Mutational landscape of inflammatory breast cancer.

BACKGROUND: Inflammatory breast cancer (IBC) is the most pro-metastatic form of BC. Better understanding of its enigmatic pathophysiology is crucial. We report here the largest whole-exome sequencing (WES) study of clinical IBC samples. METHODS: We retrospectively applied WES to 54 untreated IBC primary tumor samples and matched normal DNA. The comparator samples were 102 stage-matched non-IBC samples from TCGA. We compared the somatic mutational profiles, spectra and signatures, copy number alterations (CNAs), HRD and heterogeneity scores, and frequencies of actionable genomic alterations (AGAs) between IBCs and non-IBCs. The comparisons were adjusted for the molecular subtypes. RESULTS: The number of somatic mutations, TMB, and mutational spectra were not different between IBCs and non-IBCs, and no gene was differentially mutated or showed differential frequency of CNAs. Among the COSMIC signatures, only the age-related signature was more frequent in non-IBCs than in IBCs. We also identified in IBCs two new mutational signatures not associated with any environmental exposure, one of them having been previously related to HIF pathway activation. Overall, the HRD score was not different between both groups, but was higher in TN IBCs than TN non-IBCs. IBCs were less frequently classified as heterogeneous according to heterogeneity H-index than non-IBCs (21% vs 33%), and clonal mutations were more frequent and subclonal mutations less frequent in IBCs. More than 50% of patients with IBC harbored at least one high-level of evidence (LOE) AGA (OncoKB LOE 1-2, ESCAT LOE I-II), similarly to patients with non-IBC. CONCLUSIONS: We provide the largest mutational landscape of IBC. Only a few subtle differences were identified with non-IBCs. The most clinically relevant one was the higher HRD score in TN IBCs than in TN non-IBCs, whereas the most intriguing one was the smaller intratumor heterogeneity of IBCs.

Treatment Response, Tumor Infiltrating Lymphocytes and Clinical Outcomes in Inflammatory Breast Cancer-Treated with Neoadjuvant Systemic Therapy.

Inflammatory breast cancer (IBC) is a rare (1%-5%), aggressive form of breast cancer, accounting for approximately 10% of breast cancer mortality. In the localized setting, standard of care is neoadjuvant chemotherapy (NACT) ± anti-HER2 therapy, followed by surgery. Here we investigated associations between clinicopathologic variables, stromal tumor-infiltrating lymphocytes (sTIL), and pathologic complete response (pCR), and the prognostic value of pCR. We included 494 localized patients with IBC treated with NACT from October 1996 to October 2021 in eight European hospitals. Standard clinicopathologic variables were collected and central pathologic review was performed, including sTIL. Associations were assessed using Firth logistic regression models. Cox regressions were used to evaluate the role of pCR and residual cancer burden (RCB) on disease-free survival (DFS), distant recurrence-free survival (DRFS), and overall survival (OS). Distribution according to receptor status was as follows: 26.4% estrogen receptor negative (ER-)/HER2-; 22.0% ER-/HER2+; 37.4% ER+/HER2-, and 14.1% ER+/HER2+. Overall pCR rate was 26.3%, being highest in the HER2+ groups (45.9% for ER-/HER2+ and 42.9% for ER+/HER2+). sTILs were low (median: 5.3%), being highest in the ER-/HER2- group (median: 10%). High tumor grade, ER negativity, HER2 positivity, higher sTILs, and taxane-based NACT were significantly associated with pCR. pCR was associated with improved DFS, DRFS, and OS in multivariable analyses. RCB score in patients not achieving pCR was independently associated with survival. In conclusion, sTILs were low in IBC, but were predictive of pCR. Both pCR and RCB have an independent prognostic role in IBC treated with NACT. SIGNIFICANCE: IBC is a rare, but very aggressive type of breast cancer. The prognostic role of pCR after systemic therapy and the predictive value of sTILs for pCR are well established in the general breast cancer population; however, only limited information is available in IBC. We assembled the largest retrospective IBC series so far and demonstrated that sTIL is predictive of pCR. We emphasize that reaching pCR remains of utmost importance in IBC.

[Medical thesis publication of medical oncology residents in France: Trends and associated factors]. / Évolution et facteurs associés à la publication des travaux de thèse d'exercice par les internes d'oncologie médicale en France.

INTRODUCTION: The French medical residency system requires the completion and subsequent defense of a thesis. Only a minority of this work is eventually published in an peer-reviewed journal. The main objective of this study was to evaluate the publication rate and associated patterns among residents appointed to the medical oncology specialty in France in order to identify ways of improving their educational framework and to promote the dissemination of their results. The secondary objective was to describe the characteristics associated with a publication in a high impact journal. METHODOLOGY: Medical students who obtained a medical oncology appointment in France between 2010 and 2015 were retrospectively identified. Records of medical theses listed in the SUDOC University Documentation System catalog were used and cross-referenced with a Medline search. RESULTS: Of the one hundred and eighty-five students included in the analysis, a publication indexed in Medline was found for 55 of them (29.7%). The average impact-factor was 5.71. The main factor independently associated with publication was a delay of ≤5 years between appointment and thesis defense dates. Among the published works, the time between appointment and defense, language of publication, study design, number of centers and patients included, and the fact that the thesis reported a clinical trial, were associated with publication in a journal with a high impact factor. CONCLUSION: These results show an approximative thesis work publication rate of 70% by medical oncology residents, and suggest the importance of starting the thesis project early during the residency in order to be published.

Comparative transcriptional analyses of preclinical models and patient samples reveal MYC and RELA driven expression patterns that define the molecular landscape of IBC.

Inflammatory breast cancer (IBC) is an aggressive disease for which the spectrum of preclinical models was rather limited in the past. More recently, novel cell lines and xenografts have been developed. This study evaluates the transcriptome of an extended series of IBC preclinical models and performed a comparative analysis with patient samples to determine the extent to which the current models recapitulate the molecular characteristics of IBC observed clinically. We demonstrate that the IBC preclinical models are exclusively estrogen receptor (ER)-negative and of the basal-like subtype, which reflects to some extent the predominance of these subtypes in patient samples. The IBC-specific 79-signature we previously reported was retrained and discriminated between IBC and non-IBC preclinical models, but with a relatively high rate of false positive predictions. Further analyses of gene expression profiles revealed important roles for cell proliferation, MYC transcriptional activity, and TNFɑ/NFκB in the biology of IBC. Patterns of MYC expression and transcriptional activity were further explored in patient samples, which revealed interactions with ESR1 expression that are contrasting in IBC and nIBC and notable given the comparatively poor outcomes of ER+ IBC. Our analyses also suggest important roles for NMYC, MXD3, MAX, and MLX in shaping MYC signaling in IBC. Overall, we demonstrate that the IBC preclinical models can be used to unravel cancer cell intrinsic molecular features, and thus constitute valuable research tools. Nevertheless, the current lack of ER-positive IBC models remains a major hurdle, particularly since interactions with the ER pathway appear to be relevant for IBC.

The Management of a Comprehensive Cancer Center during the First Six Months of the COVID-19 Pandemic in the South of France: Lessons from the Paoli-Calmettes Institute's Experience.

During the COVID-19 pandemic, it was rapidly established that cancer patients have an increased risk of developing severe forms of the 2019 coronavirus disease (COVID-19) due to a backlog of cancer diagnostics and immunosuppressive treatments. Cancer centers had to quickly adapt to continue cancer therapies despite the high infection risks and major disruptions in the French healthcare system. We described and analyzed the impact of the pandemic in our institution: management adjustments, COVID-19 infection rates in patients and staff, and impacts on clinical activities and finances during the first wave of the pandemic from March to September 2020. We also compared the results to the clinical activity data from preceding periods. A crisis unit was rapidly created that met 27 times over 66 days, generating numerous changes in hospital protocol. While our area was devastated by the pandemic, the infection rate of our staff and patients remained low (less than 1.5% of all employees). However, the lockdown period was accompanied with a reduction of most clinical activities, leading to decreases of 43%, 36%, 36%, 1%, and 10% in surgery, endoscopy, radiotherapy, and in- and out-patient chemotherapy sessions, respectively, with substantial financial loss. Our report highlights the need for the rapid creation, implementation, and adaptation of new protocols during a pandemic's evolution to prevent disease transmission. Lessons from this situation should provide motivation to better prepare for/limit the dismantling of cancer therapies that can dramatically impact patient care and have deleterious consequences on an institution's financial situation.

A study of elite sport-inspired coaching for patients after allogeneic hematopoietic stem cell transplantation.

A need for social support is often expressed after hospitalization post HSCT. Emotional support and positive psychological constructs play an important role in post-HSCT recovery. Interventions generating positive affect can influence the health and well-being of transplant patients. It has been established that coaching in elite sport area leads to performance by playing a decisive role in maintaining the athlete's feelings of hope and autonomy in order to enable him or her to achieve their goals. In this single-center, prospective, one-arm study, we evaluated, in 32 post-HSCT patients, the acceptability of a coaching program inspired by elite sport coaching. Benefits were evaluated by questionnaires and semi-structured interviews. The coaching program was accepted by 97% of the patients. Analysis of the scores on the "Means" sub-dimension of Hope showed a significant increase over time (p = 0.0249 < 0.05) for every patient. Qualitative analysis of patient's satisfaction pointed out that this support facilitated the transition to a life without illness in particular in the non-hospital context of coaching sessions. Our results show that a "sport-inspired coaching" may offer an innovative approach supporting psychological and social recovery after HSCT and helping to start and/or maintain the processes leading to psychological well-being.

Immune landscape of inflammatory breast cancer suggests vulnerability to immune checkpoint inhibitors.

Background. Anti-PD1/PDL1 immune checkpoint inhibitors (ICIs) showed promising results in breast cancer, and exploration of additional actionable immune checkpoints is ongoing. Inflammatory breast cancer (IBC) is an aggressive form of disease, the immune tumor microenvironment (TME) of which is poorly known. We aimed at providing the first comprehensive immune portrait of IBCs. Methods. From the gene expression profiles of 137 IBC and 252 non-IBC clinical samples, we measured the fractions of 22 immune cell types, expression of signatures associated with tertiary lymphoid structures (TLS) and with the response to ICIs (T cell-inflamed signature: TIS) and of 18 genes coding for major actionable immune checkpoints. The IBC/non-IBC comparison was adjusted upon the clinicopathological variables. Results. The immune profiles of IBCs were heterogeneous. CIBERSORT analysis showed profiles rich in macrophages, CD8+ and CD4 + T-cells, with remarkable similarity with melanoma TME. The comparison with non-IBCs showed significant enrichment in M1 macrophages, γδ T-cells, and memory B-cells. IBCs showed higher expression of TLS and TIS signatures. The TIS signature displayed values in IBCs close to those observed in other cancers sensitive to ICIs. Two-thirds of actionable immune genes (HAVCR2/TIM3, CD27, CD70, CTLA4, ICOS, IDO1, LAG3, PDCD1, TNFRSF9, PVRIG, CD274/PDL1, and TIGIT) were overexpressed in IBCs as compared to normal breast and two-thirds were overexpressed in IBCs versus non-IBCs, with very frequent co-overexpression. For most of them, the overexpression was associated with better pathological response to chemotherapy. Conclusion. Our results suggest the potential higher vulnerability of IBC to ICIs. Clinical trials.

Prospective high-throughput genome profiling of advanced cancers: results of the PERMED-01 clinical trial.

BACKGROUND: The benefit of precision medicine based on relatively limited gene sets and often-archived samples remains unproven. PERMED-01 (NCT02342158) was a prospective monocentric clinical trial assessing, in adults with advanced solid cancer, the feasibility and impact of extensive molecular profiling applied to newly biopsied tumor sample and based on targeted NGS (t-NGS) of the largest gene panel to date and whole-genome array-comparative genomic hybridization (aCGH) with assessment of single-gene alterations and clinically relevant genomic scores. METHODS: Eligible patients with refractory cancer had one tumor lesion accessible to biopsy. Extracted tumor DNA was profiled by t-NGS and aCGH. We assessed alterations of 802 "candidate cancer" genes and global genomic scores, such as homologous recombination deficiency (HRD) score and tumor mutational burden. The primary endpoint was the number of patients with actionable genetic alterations (AGAs). Secondary endpoints herein reported included a description of patients with AGA who received a "matched therapy" and their clinical outcome, and a comparison of AGA identification with t-NGS and aCGH versus whole-exome sequencing (WES). RESULTS: Between November 2014 and September 2019, we enrolled 550 patients heavily pretreated. An exploitable complete molecular profile was obtained in 441/550 patients (80%). At least one AGA, defined in real time by our molecular tumor board, was found in 393/550 patients (71%, two-sided 90%CI 68-75%). Only 94/550 patients (17%, 95%CI 14-21) received an "AGA-matched therapy" on progression. The most frequent AGAs leading to "matched therapy" included PIK3CA mutations, KRAS mutations/amplifications, PTEN deletions/mutations, ERBB2 amplifications/mutations, and BRCA1/2 mutations. Such "matched therapy" improved by at least 1.3-fold the progression-free survival on matched therapy (PFS2) compared to PFS on prior therapy (PFS1) in 36% of cases, representing 6% of the enrolled patients. Within patients with AGA treated on progression, the use of "matched therapy" was the sole variable associated with an improved PFS2/PFS1 ratio. Objective responses were observed in 19% of patients treated with "matched therapy," and 6-month overall survival (OS) was 62% (95%CI 52-73). In a subset of 112 metastatic breast cancers, WES did not provide benefit in term of AGA identification when compared with t-NGS/aCGH. CONCLUSIONS: Extensive molecular profiling of a newly biopsied tumor sample identified AGA in most of cases, leading to delivery of a "matched therapy" in 17% of screened patients, of which 36% derived clinical benefit. WES did not seem to improve these results. TRIAL REGISTRATION: ID-RCB identifier: 2014-A00966-41; ClinicalTrials.gov identifier: NCT02342158 .

The use of 'added benefit' to determine the price of new anti-cancer drugs in France, 2004-2017.

BACKGROUND: Increasing drug prices strains budgets. Assessing the relation between added benefit and prices can help clinical decision-making and resource allocation. METHODS: We assessed, over a period of 13 years, the relation between added therapeutic benefit and prices for drugs to treat solid tumours in France using the French High Authority of Health Scale (ASMR) and the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (MCBS). RESULTS: In total, 36 medications were approved for 68 indications. There was a weak correlation between ASMR and MCBS scales (Spearman's |ρ| = 0.28). Drugs had low added benefit on both ASMR (71%) and MCBS (49%). Mean monthly price for new drugs was €4616 (S.D., €3096), ranging from €1795 to €19,675 and increased by 47% comparing 2004-2012 with 2013-2017. The mean monthly price difference of new drugs over their comparator was €3700 (S.D., €3934) ranging between a €13,853 decrease and a €19,675 increase. There was a weak but statistically significant correlation between ASMR and price (|ρ| = 0.35, p = 0.004) and between MCBS and price (|ρ| = 0.33, p = 0.005). Correlations between added benefit and prices were similar or higher for first indications (ASMR, |ρ| = 0.37, p = 0.030; MCBS, |ρ| = 0.48, p = 0.004). In first indications, mean monthly prices increased €3954 for drugs without ASMR added benefit. The mean annual price and price increase for first indications offering no ASMR benefit was €57,312 and €47,448, respectively. CONCLUSION: Prices and benefit are weakly correlated. However, prices increased substantially even for drugs with no added benefit.

[E-health and "Cancer outside the hospital walls", Big Data and artificial intelligence]. / Santé numérique et « cancer hors les murs ¼, Big Data et intelligence artificielle.

To heal otherwise in oncology has become an imperative of Public Health and an economic imperative in France. Patients can therefore receive live most of their care outside of hospital with more ambulatory care. This ambulatory shift will benefit from the digital revolution and the development of digital health or e-health. Cancer research will also benefit with Big Data and artificial intelligence, which gather and analyze a huge amount of data. In this synthesis, we describe the different e-health tools and their potential impacts in oncology, at the levels of education and information of patients and caregivers, prevention, screening and diagnosis, treatment, follow-up, and research. A few randomized studies have already demonstrated clinical benefits. Large Big Data projects such as ConSoRe and Health Data Hub have been launched in France. We also discuss the issues and limitations of "cancer outside the hospital walls and e-health" from the point of view of patients, health care professionals, health facilities and government. This new organization will have to provide remote support "outside the walls" with care and follow-up of quality, continuous and prolonged in total safety and equity. Ongoing and future randomized clinical trials will need to definitively demonstrate areas of interest, advantages and drawbacks not only for patients, but also for caregivers, health facilities and governments.

NOTCH and DNA repair pathways are more frequently targeted by genomic alterations in inflammatory than in non-inflammatory breast cancers.

Inflammatory breast cancer (IBC) is the most pro-metastatic form of breast cancer. Better understanding of its pathophysiology and identification of actionable genetic alterations (AGAs) are crucial to improve systemic treatment. We aimed to define the DNA profiles of IBC vs noninflammatory breast cancer (non-IBC) clinical samples in terms of copy number alterations (CNAs), mutations, and AGAs. We applied targeted next-generation sequencing (tNGS) and array-comparative genomic hybridization (aCGH) to 57 IBC and 50 non-IBC samples and pooled these data with four public datasets profiled using NGS and aCGH, leading to a total of 101 IBC and 2351 non-IBC untreated primary tumors. The respective percentages of each molecular subtype [hormone receptor-positive (HR+)/HER2-, HER2+, and triple-negative] were 68%, 15%, and 17% in non-IBC vs 25%, 35%, and 40% in IBC. The comparisons were adjusted for both the molecular subtypes and the American Joint Committee on Cancer (AJCC) stage. The 10 most frequently altered genes in IBCs were TP53 (63%), HER2/ERBB2 (30%), MYC (27%), PIK3CA (21%), BRCA2 (14%), CCND1 (13%), GATA3 (13%), NOTCH1 (12%), FGFR1 (11%), and ARID1A (10%). The tumor mutational burden was higher in IBC than in non-IBC. We identified 96 genes with an alteration frequency (p < 5% and q < 20%) different between IBC and non-IBC, independently from the molecular subtypes and AJCC stage; 95 were more frequently altered in IBC, including TP53, genes involved in the DNA repair (BRCA2) and NOTCH pathways, and one (PIK3CA) was more frequently altered in non-IBC. Ninety-seven percent of IBCs displayed at least one AGA. This percentage was higher than in non-IBC (87%), notably for drugs targeting DNA repair, NOTCH signaling, and CDK4/6, whose pathways were more frequently altered (DNA repair) or activated (NOTCH and CDK4/6) in IBC than in non-IBC. The genomic landscape of IBC is different from that of non-IBC. Enriched AGAs in IBC may explain its aggressiveness and provide clinically relevant targets.

A Tyrosine Kinase Expression Signature Predicts the Post-Operative Clinical Outcome in Triple Negative Breast Cancers.

Triple negative breast cancer (TNBC) represent 15% of breast cancers. Histoclinical features and marketed prognostic gene expression signatures (GES) failed to identify good- and poor-prognosis patients. Tyrosine kinases (TK) represent potential prognostic and/or therapeutic targets for TNBC. We sought to define a prognostic TK GES in a large series of TNBC. mRNA expression and histoclinical data of 6379 early BCs were collected from 16 datasets. We searched for a TK-based GES associated with disease-free survival (DFS) and tested its robustness in an independent validation set. A total of 1226 samples were TNBC. In the learning set of samples (N = 825), we identified a 13-TK GES associated with DFS. This GES was associated with cell proliferation and immune response. In multivariate analysis, it outperformed the previously published GESs and classical prognostic factors in the validation set (N = 401), in which the patients classified as "low-risk" had a 73% 5-year DFS versus 53% for "high-risk" patients (p = 1.85 × 10-3). The generation of 100,000 random 13-gene signatures by a resampling scheme showed the non-random nature of our classifier, which was also prognostic for overall survival in multivariate analysis. We identified a robust and non-random 13-TK GES that separated TNBC into subgroups of different prognosis. Clinical and functional validations are warranted.

PD-1/PD-L1 Targeting in Breast Cancer: The First Clinical Evidences Are Emerging. A Literature Review.

Recently, the development of immunotherapy through the immune checkpoint blockade led to long-lasting responses in several types of cancers that are refractory to conventional treatments, such as melanoma or non-small cell lung cancer. Immunotherapy has also demonstrated significant improvements in various other types of cancers. However, breast cancer remains one of the tumors that have not experienced the explosion of immunotherapy yet. Indeed, breast cancer was traditionally considered as being weakly immunogenic with a lower mutational load compared to other tumor types. In the last few years, anti-PD1/PD-L1 (Programmed death-ligand 1) agents have been evaluated in breast cancer, particularly in the triple negative subtype, with promising results observed when delivered as monotherapy or in combination with conventional treatments. In this review, we will report the results of the most recent studies evaluating immune checkpoint inhibitors in breast cancer. In addition, we will discuss the concomitant development of possible biomarkers, which is required for improving the selection of patients with the highest probability of benefiting from these agents.

A Comparison of DNA Mutation and Copy Number Profiles of Primary Breast Cancers and Paired Brain Metastases for Identifying Clinically Relevant Genetic Alterations in Brain Metastases.

Improving the systemic treatment of brain metastases (BM) in primary breast cancer (PBC) is impaired by the lack of genomic characterization of BM. To estimate the concordance of DNA copy-number-alterations (CNAs), mutations, and actionable genetic alterations (AGAs) between paired samples, we performed whole-genome array-comparative-genomic-hybridization, and targeted-next-generation-sequencing on 14 clinical PBC-BM pairs. We found more CNAs, more mutations, and higher tumor mutational burden, and more AGAs in BM than in PBC; 92% of the pairs harbored at least one AGA in the BM not observed in the paired PBC. This concerned various therapeutic classes, including tyrosine-kinase-receptor-inhibitors, phosphatidylinositol 3-kinase/AKT/ mammalian Target of Rapamycin (PI3K/AKT/MTOR)-inhibitors, poly ADP ribose polymerase (PARP)-inhibitors, or cyclin-dependent kinase (CDK)-inhibitors. With regards to the PARP-inhibitors, the homologous recombination defect score was positive in 79% of BM, compared to 43% of PBC, discordant in 7 out of 14 pairs, and positive in the BM in 5 out of 14 cases. CDK-inhibitors were associated with the largest percentage of discordant AGA appearing in the BM. When considering the AGA with the highest clinical-evidence level, for each sample, 50% of the pairs harbored an AGA in the BM not detected or not retained from the analysis of the paired PBC. Thus, the profiling of BM provided a more reliable opportunity, than that of PBC, for diagnostic decision-making based on genomic analysis. Patients with BM deserve an investigation of several targeted therapies.

Stem Cells Inhibition by Bevacizumab in Combination with Neoadjuvant Chemotherapy for Breast Cancer.

Preclinical works have suggested cytotoxic chemotherapies may increase the number of cancer stem cells (CSC) whereas angiogenesis inhibition may decrease CSC proliferation. We developed a proof of concept clinical trial to explore bevacizumab activity on breast CSC. Breast cancer patients requiring preoperative chemotherapy were included in this open-label, randomized, prospective, multicenter phase II trial. All received FEC-docetaxel combination, and patients randomized in the experimental arm received concomitant bevacizumab. The primary endpoint was to describe ALDH1 (Aldehyde dehydrogenase 1) positive tumor cells rate before treatment and after the fourth cycle. Secondary objectives included safety, pathological complete response (pCR) rate, disease-free survival (DFS), relapse-free survival (RFS), and overall survival (OS). Seventy-five patients were included. ALDH1+ cells rate increase was below the predefined 5% threshold in both arms for the 32 patients with two time points available. Grade 3 or 4 adverse events rates were similar in both arms. A non-significant increase in pCR was observed in the bevacizumab arm (42.6% vs. 18.2%, p = 0.06), but survival was not improved (OS: p = 0.89; DFS: p = 0.45; and RFS: p = 0.68). The increase of ALDH1+ tumor cells rate after bevacizumab-based chemotherapy was less than 5%. However, as similar results were observed with chemotherapy alone, bevacizumab impact on breast CSC cells cannot be confirmed.

The immunologic constant of rejection classification refines the prognostic value of conventional prognostic signatures in breast cancer.

BACKGROUND: The immunologic constant of rejection (ICR) is a broad phenomenon of Th-1 immunity-mediated, tissue-specific destruction. METHODS: We tested the prognostic value of a 20-gene ICR expression signature in 8766 early breast cancers. RESULTS: Thirty-three percent of tumours were ICR1, 29% ICR2, 23% ICR3, and 15% ICR4. In univariate analysis, ICR4 was associated with a 36% reduction in risk of metastatic relapse when compared with ICR1-3 (p = 2.30E-03). In multivariate analysis including notably the three major prognostic signatures (Recurrence score, 70-gene signature, ROR-P), ICR was the strongest predictive variable (p = 9.80E-04). ICR showed no prognostic value in the HR+/HER2- subtype, but prognostic value in the HER2+ and TN subtypes. Furthermore, in each molecular subtype and among the tumours defined as high risk by the three prognostic signatures, ICR4 patients had a 41-75% reduction in risk of relapse as compared with ICR1-3 patients. ICR added significant prognostic information to that provided by the clinico-genomic models in the overall population and in each molecular subtype. ICR4 was independently associated with achievement of pathological complete response to neoadjuvant chemotherapy (p = 2.97E-04). CONCLUSION: ICR signature adds prognostic information to that of current proliferation-based signatures, with which it could be integrated to improve patients' stratification and guide adjuvant treatment.