Residual Tumor and Response to Treatment (RT2Lab)

The incidence of cancer increases with age, as does the incidence of many other chronic diseases, such as diabetes, hypertension or cardiovascular disease. Comorbidity is defined as the “coexistence of disorders in addition to a primary disease of interest”. Comorbidities have been shown to influence history, cancer treatment decisions as well as short- and long-term survival.  In parallel, there is growing interest in comedications – i.e. chronically used medications - that may influence the risk for, as well as the progression of cancer.

Epidemiological evidence has reported associations between some medications such as aspirin or non-steroidal anti-inflammatory drugs (NSAID) and a decrease in cancer risk. Others, like statins, NSAIDs, beta blockers (BB) and metformin were found to be associated with a decrease in cancer recurrence or to improved survival after cancer.

We retrospectively analyzed the randomized clinical trial REMAGUS02 (neoadjuvant chemotherapy (NAC) for breast cancer +/- celecoxib) according to COX activation status evaluated by PTGS2 expression. We found a significant interaction between PTGS2 expression and celecoxib on prognosis; and we evidenced an unexpected paradoxical effect: patients in the PTGS2-low group from the celecoxib arm had impaired EFS and impaired OS compared with the standard arm, whereas no association was seen in the PTGS2-high group (Hamy et al., 2019b)

In a cohort of 1023 breast cancer patients treated with neoadjuvant chemotherapy (NAC), we systematically analyzed the concurrent comedications on the density of tumor-infiltrating lymphocytes (TILs) and pathological complete responses (pCR). Pre-NAC TIL density was increased by medications targeting nervous system in triple negative BC (TNBC), and psycholeptics use was independently associated with pathological complete response. These experiments were reproduced in BC-bearing mice, where psycholeptics reduced tumor growth and increased the anti-cancer activity of cyclophosphamide in a T cell-dependent manner (Hamy et al., 2019a).

We launched a confirmatory research program, aiming at analyzing the relationships between co-morbidities, comedications, immune infiltration, response to treatment in a large dataset of breast cancer patients (COMBIMMUNO project). Several independent cohorts from international (EORTC 10994/BIG 1-00 n=1856) or national trials (PACS-08, PACS-09, n≈1000), real-life cohorts (CANTO cohort n≈10 000, St Louis hospital cohort) were analyzed. A robust statistical methodology was developed by Aurelien Latouche (U900, statistical methodology for precision medicine) to take into account both confounding factors and the aggregation of heterogeneous data.  A large integrative analysis is currently being done on the pooled cohort of this mixed dataset.

In addition, the French health insurance system routinely collects health care reimbursements of almost 98% of the population: hospital abstracts, long-term diseases, outpatient care (medical consults, drug purchases under prescription…) and death status. The project ADRENALINE (Atlas for DRug and brEast caNcer survivAL INtEraction) analyzes the impact of comedications at diagnosis on BC survival on a French cohort using data from the French social security system.

On a cohort of 235,375 BC patients treated in France from 2011 to 2017, we identified comedication intake delivered in pharmacy the 6 months preceding BC diagnosis.

We analyzed the impact of comedications on overall survival, after adjusting on more than 100 confounding variables: social factors, comorbidities and other comedications, and using two adjustment methods: Inverse Probability of Treatment Weighting (IPTW) and matching.  Among 219 selected drugs, 91 and 171 passed the adjustment quality test for IPTW and matching, respectively. The full set of results is available on a web application.

Link to the site : adrenaline.curie.net

Among main findings, several drugs or drug classes were associated with an improved survival: proton-pump inhibitors (IPTW; HR=0.93; p=0.002); statins (e.g. rosuvastatin, IPTW, HR=0.65, p<0.001); beta-blocking agents (atenolol, IPTW, HR=0.78, p=0.003); alverine (IPTW, HR=0.78, p<0.001). Conversely, imidazoline receptor agonists may be deleterious (moxonidine; matching; HR=2.12; p = 0.001).

We built a translational drug screening research program involving several teams of institute Curie:

• Team Thierry Dubois, BCBG, “breast cancer biology group”,
• Team Anabelle Ballesta, INSERM Unit 900 “Cancer Systems Pharmacology”
• Drug screening platform Biophenics, Elaine Del Nery

Based on these epidemiological data, together with biological pathways analysis, we selected 50 drugs to be tested on triple negative breast cancer cell lines. The drug screening program will be launched January 2022.

Future research programs will involve SNDS data on ovarian cancer, and other cancer localizations (lung cancer, melanoma, kidney) in 2022.

Publications from the RT2Lab

Hamy, A.-S., Derosa, L., Valdelièvre, C., Yonekura, S., Opolon, P., Priour, M., Guerin, J., Pierga, J.-Y., Asselain, B., Croze, D.D., Pinheiro, A., Lae, M., Talagrand, L.-S., Laas, E., Darrigues, L., Grandal, B., Marangoni, E., Montaudon, E., Kroemer, G., Zitvogel, L., Reyal, F., 2019a. Comedications influence immune infiltration and pathological response to neoadjuvant chemotherapy in breast cancer. OncoImmunology 0, 1677427. https://doi.org/10.1080/2162402X.2019.1677427

Hamy, A.-S., Tury, S., Wang, X., Gao, J., Pierga, J.-Y., Giacchetti, S., Brain, E., Pistilli, B., Marty, M., Espié, M., Benchimol, G., Laas, E., Laé, M., Asselain, B., Aouchiche, B., Edelman, M., Reyal, F., 2019b. Celecoxib With Neoadjuvant Chemotherapy for Breast Cancer Might Worsen Outcomes Differentially by COX-2 Expression and ER Status: Exploratory Analysis of the REMAGUS02 Trial. JCO 37, 624–635. https://doi.org/10.1200/JCO.18.00636

Neoadjuvant setting (i.e treatment before surgery) represents an opportunity to study and monitor “in vivo” treatment-sensitivity of the tumor. A pathological complete response (pCR) obtained after neoadjuvant chemotherapy (NAC) is a surrogate marker of good prognosis outcome in triple negative (TNBC) and in HER2-positive breast cancer and is now used by the FDA to accelerate the approval process of new drugs. Residual tumor burden analysis after neoadjuvant systemic treatment is an under-explored area and a promising research field to understand resistance mechanisms to a specific treatment in breast cancer. Furthermore, from the clinical point of view, the immediate post-NAC window represents an additional opportunity to include patients in second-line trials.

High levels of tumor-infiltrating lymphocytes (TILs) at diagnosis are associated to better response to neoadjuvant chemotherapy and to better prognosis, particularly for TNBC and HER2-positive breast carcinoma. However, very few studies investigated the immune infiltration in surgical specimen after NAC and prognostic significance of post-chemotherapy lymphocyte infiltration.

Out of a unique cohort of primary BC treated by NAC in Institut Curie between 2002 and 2011, we investigated quantitative information on TIL levels in 717 pre and post-treatment BC samples.  The magnitude of the decrease in TIL levels was strongly associated with pCR rates. After chemotherapy, TIL levels were differentially associated with DFS, with high levels of post-NAC TILs being associated with an impaired outcome in HER2-positive BC (Hamy et al., 2017)   and this association was not found in other BC subtypes (Hamy et al., 2019).

We also investigated extensively extrinsic or intrinsic patients and tumor’s characteristics and provided several insights into immune infiltration in the neoadjuvant setting.

Among extrinsic factors, we found:

• Similar patterns between postpartum pregnancy associated breast cancers and control breast tumors in terms of immune infiltration(Labrosse et al., 2018);
• No impact of smoking status on tumor infiltrating lymphocyte levels, response to neoadjuvant chemotherapy and prognosis in the whole population and within each BC subtype (Simon et al., 2020);
• Body mass index (BMI) is modifying the effect of stromal TILs on pathological complete response rates and prognosis in TNBC patients treated with NAC(Floris et al., 2020).

Among tumor-intrinsic factors, we found:

• Luminal BCs were associated with higher TIL levels after chemotherapy completion in patients with BRCA pathogenic mutations (Grandal et al., 2020) ;
• PD-L1 expression levels were low in tumor and immune cells from post-NAC surgical specimens. PD-L1 positivity in tumor cells was significantly associated with aggressive post-NAC tumor characteristics(Grandal et al., 2021).

In addition, we led a comprehensive research program aiming at deciphering the complex interplay between host, tumor, immune system and response to neoadjuvant chemotherapy (NAC) in synchronous bilateral breast cancer (sBBC). Such cancer occur after both breasts have been affected by the same germline genetics, reproductive life factors and environmental exposures for decades. We showed that left and right tumors were concordant for the majority of clinical and pathological features. Intriguingly, both the levels of tumor infiltrating lymphocytes (TILs) and the response to NAC were modified by the subtype of the contralateral tumors. Whole exome sequencing and RNAseq analyses revealed that left and right tumors were independent from a somatic mutation and transcriptomic point of view, while primary tumors (PT) before NAC and specimens with residual disease (RD) after NAC were more closely related. The analysis of the TCR repertoire identified very little overlap between patients, while common clones were shared in bilateral tumors within each patient. After NAC, the TCR repertoire of RD was enriched and expanded with clones edited by the contralateral PT (Hamy et al. 2021 submitted)

Finally, we are currently leading a research program aiming at characterizing extensively the different immune subpopulations in 42 specimens of tumor resistant to treatment (RCB-III) from various subtypes TNBC (n=15)/ luminal (n=15) / and HER2-positive BC (n=12)). We are using multispectral Vectra imaging system (PerkinElmer) and Inform* software to distinguish and localize the different cell populations (stromal/tumor) and the expression of immune checkpoint / check point ligand in residual specimen of the 3 BC subtypes. Deciphering the nature of the immune infiltration in post-neoadjuvant residual tumor burden is the biological core of this project.

Publications from the RT2Lab

Floris, G., Richard, F., Hamy, A.-S., Jongen, L., Wildiers, H., Ardui, J., Punie, K., Smeets, A., Berteloot, P., Vergote, I., De Croze, D., Meseure, D., Salomon, A., Laé, M., Reyal, F., Biganzoli, E., Neven, P., Desmedt, C., 2020. Body Mass Index and Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer. J Natl Cancer Inst. https://doi.org/10.1093/jnci/djaa090

Grandal, B., Evrevin, C., Laas, E., Jardin, I., Rozette, S., Laot, L., Dumas, E., Coussy, F., Pierga, J.-Y., Brain, E., Saule, C., Stoppa-Lyonnet, D., Frank, S., Sénéchal, C., Lae, M., De Croze, D., Bataillon, G., Guerin, J., Reyal, F., Hamy, A.-S., 2020. Impact of BRCA Mutation Status on Tumor Infiltrating Lymphocytes (TILs), Response to Treatment, and Prognosis in Breast Cancer Patients Treated with Neoadjuvant Chemotherapy. Cancers (Basel) 12. https://doi.org/10.3390/cancers12123681

Grandal, B., Mangiardi-Veltin, M., Laas, E., Laé, M., Meseure, D., Bataillon, G., El-Alam, E., Darrigues, L., Dumas, E., Daoud, E., Vincent-Salomon, A., Talagrand, L.-S., Pierga, J.-Y., Reyal, F., Hamy, A.-S., 2021. PD-L1 Expression after Neoadjuvant Chemotherapy in Triple-Negative Breast Cancers Is Associated with Aggressive Residual Disease, Suggesting a Potential for Immunotherapy. Cancers (Basel) 13. https://doi.org/10.3390/cancers13040746

Hamy, A.-S., Bonsang-Kitzis, H., Croze, D.D., Laas, E., Darrigues, L., Topciu, L., Menet, E., Vincent-Salomon, A., Lerebours, F., Pierga, J.-Y., Brain, E., Feron, J.-G., Benchimol, G., Lam, G.-T., Lae, M., Reyal, F., 2019. Interaction between molecular subtypes, stromal immune infiltration before and after treatment in breast cancer patients treated with neoadjuvant chemotherapy. Clin Cancer Res clincanres.3017.2018. https://doi.org/10.1158/1078-0432.CCR-18-3017

Hamy, A.-S., Pierga, J.-Y., Sabaila, A., Laas, E., Bonsang-Kitzis, H., Laurent, C., Vincent-Salomon, A., Cottu, P., Lerebours, F., Rouzier, R., Lae, M., Reyal, F., 2017. Stromal lymphocyte infiltration after neoadjuvant chemotherapy is associated with aggressive residual disease and lower disease-free survival in HER2-positive breast cancer. Ann. Oncol. 28, 2233–2240. https://doi.org/10.1093/annonc/mdx309

Labrosse, J., Abdennebi, I., Thibault, L., Laas, E., Merckelbagh, H., Morel, C., Lam, T., Lae, M., Reyal, F., Hamy, A.-S., 2018. Chemosensitivity, tumor infiltrating lymphocytes (TILs), and survival of postpartum PABC patients treated by neoadjuvant chemotherapy. The Breast 42, 61–67. https://doi.org/10.1016/j.breast.2018.08.103

Simon, V., Laot, L., Laas, E., Rozette, S., Guerin, J., Balezeau, T., Nicolas, M., Pierga, J.-Y., Coussy, F., Laé, M., De Croze, D., Grandal, B., Abecassis, J., Dumas, E., Lerebours, F., Reyal, F., Hamy, A.-S., 2020. No Impact of Smoking Status on Breast Cancer Tumor Infiltrating Lymphocytes, Response to Neoadjuvant Chemotherapy and Prognosis. Cancers (Basel) 12. https://doi.org/10.3390/cancers12102943

Breast cancer gathers a highly heterogeneous group of tumors differing in terms of their histological features, gene expression profiles, clinical behavior, sensitivity to systemic treatment and overall prognosis (inter-tumor heterogeneity).

Our team developed a two-step biological network-driven gene selection process: (1) identification of the most variant genes displaying highly-correlated patterns of expression, (2) direct connection of these genes within known biological networks.

By applying this pipeline to different gene expression datasets,

• we identified a robust six metagene classification across TNBC, with an immune metagene being highly correlated to the prognosis of these patients(Bonsang-Kitzis et al., 2016);
• we deciphered the heterogeneity of HER2-positive BCs(Hamy et al., 2016);
• we developed a robust molecular classification of cancer cell lines displaying a greater homogeneity of drug sensitivity than cancer cell line grouped based on tissue of origin, and this classification could be used to find new therapeutic indications to known compounds(Sadacca et al., 2017).

In addition, we also investigated the impact of intra-tumor genetic heterogeneity on cancer survival. We found that the heterogeneity inference from WES data on a single sample should be considered with caution(Abécassis et al., 2019), and we proposed CloneSig, a computational method to jointly infer intra-tumor heterogeneity and mutational processes in a tumor from bulk sequencing data(Abécassis et al., 2021). We showed that using the nucleotidic context of each mutation detected by WES or WGS, in addition to the mutation frequency, increases the sensitivity of CloneSig to detect small tumor cell populations compared to existing approaches.

Publications from the RT2Lab

Abécassis, J., Hamy, A.-S., Laurent, C., Sadacca, B., Bonsang-Kitzis, H., Reyal, F., Vert, J.-P., 2019. Assessing reliability of intra-tumor heterogeneity estimates from single sample whole exome sequencing data. PLOS ONE 14, e0224143. https://doi.org/10.1371/journal.pone.0224143

Abécassis, J., Reyal, F., Vert, J.-P., 2021. CloneSig can jointly infer intra-tumor heterogeneity and mutational signature activity in bulk tumor sequencing data. Nat Commun 12, 5352. https://doi.org/10.1038/s41467-021-24992-y

Bonsang-Kitzis, H., Sadacca, B., Hamy-Petit, A.S., Moarii, M., Pinheiro, A., Laurent, C., Reyal, F., 2016. Biological network-driven gene selection identifies a stromal immune module as a key determinant of triple-negative breast carcinoma prognosis. Oncoimmunology 5, e1061176. https://doi.org/10.1080/2162402X.2015.1061176

Hamy, A.-S., Bonsang-Kitzis, H., Lae, M., Moarii, M., Sadacca, B., Pinheiro, A., Galliot, M., Abecassis, J., Laurent, C., Reyal, F., 2016. A Stromal Immune Module Correlated with the Response to Neoadjuvant Chemotherapy, Prognosis and Lymphocyte Infiltration in HER2-Positive Breast Carcinoma Is Inversely Correlated with Hormonal Pathways. PLoS ONE 11, e0167397. https://doi.org/10.1371/journal.pone.0167397

Sadacca, B., Hamy, A.-S., Laurent, C., Gestraud, P., Bonsang-Kitzis, H., Pinheiro, A., Abecassis, J., Neuvial, P., Reyal, F., 2017. New insight for pharmacogenomics studies from the transcriptional analysis of two large-scale cancer cell line panels. Sci Rep 7, 15126. https://doi.org/10.1038/s41598-017-14770-6

This section aims at providing tools useful to researchers or scientists to ease, report, visualize group publications.

• Affiliation Generator is a web application that helps doctors, researchers and scientists managing their papers authors and their affiliations. The app will let them upload a list of researchers from their team, as well as the institutions they are affiliated to. When they are writing a new paper, a user-friendly interface lets them drag and drop authors in the desired order of authorship, to automatically generate the authors and affiliations paragraph.

https://affiliation-generator.curie.net/

• And more to come !!

In France, approximately 5% of breast cancer (BC) occur in young women under the age of 40 (n=2344 cases in 2012) (INCA, 2016). Breast cancer in young women appears to be different from those encountered in older patients and presents particular characteristics such as (i) an absence of screening, (ii) a frequent delay in diagnosis, (iii) a high frequency of advanced disease at diagnosis, (iv) a particular histological profile with a high proportion of triple negative tumors, (v) a higher association with BRCA1 and BRCA2 mutation, (vi) a high recurrence risk due to the length of follow-up.

In addition, young breast cancer patients face specific issues regarding fertility preservation procedures, pregnancy, and contraception topics.

Analyzing real-life data, we notably found that:

• Pregnancy after breast cancer in patients with germline BRCA mutations did not worsen maternal prognosis and was associated with favorable fetal outcomes (Lambertini et al., 2020);
• Type of mBRCA gene and hormone receptor status strongly impacted BC clinical behavior and outcomes in mBRCA young patients(Lambertini et al., 2021);
• ART in breast cancer survivors harboring germline pathogenic variants in BRCA1/2 was safe (Condorelli et al., 2021);
• Fertility preservation procedures was insufficiently discussed with young breast cancer patients (Hours et al., 2021);
• Time from pregnancy attempt to the occurrence of an evolutive pregnancy was short in BC patients that became pregnant after BC (Labrosse et al., 2021) (Mangiardi-Veltin, n.d.);
• The contraception prevalence was not significantly different in BC survivors than in matched controls, but the methods used were different (Sebbag et al, submitted);
• Fertility concerns, pregnancy and contraception use were not different among BC survivors according to the presence of a germline BRCA1 or BRCA2 mutation (Evrevin et al, submitted);
• The use of fertility preservation methods requiring hormonal stimulation before chemotherapy was associated with a decreased likelihood of relapse (Toussaint et al, submitted).

Breast cancer care can be evaluated by European Society of Breast Cancer Specialists (EUSOMA) indicators with 17 quality indicators concerning (i) diagnosis, (i) surgery and loco-regional treatment, (iii) radiotherapy and local control, (iv) surgery and quality of life, (v) systemic treatment (vi) staging, counseling, follow up and rehabilitation.

Several important aspects are currently being investigated within the framework of the “Young Breast cancer project”, aggregating notably data from the French Health Insurance System.

1)        Delays during health pathway such as time between “first symptom- iconography”, “clinical diagnosis- iconography”, “iconography- biopsy”, “biopsy -first treatment”.

2)        Geographic data reflecting care disparities, resulting in non uniform access to specialist care and/or large variations in individual treatments.

Publications from the RT2Lab

Condorelli, M., Bruzzone, M., Ceppi, M., Ferrari, A., Grinshpun, A., Hamy, A.S., de Azambuja, E., Carrasco, E., Peccatori, F.A., Di Meglio, A., Paluch-Shimon, S., Poorvu, P.D., Venturelli, M., Rousset-Jablonski, C., Senechal, C., Livraghi, L., Ponzone, R., De Marchis, L., Pogoda, K., Sonnenblick, A., Villarreal-Garza, C., Córdoba, O., Teixeira, L., Clatot, F., Punie, K., Graffeo, R., Dieci, M.V., Pérez-Fidalgo, J.A., Duhoux, F.P., Puglisi, F., Ferreira, A.R., Blondeaux, E., Peretz-Yablonski, T., Caron, O., Saule, C., Ameye, L., Balmaña, J., Partridge, A.H., Azim, H.A., Demeestere, I., Lambertini, M., 2021. Safety of assisted reproductive techniques in young women harboring germline pathogenic variants in BRCA1/2 with a pregnancy after prior history of breast cancer. ESMO Open 6, 100300. https://doi.org/10.1016/j.esmoop.2021.100300

Hours, A., Toussaint, A., De Castelbajac, V., Sautter, C., Borghese, J., Frank, S., Coussy, F., Laas, E., Grandal, B., Dumas, E., Daoud, E., Guerin, J., Balezeau, T., Feron, J.-G., Fourchotte, V., Kirova, Y., Lerebours, F., Pierga, J.-Y., Guillot, E., Santulli, P., Grynberg, M., Sonigo, C., Reyrat, E., Soibinet-Oudot, P., Reyal, F., Hamy, A.-S., 2021. Factors Associated With the Discussion of Fertility Preservation in a Cohort of 1,357 Young Breast Cancer Patients Receiving Chemotherapy. Frontiers in Oncology 11, 3748. https://doi.org/10.3389/fonc.2021.701620

Labrosse, J., Lecourt, A., Hours, A., Sebbag, C., Toussaint, A., Laas, E., Coussy, F., Grandal, B., Dumas, E., Daoud, E., Morel, C., Feron, J.-G., Faron, M., Pierga, J.-Y., Reyal, F., Hamy, A.-S., 2021. Time to Pregnancy, Obstetrical and Neonatal Outcomes after Breast Cancer: A Study from the Maternity Network for Young Breast Cancer Patients. Cancers (Basel) 13. https://doi.org/10.3390/cancers13051070

Lambertini, M., Ameye, L., Hamy, A.-S., Zingarello, A., Poorvu, P.D., Carrasco, E., Grinshpun, A., Han, S., Rousset-Jablonski, C., Ferrari, A., Paluch-Shimon, S., Cortesi, L., Senechal, C., Miolo, G., Pogoda, K., Pérez-Fidalgo, J.A., De Marchis, L., Ponzone, R., Livraghi, L., Estevez-Diz, M.D.P., Villarreal-Garza, C., Dieci, M.V., Clatot, F., Berlière, M., Graffeo, R., Teixeira, L., Córdoba, O., Sonnenblick, A., Luna Pais, H., Ignatiadis, M., Paesmans, M., Partridge, A.H., Caron, O., Saule, C., Del Mastro, L., Peccatori, F.A., Azim, H.A., 2020. Pregnancy After Breast Cancer in Patients With Germline BRCA Mutations. JCO 38, 3012–3023. https://doi.org/10.1200/JCO.19.02399

Lambertini, M., Ceppi, M., Hamy, A.-S., Caron, O., Poorvu, P.D., Carrasco, E., Grinshpun, A., Punie, K., Rousset-Jablonski, C., Ferrari, A., Paluch-Shimon, S., Toss, A., Senechal, C., Puglisi, F., Pogoda, K., Pérez-Fidalgo, J.A., De Marchis, L., Ponzone, R., Livraghi, L., Estevez-Diz, M.D.P., Villarreal-Garza, C., Dieci, M.V., Clatot, F., Duhoux, F.P., Graffeo, R., Teixeira, L., Córdoba, O., Sonnenblick, A., Ferreira, A.R., Partridge, A.H., Di Meglio, A., Saule, C., Peccatori, F.A., Bruzzone, M., t’Kint de Roodenbeke, M.D., Ameye, L., Balmaña, J., Del Mastro, L., Azim, H.A., 2021. Clinical behavior and outcomes of breast cancer in young women with germline BRCA pathogenic variants. NPJ Breast Cancer 7, 16. https://doi.org/10.1038/s41523-021-00224-w

Mangiardi-Veltin, n.d. PREGNANCY, FERTILITY CONCERNS, AND FERTILITY PRESERVATION PROCEDURES IN FRENCH BREAST CANCER SURVIVORS IN THE FEERIC NATIONAL STUDY (ON BEHALF OF THE SEINTINELLES RESEARCH NETWORK) | MEDRXIV.

Rational

Benefits of Physical Activity in Breast Cancer

Lack of physical activity is considered the fourth leading risk factor for death worldwide (responsible for 6% of all deaths) and is the cause of 21% of breast cancers and many other chronic diseases. The physical, biological, psychological and clinical benefits of physical activity during treatment in patients with localized breast cancer have been widely demonstrated. Physical activity significantly improves cardiorespiratory fitness, body composition, quality of life and decrease the level of fatigue and treatments side effects. Moreover, observational studies also suggest a benefit of physical activity on the risk of relapse and survival. However, despite the challenges, physical activity is neither integrated, nor measured, nor monitored on a routine basis.

Digital health: a rapidly expanding sector

Digital health is a fast-growing sector that collects a large amount of data with various devices, including mobile phones and activity trackers. These devices provide longitudinal data concerning the everyday activities of patients, outside of the hospital care context and across the continuum of breast cancer care. The allow to follow and monitor remotely the patients. The huge amounts of data generated by connected devices are making it possible to develop predictive models and to forecast clinical events or complications

Research Team Objectives:

The research team is conducting several novel and innovative projects with women with breast cancer to:

• Describe the evolution of patients' digital profiles using data generated by activity trackers,
• Develop predictive models of treatment complications,
• Use connected devices to promote an active lifestyle,
• Automatically identify patients' body composition.

Projects:

1. BEFORE:

• Objectives: i) Describe preferences, barriers, and facilitators for physical activity in primary and tertiary breast cancer prevention ii) Predict users of connected devices
• Design: Prospective study by online questionnaire
• Population: Adult women from the Seintinelles community (n=2306)
• Main results:
• More than half of women use connected devices to measure distance traveled, number of steps and track sleep (54.7%)
• They would be interested in participating in research programs that include connected devices (71.9%)

2. NeoFit:

• Objectives:
• Describe and identify digital profiles (physical activity, sleep and heart rate)
• Compare the digital profiles of participants according to clinical and sociodemographic variables
• Analyze the effects of digital profiles on tumor response, immune infiltrate, treatment toxicity, surgical complications, quality of life and fatigue
• Develop models for predicting treatments complications
• Design: NeoFit is a prospective, national, multicenter, single-arm open-label study
• Population: It will include 300 women below the age of 45 years treated with neoadjuvant chemotherapy for breast cancer
• Main results: Ongoing
• Clinical Trial: NCT05011721

2. GrannyFit:

• Objectives:
• Describe and identify digital profiles (physical activity and sleep)
• Compare the digital profiles of participants according to clinical and sociodemographic variables
• Analyze the effects of digital profiles on comorbidities, quality of life and fatigue
• Develop models for predicting treatments complications
• Design: GrannyFit is a prospective, national, multicenter, single-arm open-label study
• Population: It will include 200 women above the age of 70 years treated for breast cancer
• Main results: Coming soon

3. AdjuFit:

• Objectives:
• Describe and identify digital profiles (physical activity, sleep, heart rate and weight)
• Compare the digital profiles of participants according to clinical and sociodemographic variables
• Analyze the effects of digital profiles on comorbidities, toxicities, quality of life and fatigue
• Develop models for predicting treatments complications
• Design: AdjuFit is a prospective, national, multicenter, single-arm open-label study
• Population: It will include 300 women treated with adjuvant chemotherapy for breast cancer
• Main results: Coming soon

Lidia Delrieu previously developed

1. ABLE Trial

• Objectives: Assess the feasibility of a physical activity intervention in women with metastatic breast cancer and to explore the effects of physical activity on functional, psychological, and clinical parameters
• Design: The ABLE Trial was a single-arm, 6-month intervention study with a home-based, unsupervised, and personalized walking program using an activity tracker
• Population: Metastatic breast cancer patients
• Main results:
• 96% adhered to the exercise prescription
• Statistically significant improvements in the 6-minute walking distance test (+7%, P<.001) and isometric quadriceps strength (+22%, P<.001), as well as decreases in body mass index (-2.5%, P=.03) and hip circumference (-4.0%, P<.001) were observed at 6 months.
• Quality of life remained stable and a non statistically significant decrease (-16%, P=.07) in fatigue was observed.
• Clinical Trial: NCT03148886
• Publications

1. Delrieu L, Pérol O, Fervers B, Friedenreich C, Vallance J, Febvey-Combes O, et al. A Personalized Physical Activity Program With Activity Trackers and a Mobile Phone App for Patients With Metastatic Breast Cancer: Protocol for a Single-Arm Feasibility Trial. JMIR Res Protoc 2018;7:e10487. https://doi.org/10.2196/10487.

2. Delrieu L, Pialoux V, Pérol O, Morelle M, Martin A, Friedenreich C, et al. Feasibility and Health Benefits of an Individualized Physical Activity Intervention in Women With Metastatic Breast Cancer: Intervention Study. JMIR Mhealth Uhealth 2020;8:e12306. https://doi.org/10.2196/12306.

3. Delrieu L, Vallance JK, Morelle M, Fervers B, Pialoux V, Friedenreich C, et al. Physical activity preferences before and after participation in a 6-month physical activity intervention among women with metastatic breast cancer. Eur J Cancer Care (Engl) 2019:e13169. https://doi.org/10.1111/ecc.13169.

4. Delrieu L, Martin A, Touillaud M, Pérol O, Morelle M, Febvey-Combes O, et al. Sarcopenia and serum biomarkers of oxidative stress after a 6-month physical activity intervention in women with metastatic breast cancer: results from the ABLE feasibility trial. Breast Cancer Res Treat 2021. https://doi.org/10.1007/s10549-021-06238-z.

5. Delrieu L, Touillaud M, Pérol O, Morelle M, Martin A, Friedenreich CM, et al. Impact of Physical Activity on Oxidative Stress Markers in Patients with Metastatic Breast Cancer. Oxid Med Cell Longev 2021;2021:6694594. https://doi.org/10.1155/2021/6694594.

2. ABLE02 Trial

• Objectives: Assess the efficacy of a 6 month-physical activity program using connected devices to improve health-related quality of life and to reduce fatigue in women with metastatic breast cancer.
• Design: ABLE02 is a prospective, national, multicenter, randomized, controlled and open-label study
• Population: A total of 244 patients with a metastatic breast cancer, with a first-line chemotherapy planned
• Main results: Ongoing
• Clinical Trial: NCT04354233
• Publications

       1. Delrieu L, Anota A, Trédan O, Freyssenet D, Maire A, Canada B, et al. Design and methods of a national, multicenter, randomized and controlled trial to assess the efficacy of a physical activity program to improve health-related quality of life and reduce fatigue in women with metastatic breast cancer: ABLE02 trial. BMC Cancer 2020;20:622. https://doi.org/10.1186/s12885-020-07093-9.

Ultimately, the results of the various projects will contribute to providing quality scientific data to public policy makers to support policies to promote healthier behaviors and lifestyles.

Partnerships and collaborations:

- Institut National du Sport de l’expertise et de la Performance

- Centre Léon Bérard

- Claude Bernard University Lyon 1

- Northwestern University

- Athabasca University

- Luxembourg Institute of Health

- Les Seintinelles

- Withings

- Nouveal

- Trente-Douze

- Epiconcept