[0.09;1.02] p = 0.042, respectively). HER2 status was still associated with DFS and OS after adjustment for age, HR status and NLR, with better outcomes in favor of HER2 score 2 + (HR = 0.35 [0.15-0.84] and HR = 0.24 [0.07-0.81], respectively). NLR was not associated with worse DFS or OS. CONCLUSION: In HER2-low early BC, no differences in pCR were observed between HER2 1 + and HER2 2 + tumors, however patients with HER2 2 + tumors had a better DFS and OS than those with HER2 1 + . Further investigations are needed to describe the intrinsic differences in the spectrum of HER2-low BC.

Risk of early progression according to circulating ESR1 mutation, CA-15.3 and cfDNA increases under first-line anti-aromatase treatment in metastatic breast cancer.

BACKGROUND: Endocrine therapy is recommended as a first-line treatment for hormone receptor-positive metastatic breast cancer (HR+MBC) patients. No biomarker has been validated to predict tumor progression in that setting. We aimed to prospectively compare the risk of early progression according to circulating ESR1 mutations, CA-15.3, and circulating cell-free DNA in MBC patients treated with a first-line aromatase inhibitor (AI). METHODS: Patients with MBC treated with a first-line AI were prospectively included. Circulating biomarker assessment was performed every 3 months. The primary objective was to determine the risk of progression or death at the next follow-up visit (after 3 months) in case of circulating ESR1 mutation detection among patients treated with a first-line AI for HR+MBC. RESULTS: Overall, 103 patients were included, and 70 (68%) had progressive disease (PD). Circulating ESR1 mutations were detected in 22/70 patients with PD and in 0/33 patients without progression (p < 0.001). Among the ESR1-mutated patients, 18/22 had a detectable mutation prior to progression, with a median delay of 110 days from first detection to PD. The detection of circulating ESR1 mutations was associated with a 4.9-fold (95% CI 3.0-8.0) increase in the risk of PD at 3 months. Using a threshold value of 25% or 100%, a CA-15.3 increase was also correlated with progression (p < 0.001 and p = 0.003, respectively). In contrast to ESR1, the CA-15.3 increase occurred concomitantly with PD in most cases, in 27/47 (57%) with a 25% threshold and in 21/25 (84%) with a 100% threshold. Using a threshold value of either 25% or 100%, cfDNA increase was not correlated with progression. CONCLUSION: The emergence of circulating ESR1 mutations is associated with a 4.9-fold increase in the risk of early PD during AI treatment in HR+MBC. Our results also highlighted that tracking circulating ESR1 mutations is more relevant than tracking CA-15.3 or cfDNA increase to predict progression in this setting. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02473120. Registered 16 June 2015-retrospectively registered after one inclusion (first inclusion 1 June 2015).

A Real-Life Experience of Bevacizumab in Elderly Women With Advanced Ovarian Carcinoma.

OBJECTIVE: This study aimed to assess the tolerance of bevacizumab (BEVA) among older ovarian cancer patients in daily clinical practice and identify a subpopulation of patients with a high risk of severe adverse effects. METHODS: Consecutive patients with a pathologically proven high-grade serous ovarian, tubal, or peritoneal carcinoma who received BEVA between January 2006 and June 2014 were included in a retrospective analysis. RESULTS: Among 86 BEVA-treated patients, 42 (48.8%) received concomitant chemotherapy, 26 (30%) had baseline arterial hypertension (HTN), and 33 (38.4%) were considered elderly (>70 years). Incidence of arterial, venous thromboembolism, hemorrhage, and bowel perforation were 2%, 8%, 12%, and 0%, respectively, and was not related to age. Incidence of severe (NCI-CTC v4 G3-4) HTN was significantly higher in elderly patients than in younger ones (39%; 95% confidence interval [CI], 22%-56% vs 17%; 95% CI, 7%-27%) (P = 0.017 by χ test) and in patients with baseline HTN (P < 0.05). Twenty-three percent of younger patients had baseline HTN compared with 42% of older ones (P = 0.052). Among patients without baseline HTN, older age was not associated with increased risk of severe HTN. However, incidence of severe HTN reached 71% (95% CI, 47%-95%) in older patients with baseline HTN. Exploratory analysis indicates that progression-free survival was similar in younger and older patients. CONCLUSIONS: Bevacizumab is feasible in patients older than 70 years with advanced ovarian carcinoma. More attention must be paid to elderly patients with baseline HTN.

Baseline and early 18F-FDG PET/CT evaluations as predictors of progression-free survival in metastatic breast cancer patients treated with targeted anti-CDK therapy.

BACKGROUND: Exploring the value of baseline and early 18F-FDG PET/CT evaluations in prediction PFS in ER+/HER2- metastatic breast cancer patients treated with a cyclin-dependent kinase inhibitor in combination with an endocrine therapy. METHODS: Sixty-six consecutive breast cancer patients who underwent a pre-therapeutic 18F-FDG PET/CT and a second PET/CT within the first 6 months of treatment were retrospectively included. Metabolic tumour volume (MTV) and total lesion glycolysis (TLG) and Dmax, which represents tumour dissemination and is defined as the distance between the two most distant lesions, were computed. The variation in these parameters between baseline and early evaluation PET as well as therapeutic evaluation using PERCIST were assessed as prognosticators of PFS at 18 months. RESULTS: The median follow-up was equal to 22.5 months. Thirty progressions occurred (45.4%). The average time to event was 17.8 ± 10.4 months. At baseline, Dmax was the only predictive metabolic parameter. Patients with a baseline Dmax ≤ 18.10 cm had a significantly better 18 m-PFS survival than the others: 69.2% (7.7%) versus 36.7% (8.8%), p = 0.017. There was no association between PERCIST evaluation and 18 m-PFS status (p = 0.149) and there was no difference in 18 m-PFS status between patients classified as complete, partial metabolic responders or having stable metabolic disease. CONCLUSION: Disease spread at baseline PET, as assessed by Dmax, is predictive of an event occurring within 18 months. In the absence of early metabolic progression, which occurs in 15% of patients, treatment should be continued regardless of the quality of the initial response to treatment.

Overall Survival With Circulating Tumor Cell Count-Driven Choice of Therapy in Advanced Breast Cancer: A Randomized Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer, the STIC CTC trial established that, for choosing between endocrine therapy (ET) or chemotherapy, the use of circulating tumor cell (CTC) count is noninferior to the investigator's choice in terms of progression-free survival. Here, we report overall survival (OS) results, a secondary end point. Patients were randomly assigned in a 1:1 ratio to have their first-line treatment (ET or chemotherapy) determined by investigators or CTC count (chemotherapy if ≥ 5 CTCs/7.5 mL; ET if low CTC count; CellSearch). OS was assessed at the discontinuation of follow-up. After a median follow-up of 4.7 years, 382 deaths (50.6%) had occurred among 755 patients. Median OS was 51.3 months (95% CI, 46.8 to 55.1) in the CTC arm and 45.5 months (95% CI, 40.9 to 51.1) in the standard arm (hazard ratio [HR] for death, 0.85; 95% CI, 0.69 to 1.03; P = .11). Among 189 patients (25.0%) with ET recommended by clinicians and high CTC count, chemotherapy was superior to ET (HR for death, 0.53; 95% CI, 0.36 to 0.78; P = .001). In case of a discordant estimate, OS data demonstrate the clinical utility of CTC count.

First-line real-world treatment patterns and survival outcomes in women younger or older than 40 years with metastatic breast cancer in the real-life multicenter French ESME cohort.

AIM: To describe first-line treatment patterns, overall survival (OS) and real-world progression-free survival (rwPFS) in young women (<40) with metastatic breast cancer (mBC), as compared to women aged 40-69. MATERIALS AND METHODS: Data on adult women diagnosed with mBC (2008-2017) were extracted from the ESME mBC database (NCT03275311) which includes consecutive patients starting first-line metastatic treatment in one of the 18 French Comprehensive cancer centers. We reported first-line therapeutic strategy and prognostic factors of OS and rwPFS for women aged < 40 and 40-69. RESULTS: In total, 14,897 mBC women were included (1512 aged <40). HR+ /HER2- mBC was the most frequent subtype. First-line treatment differed between young patients and older ones for HR+ /HER2- and Triple Negative (TN) mBC. Median OS for women aged < 40 and 40-69, respectively, was 46.9 and 46.2 months for HR+ /HER2- mBC; 13.5 and 15.2 for TN mBC; and, 60.7 and 55.1 for HER2 + mBC. Median rwPFS under first line treatment was 11.6 and 11.9 months for HR+ /HER2- in women aged < 40 and 40-69, respectively; 5.5 and 5.9 for TN, and, 13.3 and 12.9 for HER2 + . Factors associated with shorter OS and rwPFS were similar for both women aged < 40 and 40-69 and included ≥ 3 metastatic sites, visceral metastases, and longer MFI, with time-varying effects observed for several prognostic factors. CONCLUSION: Young women presented more frequently with TN and HER2 + subtypes and aggressive mBC than women aged 40-69 did. Prognostic factors of OS and rwPFS were quite similar between age groups and mBC subtypes.

A clinical experience of single agent bevacizumab in relapsing ovarian cancer.

OBJECTIVE: The objective of this study is to report the efficacy and tolerance of single agent bevacizumab (BEVA) in relapsing ovarian cancer patients treated in a single institution outside a clinical trial. METHODS: To receive single agent BEVA, patients must have to relapse after at least one previous line of chemotherapy and to not have clinical conditions associated with high risk of gastrointestinal perforation. Dose-intensity of BEVA was 2.5mg/kg/week. RESULTS: 37 previously treated patients (33 with platinum resistant disease) were included in this retrospective analysis. The median number of BEVA infusion by patient was 5 (range: 1-61). The most frequent adverse effect was arterial hypertension, observed in 23 patients (62%), including 11 with G3 (30%) and 1 with G4. No intestinal perforation was reported. Tumor response rate according to CA 125 level (GCIG criteria) was 37% (11 of 30 patients). The median PFS and OS were 4 (range: 1 to +56) and 16 (range: 1 to +65) months (ms), respectively. 12-ms PFS was 25% (95% CI: 11-39%). The PFS tended to be better in patients who experienced grade 3-4 arterial hypertension during the first month of treatment (median: 10ms) compared to patients who did not (median: 3ms) (HR: 0.49 (95% CI: 0.18-1.03), p=0.06 by log rank test). CONCLUSION: Single agent BEVA could be a reasonable option with favorable therapeutic index in pretreated ovarian cancer patients who do not want to suffer the side effects of chemotherapy provided to exclude those with high risk of intestinal perforation and carefully monitor blood pressure.

Association between high antitumor activity of oxaliplatin and cyclophosphamide and constitutional GSTM1 homozygous deletion in an advanced ovarian cancer patient.

BACKGROUND: Although the efficiency of oxaliplatin in patients with advanced ovarian cancer has been demonstrated, it is not commonly used. In cells, oxaliplatin is metabolized by the enzymes belonging to the glutathione-S-transferase (GST) family. CASE: A 55-year-old woman with advanced ovarian cancer received 6 cycles of paclitaxel and carboplatin after debulking surgery. Six months later, she experienced a clinical recurrence. A second-line chemotherapy combining 500 mg/m² cyclophosphamide with 100 mg/m² oxaliplatin was initiated and maintained for 10 cycles. The patient thus experienced a second complete remission that lasted for 6 years. We found that she had deficient GSTM1 enzyme activity with homozygous deletion and normal GSTP1 and GSTT1 activities. CONCLUSION: The association of a homozygous deletion of GSTM1 with hypersensitivity to oxaliplatin and cyclophosphamide combination chemotherapy has not been described to date in ovarian cancer. Further study of its potential interest to personalized second-line therapy in these patients is called for.

Baseline lymphopenia as prognostic factor in patients with metastatic breast cancer treated with palbociclib.

Cyclin-dependent-kinase 4-6 inhibitors (CDK4/6i) have improved the management of hormone receptor (HR)+/human epidermal growth factor receptor (HER)2- metastatic breast cancer (mBC). Currently, there are no valid prognostic factors for response to CDK4/6i. Baseline lymphopenia is reported as a prognostic factor in several types of cancer. The present retrospective study aimed to evaluate the effect of baseline absolute lymphocyte count (ALC) on response to palbociclib. Progression-free survival (PFS) was the primary endpoint. Secondary endpoints were overall survival (OS), best response and safety. A total of 114 patients treated for mBC between 2016 and 2019 were included. Median baseline ALC was 1.4 g/l (range, 0.2-4.3 g/l). A total of 65 (57%) and 49 (43%) patients had baseline ALC values of <1.5 and ≥1.5 g/l, respectively. Patients with baseline lymphopenia exhibited significantly shorter PFS (6 vs. 10 months; P=0.004) and OS (20 vs. 33 months; P=0.02). ALC <1.5 g/l independently predicted worse survival, as indicated by multivariate analysis (P=0.04; hazard ratio, 1.76; 95% confidence interval, 1.02-3.02). Patients with baseline ALC <1.5 g/l had significantly less partial response (14 vs. 22%; P=0.016) and more disease progression (46 vs. 20%; P=0.016) than those with ALC ≥1.5 g/l. ALC is a strong and easy-to-use dosage with prognostic factor for patients with HR+/HER2- mBC treated with palbociclib and endocrine therapy. Lymphopenia may also be a predictive factor of early progression. These data need to be verified in a larger prospective study.

Sleep-dependent memory consolidation in breast cancer: Use of a virtual reality prospective memory task.

Background: Previous studies have revealed both sleep alterations and prospective memory (PM) impairments in breast cancer (BC) patients. PM refers to memory of intended actions and is crucial for daily living tasks and treatment compliance. As sleep is known to favor memory consolidation, one may expect that changes in sleep quality related to BC would have an impact on PM performance. This study aimed at assessing sleep-dependent consolidation of intentions using an ecological, virtual reality-based PM task in BC patients not treated with chemotherapy. Materials and methods: Thirty-seven early stages BC patients and 21 healthy controls (HC) participated in this study. PM was assessed using a virtual reality task, during which participants learnt a list of intentions and recalled them after a retention interval filled with a day awake or a night of sleep monitored by polysomnography. Sleep spindles and slow waves, brain oscillations involved in sleep-dependent memory consolidation, were quantified automatically using the Aseega software (Physip). Subjective sleep disturbances and markers of quality of life (psychological distress, fatigue, and well-being) were assessed by questionnaires. Results: Greater PM performance was observed after sleep than after an equivalent period of daytime wakefulness for both groups (HC and BC). PM performance after sleep did not differ significantly between groups. Yet, BC patients reported greater sleep disturbances than HC which were related with poorer intentions retrieval, greater psychological distress, fatigue and poorer well-being. The frequency of spindles was higher and the amplitude of slow waves lower in BC patients compared to HC. However, no significant association was observed between polysomnography parameters and PM scores in the whole sample of participants. Conclusion: Although subtle changes in brain oscillations involved in sleep-dependent memory consolidation were observed, these changes did not significantly impair overnight PM consolidation in BC patients. Nevertheless, poorer PM performance was associated with greater sleep complaints which in turn were related to poorer quality of life. Overall, these data suggest that sleep-dependent PM consolidation mechanisms are not altered in early stages BC patients not treated with chemotherapy. Further investigations are needed to understand the association between markers of quality of life and sleep-dependent memory consolidation.

Pretreatment neutrophil to lymphocyte ratio as prognostic factor in metastatic breast cancer treated with cyclin dependent kinase 4/6 inhibitors.

Background: Cyclin dependent kinase inhibitors (CdK4/6i) changed the course of hormone receptor positive (HR+) HER2 negative (HER2-) metastatic breast cancer (mBC). To date, no factors have been shown to predict response to CdK4/6i. Neutrophil-to-lymphocyte ratio (NLR), an indicator of the host systemic inflammatory response, is an independent prognostic factor for survival in cancers. We conducted this study to evaluate the impact of NLR on survival in mBC patients treated with first line CdK4/6i. Methods: All mBC patients treated with first line CdK4/6i between November 2015 and December 2019 were retrospectively included. The biomarker threshold was defined using ROC curves. We analyzed progression free survival (PFS), overall survival (OS), 12-month PFS and response rate according to NLR in univariable and multivariable analysis. Results: A total of 126 patients treated with palbociclib (n=101), ribociclib (n=18) or abemaciclib (n=7) were included, with a median follow-up of 33 months [range: 2.9-57]. Median age was 65 years [29-86], 40% patients had good performance status (ECOG-PS 0). Most patients (71%) were included at the metastatic relapse stage and 29% had only bone metastases. Median PFS and median OS were 27 and 51 months, respectively. High NLR (≥ 2.53) was significantly associated with worse PFS (Hazard Ratio (HR)=0.50, CI95% = [0.32-0.79]) and worse OS (HR=0.45, [CI95%: 0.23-0.87]). In multivariable analysis, NLR and ECOG PS were independently factors associated with PFS (p=0.016 and p=0.001, respectively). Conclusion: High NLR was associated with worse PFS and OS in HR+ HER2- mBC patients treated with first line CdK4/6i. NLR is a reliable and inexpensive prognostic marker, easily accessible in routine clinical practice, which could help optimize the therapeutic strategy. These results need to be confirmed in larger prospective studies.

Rest activity rhythms characteristics of breast cancer women following endocrine therapy.

Rest-activity rhythm (RAR) disruptions are frequently associated with chemotherapy in breast cancer (BC), but they are less known in BC with endocrine therapy (ET). The aim of this ancillary study was to characterize the RAR and estimated sleep characteristics from actigraphy in BC patients either treated (ET+) or untreated with ET (ET-), compared to healthy controls (HC) and using a cross-sectional design. Eighteen ET+, 18 ET-, and 16 HC completed questionnaires and wore wrist actigraphs at home for 2 weeks. Parametric and nonparametric RAR, sleep parameters, and quality of life were compared between groups (p < .05). BC groups presented lower daytime activity than HC according to RAR analysis (mesor and M10 parameters). Compared to HC, ET- had lower inter-daily stability and ET+ had greater sleep complaints. Compared to ET-, ET+ had lower sleep efficiency, more time awake, and higher activity levels at night, as assessed with actigraphy. Our results suggest an effect of cancer independent of treatment on RAR in BC, highlighting the need for further investigation of this topic. In contrast, sleep as assessed with actigraphy seems modified only during ET which matches with patients' sleep complaints. Further longitudinal studies would aid in confirming the latter hypothesis.

Comparison of Management and Outcomes in ERBB2-Low vs ERBB2-Zero Metastatic Breast Cancer in France.

Importance: ERBB2-low (ie, ERBB2 immunohistochemistry score of 1+ or 2+ in the absence of ERBB2 gene amplification) breast cancer (BC) is a new entity, with emerging dedicated treatments. Little is known about its prognosis and response to conventional therapy compared with ERBB2-zero breast tumors (ie, those with an immunohistochemistry score of 0). Objective: To compare the outcomes for patients with ERBB2-low metastatic BC (MBC) with those of patients with ERBB2-zero MBC. Design, Setting, and Participants: This cohort study was conducted from the Epidemiological Strategy and Medical Economics MBC platform and included patients with MBC treated between 2008 and 2016 in 18 French comprehensive cancer centers. The data analysis was conducted from July 16, 2020, to April 1, 2022. Main Outcomes and Measures: The main outcome was overall survival (OS), and the secondary outcome was progression-free survival under first-line treatments (PFS1). Results: The median (range) age was 60.0 (22.0-103.0) years. Among 15 054 patients with MBC, 4671 (31%) had ERBB2-low MBC and 10 383 (69%) had ERBB2-zero MBC. The proportion of ERBB2-low cancers was higher among patients with hormone receptor-positive MBC than those with hormone receptor-negative disease (4083 patients [33.0%] vs 588 patients [21.0%]). With a median follow-up of 49.5 months (95% CI, 48.6-50.4 months), the median OS of the ERBB2-low group was 38.0 months (95% CI, 36.4-40.5 months) compared with 33.9 months (95% CI, 32.9-34.9 months) for the ERBB2-zero group (P < .001). After adjustment for age, visceral metastases, number of metastatic sites, de novo disease, period of care, and hormone receptor status, patients with ERBB2-low MBC had slightly better OS compared with patients with ERBB2-zero MBC (adjusted hazard ratio, 0.95; 95% CI, 0.91-0.99; P = .02). In contrast, PFS1 did not differ by ERBB2 status (adjusted hazard ratio, 0.99; 95% CI, 0.95-1.02; P = .45). No significant differences in OS and PFS1 were observed in multivariate analyses by hormone receptor status and types of frontline treatment. Conclusions and Relevance: In this large cohort study, patients with ERBB2-low MBC had a slightly better OS than those with completely ERBB2-zero tumors, but identical PFS1, which could help guide treatment selection.

Efficacy of trastuzumab emtansine (T-DM1) and lapatinib after dual HER2 inhibition with trastuzumab and pertuzumab in patient with metastatic breast cancer: Retrospective data from a French multicenter real-life cohort.

PURPOSE: Trastuzumab-emtansine (T-DM1), as well as lapatinib plus capecitabine were proven effective in two Phase III studies, following first-line trastuzumab plus a taxane. The introduction of dual HER2 blockade by trastuzumab and pertuzumab as first-line has positioned T-DM1 into second-line, and lapatinib plus capecitabine beyond, without formal evaluation of these strategies. METHODS: ESME Data Platform (NCT03275311) included individual data from all patients aged ≥18 years, in whom first-line treatment for metastatic breast cancer (MBC) was initiated between January 1, 2008 and December 31, 2016 in one of the 18 French Comprehensive Cancer Centers. The efficacy of T-DM1 and lapatinib plus capecitabine combination, following double blockade associating trastuzumab and pertuzumab were evaluated in this national real-life database. Eligibility criteria were: female, MBC, HER2+ tumor, first-line taxane-based chemotherapy and dual HER2-blockage by trastuzumab plus pertuzumab. Cohort A received second-line T-DM1, and Cohort B second-line T-DM1 and third or fourth-line lapatinib plus capecitabine. RESULTS: Cohort A comprised 233 patients, and Cohort B 47 patients. Median progression-free survival (PFS) was 7.1 months in Cohort A and 4.6 months in Cohort B. Median overall survival were 36.7 months and 12.9 months, respectively. PFS was significantly dependent on the preceding treatment line's duration. In cohort A, HER2 expression status was a significant predictive factor of PFS. CONCLUSION: First-line trastuzumab plus pertuzumab do not markedly diminish T-DM1's efficacy in second-line. Similarly, sequential treatment with trastuzumab plus pertuzumab then T-DM1 does not noticeably modify the efficacy of lapatinib plus capecitabine.

Impact of body mass index on overall survival in patients with metastatic breast cancer.

BACKGROUND: High Body mass index (BMI) is a risk factor for breast cancer among postmenopausal women and an adverse prognostic factor in early-stage. Little is known about its impact on clinical outcomes in patients with metastatic breast cancer (MBC). METHODS: The National ESME-MBC observational cohort includes all consecutive patients newly diagnosed with MBC between Jan 2008 and Dec 2016 in the 18 French comprehensive cancer centers. RESULTS: Of 22 463 patients in ESME-MBC, 12 999 women had BMI data available at MBC diagnosis. Median BMI was 24.9 kg/m2 (range 12.1-66.5); 20% of women were obese and 5% underweight. Obesity was associated with more de novo MBC, while underweight patients had more aggressive cancer features. Median overall survival (OS) of the BMI cohort was 47.4 months (95% CI [46.2-48.5]) (median follow-up: 48.6 months). Underweight was independently associated with a worse OS (median OS 33 months; HR 1.14, 95%CI, 1.02-1.27) and first line progression-free survival (HR, 1.11; 95%CI, 1.01; 1.22), while overweight or obesity had no effect. CONCLUSION: Overweight and obesity are not associated with poorer outcomes in women with metastatic disease, while underweight appears as an independent adverse prognostic factor.