A bio-behavioral model of systemic inflammation at breast cancer diagnosis and fatigue of clinical importance 2 years later.

BACKGROUND: We aimed to generate a model of cancer-related fatigue (CRF) of clinical importance 2 years after diagnosis of breast cancer building on clinical and behavioral factors and integrating pre-treatment markers of systemic inflammation. PATIENTS AND METHODS: Women with stage I-III hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer were included from the multimodal, prospective CANTO cohort (NCT01993498). The primary outcome was global CRF of clinical importance [European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 ≥40/100] 2 years after diagnosis (year 2). Secondary outcomes included physical, emotional, and cognitive CRF (EORTC QLQ-FA12). All pre-treatment candidate variables were assessed at diagnosis, including inflammatory markers [interleukin (IL)-1α, IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, interferon γ, IL-1 receptor antagonist, tumor necrosis factor-α, and C-reactive protein], and were tested in multivariable logistic regression models implementing multiple imputation and validation by 100-fold bootstrap resampling. RESULTS: Among 1208 patients, 415 (34.4%) reported global CRF of clinical importance at year 2. High pre-treatment levels of IL-6 (quartile 4 versus 1) were associated with global CRF at year 2 [adjusted odds ratio (aOR): 2.06 (95% confidence interval [CI] 1.40-3.03); P = 0.0002; area under the receiver operating characteristic curve = 0.74]. Patients with high pre-treatment IL-6 had unhealthier behaviors, including being frequently either overweight or obese [62.4%; mean body mass index 28.0 (standard deviation 6.3 kg/m2)] and physically inactive (53.5% did not meet World Health Organization recommendations). Clinical and behavioral associations with CRF at year 2 included pre-treatment CRF [aOR versus no pre-treatment CRF: 3.99 (95% CI 2.81-5.66)], younger age [aOR per 1-year decrement: 1.02 (95% CI 1.01-1.03)], current tobacco smoking [aOR versus never: 1.81 (95% CI 1.26-2.58)], and worse insomnia or pain [aOR per 10-unit increment: 1.08 (95% CI 1.04-1.13), and 1.12 (95% CI 1.04-1.21), respectively]. Secondary analyses indicated additional associations of IL-2 [aOR per log-unit increment: 1.32 (95% CI 1.03-1.70)] and IL-10 [0.73 (95% CI 0.57-0.93)] with global CRF and of C-reactive protein [1.42 (95% CI 1.13-1.78)] with cognitive CRF at year 2. Emotional distress was consistently associated with physical, emotional, and cognitive CRF. CONCLUSIONS: This study proposes a bio-behavioral framework linking pre-treatment systemic inflammation with CRF of clinical importance 2 years later among a large prospective sample of survivors of breast cancer.

The ESMO Tumour-Agnostic Classifier and Screener (ETAC-S): a tool for assessing tumour-agnostic potential of molecularly guided therapies and for steering drug development.

BACKGROUND: Advances in precision oncology led to approval of tumour-agnostic molecularly guided treatment options (MGTOs). The minimum requirements for claiming tumour-agnostic potential remain elusive. METHODS: The European Society for Medical Oncology (ESMO) Precision Medicine Working Group (PMWG) coordinated a project to optimise tumour-agnostic drug development. International experts examined and summarised the publicly available data used for regulatory assessment of the tumour-agnostic indications approved by the US Food and Drug Administration and/or the European Medicines Agency as of December 2023. Different scenarios of minimum objective response rate (ORR), number of tumour types investigated, and number of evaluable patients per tumour type were assessed for developing a screening tool for tumour-agnostic potential. This tool was tested using the tumour-agnostic indications approved during the first half of 2024. A taxonomy for MGTOs and a framework for tumour-agnostic drug development were conceptualised. RESULTS: Each tumour-agnostic indication had data establishing objective response in at least one out of five patients (ORR ≥ 20%) in two-thirds (≥4) of the investigated tumour types, with at least five evaluable patients in each tumour type. These minimum requirements were met by tested indications and may serve as a screening tool for tumour-agnostic potential, requiring further validation. We propose a conceptual taxonomy classifying MGTOs based on the therapeutic effect obtained by targeting a driver molecular aberration across tumours and its modulation by tumour-specific biology: tumour-agnostic, tumour-modulated, or tumour-restricted. The presence of biology-informed mechanistic rationale, early regulatory advice, and adequate trial design demonstrating signs of biology-driven tumour-agnostic activity, followed by confirmatory evidence, should be the principles for tumour-agnostic drug development. CONCLUSION: The ESMO Tumour-Agnostic Classifier (ETAC) focuses on the interplay of targeted driver molecular aberration and tumour-specific biology modulating the therapeutic effect of MGTOs. We propose minimum requirements to screen for tumour-agnostic potential (ETAC-S) as part of tumour-agnostic drug development. Definition of ETAC cut-offs is warranted.

Feasibility and Safety of the "One-Week Breast Radiation Therapy" Program.

AIMS: FAST-Forward and UK-FAST-trials have demonstrated the safety and efficacy of five-fraction breast adjuvant radiation therapy (RT) and have become the standard of care for selected early breast cancer patients. In response to the additional burden caused by the COVID-19 pandemic, we implemented "One-Week Breast RT," an innovative program delivering five-fraction whole breast RT in a complete 5-day workflow. The primary objective of this study was to demonstrate the feasibility and safety of our program. The secondary objective was to evaluate cosmetic results. MATERIAL AND METHODS: A total of 120 patients treated from February 2021 to March 2022, received whole breast RT without lymph node irradiation nor boost, with 26 Gy in five fractions over one week. Inverse planning with restricted optimization parameters offers systematic deep inspiration breath-hold aimed to provide treatment plans compliant with FAST-Forward recommendations. Toxicity and cosmetic evaluations were prospectively registered prior (pre-RT), at the end (end-RT), and 6 months after RT (6 months) based on Common Terminology Criteria for Adverse Events v. 4.03 and Harvard scale. RESULTS: With a median age of 70 years (interquartile range (IQR): 66-74) and a median follow-up of 6 months (IQR: 6.01-6.25), most patients (93.3%) completed their RT in one week from baseline to the end of the treatment consultation. The most common acute toxicities (at end-RT) were skin-related: radio-dermatitis (72%), induration (35%), hyperpigmentation (8%), and breast edema (16%). The rate of radio-dermatitis decreased from end-RT to 6 months (71.7% vs 5.4%, P< 0.001). No patient experienced grade ≥3 toxicity. At 6 months, cosmetic results were generally good or excellent (94.1%). CONCLUSION: This study confirms the feasibility and acute safety of the "One-Week Breast RT" in real life. Favorable toxicity profiles and good cosmetic outcomes are in line with FAST-Forward results. A prospective national cohort, aimed at decreasing treatment burden, maintaining safety, efficacy, and improving RT workflow efficiency with longer follow-up is ongoing.

Recommendations for the use of next-generation sequencing (NGS) for patients with advanced cancer in 2024: a report from the ESMO Precision Medicine Working Group.

BACKGROUND: Advancements in the field of precision medicine have prompted the European Society for Medical Oncology (ESMO) Precision Medicine Working Group to update the recommendations for the use of tumour next-generation sequencing (NGS) for patients with advanced cancers in routine practice. METHODS: The group discussed the clinical impact of tumour NGS in guiding treatment decision using the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) considering cost-effectiveness and accessibility. RESULTS: As for 2020 recommendations, ESMO recommends running tumour NGS in advanced non-squamous non-small-cell lung cancer, prostate cancer, colorectal cancer, cholangiocarcinoma, and ovarian cancer. Moreover, it is recommended to carry out tumour NGS in clinical research centres and under specific circumstances discussed with patients. In this updated report, the consensus within the group has led to an expansion of the recommendations to encompass patients with advanced breast cancer and rare tumours such as gastrointestinal stromal tumours, sarcoma, thyroid cancer, and cancer of unknown primary. Finally, ESMO recommends carrying out tumour NGS to detect tumour-agnostic alterations in patients with metastatic cancers where access to matched therapies is available. CONCLUSION: Tumour NGS is increasingly expanding its scope and application within oncology with the aim of enhancing the efficacy of precision medicine for patients with cancer.

Moving toward precision medicine to predict drug sensitivity in patients with metastatic breast cancer.

Tumor heterogeneity represents a major challenge in breast cancer, being associated with disease progression and treatment resistance. Precision medicine has been extensively applied to dissect tumor heterogeneity and, through a deeper molecular understanding of the disease, to personalize therapeutic strategies. In the last years, technological advances have widely improved the understanding of breast cancer biology and several trials have been developed to translate these new insights into clinical practice, with the ultimate aim of improving patients' outcomes. In the era of molecular oncology, genomics analyses and other methodologies are shaping a new treatment algorithm in breast cancer care. In this manuscript, we review the main steps of precision medicine to predict drug sensitivity in breast cancer from a translational point of view. Genomic developments and their clinical implications are discussed, along with technological advancements that could broaden precision medicine applications. Current achievements are put into perspective to provide an overview of the state-of-art of breast cancer precision oncology as well as to identify future research directions.

Does vibration frequency and location influence the effect of neck muscle vibration on postural sway? A cross-sectional study in asymptomatic participants.

INTRODUCTION: Postural control is of utmost importance for human functioning. Cervical proprioception is crucial for balance control. Therefore, any change to it can lead to balance problems. Previous studies used neck vibration to change cervical proprioception and showed changes in postural control, but it remains unknown which vibration frequency or location causes the most significant effect. Therefore, this study aimed to investigate the effect of different vibration frequencies and locations on postural sway and to serve as future research protocol guidance. METHODS: Seventeen healthy young participants were included in the study. We compared postural sway without vibration to postural sway with six different combinations of vibration frequency (80, 100, and 150 Hz) and location (dorsal neck muscles and sternocleidomastoid). Postural sway was evaluated using a force platform. The mean center of pressure (CoP) displacement, the root mean square (RMS), and the mean velocity in the anteroposterior and mediolateral direction were calculated, as well as the sway area. The aligned rank transform tool and a three-way repeated measures ANOVA were used to identify significant differences in postural sway variables. RESULTS: Neck vibration caused a significant increase in all postural sway variables (p < 0.001). Neither the vibration frequency (p > 0.34) nor location (p > 0.29) nor the interaction of both (p > 0.30) influenced the magnitude of the change in postural sway measured during vibration. CONCLUSION: Neck muscle vibration significantly changes CoP displacement, mean velocity, RMS, and area. However, we investigated and found that there were no significant differences between the different combinations of vibration frequency and location.

Single-cell DNA-seq depicts clonal evolution of multiple driver alterations in osimertinib-resistant patients.

BACKGROUND: The development of targeted agents, such as osimertinib for EGFR-mutated non-small-cell lung cancer (NSCLC), has drastically improved patient outcome, but tumor resistance eventually always occurs. In osimertinib-resistant NSCLC, the emergence of a second molecular driver alteration (such as ALK, RET, FGFR3 fusions or BRAF, KRAS mutations) has been described. Whether those alterations and the activating EGFR mutations occur within a single cancer cell or in distinct cell populations is largely debated. PATIENTS AND METHODS: Tumor sequencing was used to identify the acquired resistance mechanisms to osimertinib in the MATCH-R trial (NCT0251782). We implemented single-cell next-generation sequencing to investigate tumor heterogeneity on patient's frozen tissues in which multiple alterations have been identified. Patient-derived models, cell lines, and patient-derived xenografts were exposed to specific inhibitors to investigate combination treatment strategies. RESULTS: Among the 45 patients included in MATCH-R who progressed on osimertinib, 9 developed a second targetable alteration (n = 2 FGFR3-TACC3, n = 1 KIF5B-RET, n = 1 STRN-ALK fusions; n = 2 BRAFV600E, n = 1 KRASG12V, n = 1 KRASG12R, n = 1 KRASG12D mutations). Single-cell analysis revealed that the two driver alterations coexist within one single cancer cell in the four patients whose frozen samples were fully contributive. A high degree of heterogeneity within samples and sequential acquisitions of molecular events were highlighted. A combination treatment concomitantly targeting the two driver alterations was required on the corresponding patient-derived models to restore cell sensitivity, which was consistent with clinical data showing efficacy of brigatinib in the patient with ALK fusion after progression to osimertinib and crizotinib administered sequentially. CONCLUSIONS: Distinct molecular driver alterations at osimertinib resistance coexist with initial EGFR mutations in single cancer cells. The clonal evolution of cancer cell populations emphasized their heterogeneity leading to osimertinib relapse. Combining two targeted treatments is effective to achieve clinical benefit.

[Surgery or not on an atypical breast lesion? Taking anxiety into account in shared decision support from a prospective cohort of 300 patients]. / Opérer ou non une lésion atypique du sein ? Prise en compte de l'anxiété dans l'aide à la décision partagée à partir d'une cohorte prospective de 300 patientes.

INTRODUCTION: Organized and individual breast screening have been accompanied by an increase in the detection of "atypical breast lesions (ABL)". Recently, the NOMAT multicenter study proposed a predictive model of the risk of developing breast cancer after detection of an ABL in order to avoid surgical removal of "low-risk" lesions. It also aimed to provide information on psychological experience, in particularly anxiety, to assist in the shared medical decision process. METHODS: Three hundred women undergoing surgery for ABL were included between 2015 and 2018 at 18 French centers. Women completed questionnaires before and after surgery assessing their level of anxiety (STAI-State, STAI-Trait), their level of tolerance to uncertainty, their perceived risk of developing a breast cancer, and their satisfaction with the management care. RESULTS: One hundred nighty nine patients completed the STAI-Status before and after surgery. Overall, a decrease in anxiety level (35.4 vs 42.7, P<0.001) was observed. Anxious temperament and greater intolerance to uncertainty were significantly associated swith decreased anxiety (33%), whereas younger age was associated with increased anxiety (8%). CONCLUSION: Surgery for ABL seems to be associated with only a few cases with an increase in anxiety and seems to increase the perception of the risk of developing breast cancer. Taking into account the psychological dimension remains in all cases essential in the process of shared therapeutic decision.

The journey of tumor-infiltrating lymphocytes as a biomarker in breast cancer: clinical utility in an era of checkpoint inhibition.

In 2014, we described a method to quantify percentage of tumor-infiltrating lymphocytes (TILs) on hematoxylin and eosin-stained slides of breast cancer samples using light microscopy that could be performed easily by pathologists with no extra stains. The aim of detailing the method was to facilitate independent research groups replicating our prognostic findings using TIL quantity in early-stage breast cancers. A global working group of breast pathologists was convened to standardize, test reproducibility, and refine the method. A website was also established which allowed free training (www.tilsinbreastcancer.org). As a result of this work, TIL data have been collected in over 20 000 primary breast cancer samples worldwide and the robust associations with better prognoses in triple-negative breast cancer (TNBC) and HER2+ BC have been confirmed. This has resulted in the inclusion of the TIL biomarker in several international breast cancer guidelines as well as in national criteria for routine pathology reporting. TIL therefore represents the first biological prognostic biomarker for early-stage TNBCs, and here its prognostic effect is linear, with values of 30%-50% being suggested as suitable for use in potential chemotherapy de-escalation studies. The efficacy of immune checkpoint-targeted agents in breast cancer now provides direct evidence that host immune responses can modify tumor growth in some patients. With the recent granting of accelerated approvals for the first PD-1/PD-L1 targeting agents in early and advanced TNBC, our focus has now moved to investigating the clinical utility of TIL in the setting of immune checkpoint agents, with or without PD-L1 protein assessment. Emerging data suggest that TIL quantity can help clinicians identify patients with breast cancer who benefit most from PD-1/PD-L1 inhibition. In patients with advanced TNBC and HER2+ disease a TIL cut-off of 5% or 10%, with PD-L1 expression can define 'immune-enriched' tumors and currently seems to have the most clinical relevance in this context.

Recommendations for the use of next-generation sequencing (NGS) for patients with metastatic cancers: a report from the ESMO Precision Medicine Working Group.

Next-generation sequencing (NGS) allows sequencing of a high number of nucleotides in a short time frame at an affordable cost. While this technology has been widely implemented, there are no recommendations from scientific societies about its use in oncology practice. The European Society for Medical Oncology (ESMO) is proposing three levels of recommendations for the use of NGS. Based on the current evidence, ESMO recommends routine use of NGS on tumour samples in advanced non-squamous non-small-cell lung cancer (NSCLC), prostate cancers, ovarian cancers and cholangiocarcinoma. In these tumours, large multigene panels could be used if they add acceptable extra cost compared with small panels. In colon cancers, NGS could be an alternative to PCR. In addition, based on the KN158 trial and considering that patients with endometrial and small-cell lung cancers should have broad access to anti-programmed cell death 1 (anti-PD1) antibodies, it is recommended to test tumour mutational burden (TMB) in cervical cancers, well- and moderately-differentiated neuroendocrine tumours, salivary cancers, thyroid cancers and vulvar cancers, as TMB-high predicted response to pembrolizumab in these cancers. Outside the indications of multigene panels, and considering that the use of large panels of genes could lead to few clinically meaningful responders, ESMO acknowledges that a patient and a doctor could decide together to order a large panel of genes, pending no extra cost for the public health care system and if the patient is informed about the low likelihood of benefit. ESMO recommends that the use of off-label drugs matched to genomics is done only if an access programme and a procedure of decision has been developed at the national or regional level. Finally, ESMO recommends that clinical research centres develop multigene sequencing as a tool to screen patients eligible for clinical trials and to accelerate drug development, and prospectively capture the data that could further inform how to optimise the use of this technology.

Differential impact of endocrine therapy and chemotherapy on quality of life of breast cancer survivors: a prospective patient-reported outcomes analysis.

BACKGROUND: In early breast cancer (BC), there has been a trend to escalate endocrine therapy (ET) and to de-escalate chemotherapy (CT). However, the impact of ET versus CT on the quality of life (QoL) of early BC patients is unknown. Here, we characterize the independent contribution of ET and CT on patient-reported outcomes (PROs) at 2 years after diagnosis. PATIENTS AND METHODS: We prospectively collected PROs in 4262 eligible patients using the European Organization for Research and Treatment of Cancer QLQ-C30/BR23 questionnaires inside CANTO trial (NCT01993498). The primary outcome was the C30 summary score (C30-SumSc) at 2 years after diagnosis. RESULTS: From eligible patients, 37.2% were premenopausal and 62.8% postmenopausal; 81.9% received ET and 52.8% CT. In the overall cohort, QoL worsened by 2 years after diagnosis in multiple functions and symptoms; exceptions included emotional function and future perspective, which improved over time. ET (Pint = 0.004), but not CT (Pint = 0.924), had a persistent negative impact on the C30-SumSc. In addition, ET negatively impacted role and social function, pain, insomnia, systemic therapy side-effects, breast symptoms and further limited emotional function and future perspective recovery. Although CT had no impact on the C30-SumSc at 2-years it was associated with deteriorated physical and cognitive function, dyspnea, financial difficulties, body image and breast symptoms. We found a differential effect of treatment by menopausal status; in premenopausal patients, CT, despite only a non-significant trend for deteriorated C30-SumSc (Pint = 0.100), was more frequently associated with QoL domains deterioration than ET, whereas in postmenopausal patients, ET was more frequently associated with QoL deterioration, namely using the C30-SumSc (Pint = 0.004). CONCLUSION(S): QoL deterioration persisted at 2 years after diagnosis with different trajectories by treatment received. ET, but not CT, had a major detrimental impact on C30-SumSc, especially in postmenopausal women. These findings highlight the need to properly select patients for adjuvant ET escalation.

Prognostic value of tumor-infiltrating lymphocytes in patients with early-stage triple-negative breast cancers (TNBC) who did not receive adjuvant chemotherapy.

BACKGROUND: Although stromal tumor-infiltrating lymphocytes (sTILs) have been considered an important prognostic factor in early-stage triple-negative breast cancer (TNBC), there have been limited data on their prognostic value in the absence of adjuvant chemotherapy. PATIENTS AND METHODS: A pooled analysis was carried out using four cohorts of TNBC patients not treated with chemotherapy. sTILs were evaluated in the most representative tumoral block of surgical specimens. Cox proportional hazards regression models were used for invasive disease-free survival (iDFS), distant disease-free survival (D-DFS), and overall survival (OS), fitting sTILs as a continuous variable adjusted for clinicopathologic factors. RESULTS: We analyzed individual data of 476 patients from 4 centers diagnosed between 1989 and 2015. Their median age was 64 years. The median tumor size was 1.6 cm and 83% were node-negative. The median level of sTILs was 10% (Q1-Q3, 4%-30%). Higher grade was associated with higher sTILs (P < 10-3). During follow-up, 107 deaths, and 173 and 118 events for iDFS and D-DFS were observed, respectively. In the multivariable analysis, sTILs obtained an independent prognostic value for all end points (likelihood ratio χ2 = 7.14 for iDFS; P < 10-2; χ2 = 9.63 for D-DFS, P < 10-2; χ2 = 5.96 for OS, P = 0.015). Each 10% increment in sTILs corresponded to a hazard ratio of 0.90 [95% confidence interval (CI) 0.82 - 0.97] for iDFS, 0.86 (95% CI 0.77 - 0.95) for D-DFS, and 0.88 (95% CI 0.79 - 0.98) for OS, respectively. In patients with pathological stage I tumors with sTILs ≥30% (n = 74), 5-year iDFS was 91% (95% CI 84% to 96%), D-DFS was 97% (95% CI 93% to 100%), and OS was 98% (95% CI 95% to 100%). CONCLUSION: sTILs add important prognostic information in systemically untreated early-stage TNBC patients. Notably, sTILs can identify a subset of stage I TNBC patients with an excellent prognosis without adjuvant chemotherapy.

EPAC-lung: pooled analysis of circulating tumour cells in advanced non-small cell lung cancer.

INTRODUCTION: We assessed the clinical validity of circulating tumour cell (CTC) quantification for prognostication of patients with advanced non-small cell lung cancer (NSCLC) by undertaking a pooled analysis of individual patient data. METHODS: Nine European NSCLC CTC centres were asked to provide reported/unreported pseudo-anonymised data for patients with advanced NSCLC who participated in CellSearch CTC studies from January 2003 to March 2017. We used Cox regression models, stratified by centres, to establish the association between CTC count and survival. We assessed the added value of CTCs to prognostic clinicopathological models using likelihood ratio (LR) statistics and c-indices. RESULTS: Seven out of nine eligible centres provided data for 550 patients with prognostic information for overall survival. CTC counts of ≥2 and ≥ 5 per 7·5 mL were associated with reduced progression-free survival (≥2 CTCs: hazard ratio [HR] = 1.72, p < 0·001; ≥5 CTCs: HR = 2.21, p < 0·001) and overall survival (≥2 CTCs: HR = 2·18, p < 0·001; ≥5 CTCs: HR = 2·75, p < 0·001), respectively. Survival prediction was significantly improved by addition of baseline CTC count to LR clinicopathological models (log-transformed CTCs p < 0·001; ≥2 CTCs p < 0·001; ≥5 CTCs p ≤ 0·001 for both survival end-points), whereas moderate improvements were observed with the use of c-index models. There was some evidence of between-centre heterogeneity, especially when examining continuous counts of CTCs. CONCLUSIONS: These data confirm CTCs as an independent prognostic indicator of progression-free survival and overall survival in advanced NSCLC and also reveal some evidence of between-centre heterogeneity. CTC count improves prognostication when added to full clinicopathological predictive models.

Prognostic implications of residual disease tumor-infiltrating lymphocytes and residual cancer burden in triple-negative breast cancer patients after neoadjuvant chemotherapy.

BACKGROUND: For primary triple-negative breast cancer (TNBC) treated with neoadjuvant chemotherapy (NAC), higher pretreatment tumor-infiltrating lymphocytes (TILs) correlates with increased pathologic complete response (pCR) rates, and improved survival. We evaluated the added prognostic value of residual disease (RD) TILs to residual cancer burden (RCB) in predicting survival post-NAC. PATIENTS AND METHODS: We combined four TNBC NAC patient cohorts who did not achieve pCR. RD TILs were investigated for associations with recurrence-free survival (RFS), and overall survival (OS) using Cox models with stromal TILs as a continuous variable (per 10% increment). The likelihood ratio test was used to evaluate added prognostic value of RD TILs. RESULTS: A total of 375 RD TNBC samples were evaluable for TILs and RCB. The median age was 50 years, with 62% receiving anthracycline/taxane chemotherapy. The RCB class after NAC was 11%, 50%, and 39% for I, II, and III, respectively. The median RD TIL level was 20% (IQR 10-40). There was a positive correlation between RD TIL levels and CD8+ T-cell density (ρ = 0.41). TIL levels were significantly lower with increasing post-NAC tumor (P = 0.005), nodal stage (P = 0.032), but did not differ by RCB class (P = 0.84). Higher RD TILs were significantly associated with improved RFS (HR: 0.86; 95% CI 0.79-0.92; P < 0.001), and improved OS (HR: 0.87; 95% CI 0.80-0.94; P < 0.001), and remained significant predictors in multivariate analysis (RFS P = 0.032; OS P = 0.038 for OS). RD TILs added significant prognostic value to multivariate models including RCB class (P < 0.001 for RFS; P = 0.021 for OS). The positive prognostic effect of RD TILs significantly differed by RCB class for RFS (PInt=0.003) and OS (PInt=0.008) with a greater magnitude of positive effect observed for RCB class II than class III. CONCLUSIONS: TIL levels in TNBC RD are significantly associated with improved RFS and OS and add further prognostic information to RCB class, particularly in RCB class II.

Update of survival and cost of metastatic melanoma with new drugs: Estimations from the MelBase cohort.

PURPOSE: Since 2011, significant progress was observed in metastatic melanoma (MM), with the commercialisation of seven immunotherapies or targeted therapies, which showed significant improvement in survival. In France, in 2004, the cost of MM was estimated at €1634 per patient; this cost has not been re-estimated since. This study provided an update on survival and cost in real-life clinical practice. METHODS: Clinical and economic data (treatments, hospitalisations, radiotherapy sessions, visits, imaging and biological exams) were extracted from the prospective MelBase cohort, collecting individual data in 955 patients in 26 hospitals, from diagnosis of metastatic disease until death. Survival was estimated by the Kaplan-Meier method. Costs were calculated from the health insurance perspective using French tariffs. For live patients, survival and costs were extrapolated using a multistate model, describing the 5-year course of the disease according to patient prognostic factors and number of treatment lines. RESULTS: Since the availability of new drugs, the mean survival time of MM patients has increased to 23.6 months (95%confidence interval [CI] :21.2;26.6), with 58% of patients receiving a second line of treatment. Mean management costs increased to €269,682 (95%CI:244,196;304,916) per patient. Drugs accounted for 80% of the total cost. CONCLUSION: This study is the first that evaluated the impact of immunotherapies and targeted therapies both on survival and cost in real-life conditions. Alongside the introduction of breakthrough therapies in the first and subsequent lines, MM has been associated with a significant increase in survival but also in costs, raising the question of financial sustainability.

Scoring of tumor-infiltrating lymphocytes: From visual estimation to machine learning.

The extent of tumor-infiltrating lymphocytes (TILs), along with immunomodulatory ligands, tumor-mutational burden and other biomarkers, has been demonstrated to be a marker of response to immune-checkpoint therapy in several cancers. Pathologists have therefore started to devise standardized visual approaches to quantify TILs for therapy prediction. However, despite successful standardization efforts visual TIL estimation is slow, with limited precision and lacks the ability to evaluate more complex properties such as TIL distribution patterns. Therefore, computational image analysis approaches are needed to provide standardized and efficient TIL quantification. Here, we discuss different automated TIL scoring approaches ranging from classical image segmentation, where cell boundaries are identified and the resulting objects classified according to shape properties, to machine learning-based approaches that directly classify cells without segmentation but rely on large amounts of training data. In contrast to conventional machine learning (ML) approaches that are often criticized for their "black-box" characteristics, we also discuss explainable machine learning. Such approaches render ML results interpretable and explain the computational decision-making process through high-resolution heatmaps that highlight TILs and cancer cells and therefore allow for quantification and plausibility checks in biomedical research and diagnostics.

Modulation of Rb phosphorylation and antiproliferative response to palbociclib: the preoperative-palbociclib (POP) randomized clinical trial.

Background: The cyclin-dependent kinase 4 (CDK4)/6 inhibitor Palbociclib is a new standard treatment in hormone-receptor positive breast cancer patients. No predictive biomarkers have been identified and no pharmacodynamics has properly been described so far. Patients and methods: Patients with early-breast cancer were randomized 3 : 1 to oral palbociclib 125 mg daily for 14 days until the day before the surgery versus no treatment. Primary objective was antiproliferative response defined as a natural logarithm of Ki67 expression at day 15 below 1. Secondary end points were subgroups analyses and safety. Exploratory analyses included search for predictive biomarkers. Immunostainings (Ki67, RB, pRB, p16, pAKT, pER, pCDK2, CyclinD1), FISH (CCND1) and gene expression (GE) arrays were carried out at baseline and at surgery. In addition, activating PIK3CA and AKT1 mutations were assessed at baseline. Results: 74 patients were allocated to palbociclib and 26 to control. Most patients (93%) were hormone-receptor (HR)-positive, whereas 8% were HER2-positive. Palbociclib led to significantly more antiproliferative responses when compared with control (58% versus 12%, P < 0.001), and to a significantly higher Ki67 decrease (P < 0.001). In the HR-positive/HER2-negative subgroup, this antiproliferative effect was even more marked in the palbociclib arm when compared with control (70% versus 9%, P < 0.001). Palbociclib treatment led also to a significantly higher decrease from baseline in phospho-Rb when compared with control (P < 0.001). Among treated patients, changes in Ki67 correlated with changes in phospho-Rb (Spearman rank r = 0.41, P < 0.0001). GE analyses confirmed a major effect on proliferation and cell cycle genes. Among treated patients, CCNE2 expression was significantly more decreased in antiproliferative responders versus nonresponders (P = 0.006). Conclusion: Short-term preoperative palbociclib decreases Ki67 in early-breast cancer patients. Early decrease of Rb phosphorylation correlates with drug's effect on cell proliferation and could potentially identify patients with primary resistance. Clinical trial registration: NCT02008734.

A gene signature to predict high tumor-infiltrating lymphocytes after neoadjuvant chemotherapy and outcome in patients with triple-negative breast cancer.

Background: In patients with triple-negative breast cancer (TNBC), the extent of tumor-infiltrating lymphocytes (TILs) in the residual disease after neoadjuvant chemotherapy (NACT) is associated with better prognosis. Our objective was to develop a gene signature from pretreatment samples to predict the extent of TILs after NACT and then to test its prognostic value on survival. Patients and methods: Using 99 pretreatment samples, we generated a four-gene signature associated with high post-NACT TILs. Prognostic value of the signature on distant relapse-free survival (DRFS) was first assessed on the training set (n = 99) and then on an independent validation set (n = 115). Results: A four-gene signature combining the expression levels of HLF, CXCL13, SULT1E1, and GBP1 was developed in baseline samples to predict the extent of lymphocytic infiltration after NACT. In a multivariate analysis performed on the training set, this signature was associated with DRFS [hazard ratio (HR): 0.28, for a one-unit increase in the value of the four-gene signature, 95% confidence interval (CI): 0.13-0.63)]. In a multivariate analysis performed on an independent validation set, the four-gene signature was significantly associated with DRFS (HR: 0.17, 95% CI: 0.06-0.43). The four-gene signature added significant prognostic information when compared with the clinicopathologic pretreatment model (likelihood ratio test in the training set P = 0.004 and in the validation set P = 0.002). Conclusions: A four-gene signature predicts high levels of TILs after anthracycline-containing NACT and outcome in patients with TNBC and adds prognostic information to a clinicopathological model at diagnosis.

The European Society for Medical Oncology (ESMO) Precision Medicine Glossary.

Background: Precision medicine is rapidly evolving within the field of oncology and has brought many new concepts and terminologies that are often poorly defined when first introduced, which may subsequently lead to miscommunication within the oncology community. The European Society for Medical Oncology (ESMO) recognises these challenges and is committed to support the adoption of precision medicine in oncology. To add clarity to the language used by oncologists and basic scientists within the context of precision medicine, the ESMO Translational Research and Personalised Medicine Working Group has developed a standardised glossary of relevant terms. Materials and methods: Relevant terms for inclusion in the glossary were identified via an ESMO member survey conducted in Autumn 2016, and by the ESMO Translational Research and Personalised Medicine Working Group members. Each term was defined by experts in the field, discussed and, if necessary, modified by the Working Group before reaching consensus approval. A literature search was carried out to determine which of the terms, 'precision medicine' and 'personalised medicine', is most appropriate to describe this field. Results: A total of 43 terms are included in the glossary, grouped into five main themes-(i) mechanisms of decision, (ii) characteristics of molecular alterations, (iii) tumour characteristics, (iv) clinical trials and statistics and (v) new research tools. The glossary classes 'precision medicine' or 'personalised medicine' as technically interchangeable but the term 'precision medicine' is favoured as it more accurately reflects the highly precise nature of new technologies that permit base pair resolution dissection of cancer genomes and is less likely to be misinterpreted. Conclusions: The ESMO Precision Medicine Glossary provides a resource to facilitate consistent communication in this field by clarifying and raising awareness of the language employed in cancer research and oncology practice. The glossary will be a dynamic entity, undergoing expansion and refinement over the coming years.

Predictors of responses to immune checkpoint blockade in advanced melanoma.

Immune checkpoint blockers (ICB) have become pivotal therapies in the clinical armamentarium against metastatic melanoma (MMel). Given the frequency of immune related adverse events and increasing use of ICB, predictors of response to CTLA-4 and/or PD-1 blockade represent unmet clinical needs. Using a systems biology-based approach to an assessment of 779 paired blood and tumor markers in 37 stage III MMel patients, we analyzed association between blood immune parameters and the functional immune reactivity of tumor-infiltrating cells after ex vivo exposure to ICB. Based on this assay, we retrospectively observed, in eight cohorts enrolling 190 MMel patients treated with ipilimumab, that PD-L1 expression on peripheral T cells was prognostic on overall and progression-free survival. Moreover, detectable CD137 on circulating CD8+ T cells was associated with the disease-free status of resected stage III MMel patients after adjuvant ipilimumab + nivolumab (but not nivolumab alone). These biomarkers should be validated in prospective trials in MMel.The clinical management of metastatic melanoma requires predictors of the response to checkpoint blockade. Here, the authors use immunological assays to identify potential prognostic/predictive biomarkers in circulating blood cells and in tumor-infiltrating lymphocytes from patients with resected stage III melanoma.