Updated recommendations regarding the management of older patients with breast cancer: a joint paper from the European Society of Breast Cancer Specialists (EUSOMA) and the International Society of Geriatric Oncology (SIOG).

Breast cancer is increasingly prevalent in older adults and is a substantial part of routine oncology practice. However, management of breast cancer in this population is challenging because the disease is highly heterogeneous and there is insufficient evidence specific to older adults. Decision making should not be driven by age alone but should involve geriatric assessments plus careful consideration of life expectancy, competing risks of mortality, and patient preferences. A multidisciplinary taskforce, including members of the European Society of Breast Cancer Specialists and International Society of Geriatric Oncology, gathered to expand and update the previous 2012 evidence-based recommendations for the management of breast cancer in older individuals with the endorsement of the European Cancer Organisation. These guidelines were expanded to include chemotherapy toxicity prediction calculators, cultural and social considerations, surveillance imaging, genetic screening, gene expression profiles, neoadjuvant systemic treatment options, bone-modifying drugs, targeted therapies, and supportive care. Recommendations on geriatric assessment, ductal carcinoma in situ, screening, primary endocrine therapy, surgery, radiotherapy, adjuvant systemic therapy, and secondary breast cancer were updated.

Circulating tumor cells and palbociclib treatment in patients with ER-positive, HER2-negative advanced breast cancer: results from a translational sub-study of the TREnd trial.

BACKGROUND: Circulating tumor cells (CTCs) are prognostic in patients with advanced breast cancer (ABC). However, no data exist about their use in patients treated with palbociclib. We analyzed the prognostic role of CTC counts in patients enrolled in the cTREnd study, a pre-planned translational sub-study of TREnd (NCT02549430), that randomized patients with ABC to palbociclib alone or palbociclib plus the endocrine therapy received in the prior line of treatment. Moreover, we evaluated RB1 gene expression on CTCs and explored its prognostic role within the cTREnd subpopulation. METHODS: Forty-six patients with ER-positive, HER2-negative ABC were analyzed. Blood samples were collected before starting palbociclib treatment (timepoint T0), after the first cycle of treatment (timepoint T1), and at disease progression (timepoint T2). CTCs were isolated and counted by CellSearch® System using the CellSearch™Epithelial Cell kit. Progression-free survival (PFS), clinical benefit (CB) during study treatment, and time to treatment failure (TTF) after study treatment were correlated with CTC counts. Samples with ≥ 5 CTCs were sorted by DEPArray system® (DA). RB1 and GAPDH gene expression levels were measured by ddPCR. RESULTS: All 46 patients were suitable for CTCs analysis. CTC count at T0 did not show significant prognostic value in terms of PFS and CB. Patients with at least one detectable CTC at T1 (n = 26) had a worse PFS than those with 0 CTCs (n = 16) (p = 0.02). At T1, patients with an increase of at least three CTCs showed reduced PFS compared to those with no increase (mPFS = 3 versus 9 months, (p = 0.004). Finally, patients with ≥ 5 CTCs at T2 (n = 6/23) who received chemotherapy as post-study treatment had a shorter TTF (p = 0.02). Gene expression data for RB1 were obtained from 19 patients. CTCs showed heterogeneous RB1 expression. Patients with detectable expression of RB1 at any timepoint showed better, but not statistically significant, outcomes than those with undetectable levels. CONCLUSIONS: CTC count seems to be a promising modality in monitoring palbociclib response. Moreover, CTC count at the time of progression could predict clinical outcome post-palbociclib. RB1 expression analysis on CTCs is feasible and may provide additional prognostic information. Results should be interpreted with caution given the small studied sample size.

Precision Oncology via NMR-Based Metabolomics: A Review on Breast Cancer.

Precision oncology is an emerging approach in cancer care. It aims at selecting the optimal therapy for the right patient by considering each patient's unique disease and individual health status. In the last years, it has become evident that breast cancer is an extremely heterogeneous disease, and therefore, patients need to be appropriately stratified to maximize survival and quality of life. Gene-expression tools have already positively assisted clinical decision making by estimating the risk of recurrence and the potential benefit from adjuvant chemotherapy. However, these approaches need refinement to further reduce the proportion of patients potentially exposed to unnecessary chemotherapy. Nuclear magnetic resonance (NMR) metabolomics has demonstrated to be an optimal approach for cancer research and has provided significant results in BC, in particular for prognostic and stratification purposes. In this review, we give an update on the status of NMR-based metabolomic studies for the biochemical characterization and stratification of breast cancer patients using different biospecimens (breast tissue, blood serum/plasma, and urine).

EFFECT: a randomized phase II study of efficacy and impact on function of two doses of nab-paclitaxel as first-line treatment in older women with advanced breast cancer.

BACKGROUND: Limited data are available regarding the use of nab-paclitaxel in older patients with breast cancer. A weekly schedule is recommended, but there is a paucity of evidence regarding the optimal dose. We evaluated the efficacy of two different doses of weekly nab-paclitaxel, with a specific focus on their corresponding impact on patient function, in order to address the lack of data specifically relating to the older population. METHODS: EFFECT is an open-label, phase II trial wherein 160 women with advanced breast cancer aged ≥ 65 years were enrolled from 15 institutions within Italy. Patients were randomly assigned 1:1 to receive nab-paclitaxel 100 mg/m2 (arm A) or 125 mg/m2 (arm B) on days 1, 8, and 15 on a 28-day cycle, as first-line treatment for advanced disease. The primary endpoint was event-free survival (EFS), wherein an event was defined as disease progression (PD), functional decline (FD), or death. In each arm, the null hypothesis that the median EFS would be ≤ 7 months was tested against a one-sided alternative according to the Brookmeyer Crowley test. Secondary endpoints included objective response rate (ORR), clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: After a median follow-up of 32.6 months, 140 events were observed in 158 evaluable patients. Median EFS was 8.2 months (90% CI, 5.9-8.9; p = 0.188) in arm A vs 8.3 months (90% CI, 6.2-9.7, p = 0.078) in arm B. Progression-free survival, overall survival, and response rates were similar in both groups. A higher percentage of dose reductions and discontinuations due to adverse events (AEs) was noted in arm B. The most frequently reported non-haematological AEs were fatigue (grade [G] 2-3 toxicity occurrence in arm A vs B, 43% and 51%, respectively) and peripheral neuropathy (G2-3 arm A vs B, 19% and 38%, respectively). CONCLUSION: Pre-specified outcomes were similar in both treatment arms. However, 100 mg/m2 was significantly better tolerated with fewer neurotoxicity-related events, representing a more feasible dose to be recommended for older patients with advanced disease. TRIAL REGISTRATION: EudraCT, 2012-002707-18 . Registered on June 4, 2012. NIH ClinicalTrials.gov, NCT02783222 . Retrospectively registered on May 26, 2016.

Potential through simplicity: thymidine kinase-1 as a biomarker for CDK4/6 inhibitors.

We describe a potential role for thymidine kinase-1, a general marker of cellular proliferation, to act as a prognostic biomarker in patients receiving CDK4/6 inhibitors for advanced hormone receptor-positive, HER2-negative breast cancer, with early data suggesting that it may also provide early indication of treatment response.

Clinical outcomes after palbociclib with or without endocrine therapy in postmenopausal women with hormone receptor positive and HER2-negative metastatic breast cancer enrolled in the TREnd trial.

Currently, there is limited data regarding the effectiveness of standard subsequent line therapies such as endocrine therapy, chemotherapy, or targeted agents after progression on CDK4/6 inhibitor-based regimens. This paper describes time-to-treatment failure beyond progression on palbociclib or palbociclib+endocrine therapy in patients enrolled in the phase II, multicenter TREnd trial. Our results indicate that there is limited benefit from post-palbociclib treatment, regardless of the type of therapy received. A small population of long responders were identified who demonstrated ongoing benefit from a subsequent line of endocrine therapy after progression to palbociclib-based regimens. A translational research program is ongoing on this population of outliers.

Early triple negative breast cancer: Are we getting better outcomes? A retrospective analysis from a single institution.

Overall survival (OS), disease-free survival (DFS), and distant recurrence-free interval (DRFI) were evaluated from 169 patients diagnosed with early triple negative breast cancer. Overall, 5 and 10 years OS, DFS, and DRFI were 77% and 65%; 60% and 46%; and 74% and 73%, respectively. Forty-seven patients did not receive chemotherapy. A separate analysis was performed excluding those patients. In this subgroup, 5- and 10-year OS, DFS, and DRFI were 86% and 77%; 68% and 54%, 77% both at 5 and 10 years. Prognosis is better than previously described; adjuvant chemotherapy should be offered to fit elderly patients if clinically warranted.

A gene expression signature of Retinoblastoma loss-of-function predicts resistance to neoadjuvant chemotherapy in ER-positive/HER2-positive breast cancer patients.

PURPOSE: HER2-positive (HER2+) breast cancers show heterogeneous response to chemotherapy, with the ER-positive (ER+) subgroup deriving less benefit. Loss of retinoblastoma tumor suppressor gene (RB1) function has been suggested as a cardinal feature of breast cancers that are more sensitive to chemotherapy and conversely resistant to CDK4/6 inhibitors. We performed a retrospective analysis exploring RBsig, a gene signature of RB loss, as a potential predictive marker of response to neoadjuvant chemotherapy in ER+/HER2+ breast cancer patients. METHODS: We selected clinical trials of neoadjuvant chemotherapy ± anti-HER2 therapy in HER2+ breast cancer patients with available information on gene expression data, hormone receptor status, and pathological complete response (pCR) rates. RBsig expression was computed in silico and correlated with pCR. RESULTS: Ten studies fulfilled the inclusion criteria and were included in the analysis (514 patients). Overall, of 211 ER+/HER2+ breast cancer patients, 49 achieved pCR (23%). The pCR rate following chemotherapy ± anti-HER2 drugs in patients with RBsig low expression was significantly lower compared to patients with RBsig high expression (16% vs. 30%, respectively; Fisher's exact test p = 0.015). The area under the ROC curve (AUC) was 0.62 (p = 0.005). In the 303 ER-negative (ER-)/HER2+ patients treated with chemotherapy ± anti-HER2 drugs, the pCR rate was 43%. No correlation was found between RBsig expression and pCR rate in this group. CONCLUSIONS: Low expression of RBsig identifies a subset of ER+/HER2+ patients with low pCR rates following neoadjuvant chemotherapy ± anti-HER2 therapy. These patients may potentially be spared chemotherapy in favor of anti-HER2, endocrine therapy, and CDK 4/6 inhibitor combinations.

Factors Influencing COVID-19 Vaccine Hesitancy among Patients with Serious Chronic Illnesses during the Initial Australian Vaccine Rollout: A Multi-Centre Qualitative Analysis Using the Health Belief Model.

Background: People with chronic illnesses have increased morbidity and mortality associated with COVID-19 infection. The influence of a person's serious and/or comorbid chronic illness on COVID-19 vaccine uptake is not well understood. Aim: To undertake an in-depth exploration of factors influencing COVID-19 vaccine uptake among those with various serious and/or chronic diseases in the Australian context, using secondary data analysis of a survey study. Methods: Adults with cancer, diabetes and multiple sclerosis (MS) were recruited from 10 Australian health services to undertake a cross-sectional online survey (30 June to 5 October 2021) about COVID-19 vaccine uptake, vaccine hesitancy, confidence and complacency and disease-related decision-making impact. Free-text responses were invited regarding thoughts and feelings about the interaction between the participant's disease, COVID-19, and vaccination. Qualitative thematic analysis was undertaken using an iterative process and representative verbatim quotes were chosen to illustrate the themes. Results: Of 4683 survey responses (cancer 3560, diabetes 842, and MS 281), 1604 (34.3%) included free-text comments for qualitative analysis. Participants who provided these were significantly less likely to have received a COVID-19 vaccination than those who did not comment (72.4% and 86.2%, respectively). People with diabetes were significantly less likely to provide free-text comments than those with cancer or MS (29.0%, 35.1% and 39.9%, respectively). Four key themes were identified from qualitative analysis, which were similar across disease states: (1) having a chronic disease heightened perceived susceptibility to and perceived severity of COVID-19; (2) perceived impact of vaccination on chronic disease management and disease-related safety; (3) uncertain benefits of COVID-19 vaccine; and (4) overwhelming information overload disempowering patients. Conclusions: This qualitative analysis highlights an additional layer of complexity related to COVID-19 vaccination decision making in people with underlying health conditions. Appreciation of higher susceptibility to severe COVID-19 outcomes appears to be weighed against uncertain impacts of the vaccine on the progression and management of the comorbid disease. Interactions by clinicians addressing individual factors may alleviate concerns and maximise vaccine uptake in people with significant underlying health conditions.

European Society of Breast Cancer Specialists/Advanced Breast Cancer Global Alliance quality indicators for metastatic breast cancer care.

AIMS: Improvement in the care of patients with metastatic breast cancer (MBC) can only occur if the adequate quality of care is implemented and verified, including access to multidisciplinary, specialised care given in accordance with high-quality guidelines. To this purpose, European Society of Breast Cancer Specialists and the Advanced Breast Cancer Global Alliance joined efforts to develop the first set of quality indicators (QI) specifically for MBC that should be routinely measured and evaluated to ensure that breast cancer centres meet the required standards. METHODS: A working group of multidisciplinary European experts in breast cancer met to discuss each identified QI, reporting the definition, the minimum and target standard for breast cancer centres to achieve, and the motivation for selection. The level of evidence was determined according to the short version of the United States Agency for Healthcare Research and Quality classification. RESULTS: QI to measure access to and involvement in multidisciplinary and supportive care, appropriate pathological characterisation of disease, systemic therapies and radiotherapy were developed with the consensus of the working group. CONCLUSIONS: This is the first effort of a multistep project that aims to have QI for MBC routinely measured and evaluated to ensure that breast cancer centres achieve mandated standards in the care of patients with metastatic disease.

COVID-19 vaccination rates, intent, and hesitancy in patients with solid organ and blood cancers: A multicenter study.

INTRODUCTION: People with cancer are at higher risk of serious illness and death from COVID-19 infection. We investigated COVID-19 vaccine uptake among patients with solid organ and blood cancers and explored factors related to hesitancy. METHODS: Cross-sectional online survey of adults with a history of cancer at three health services across metropolitan and regional Victoria. Vaccine hesitancy was measured by the validated Oxford COVID-19 vaccine hesitancy scale. RESULTS: There were 1073 respondents: 56% female; median age 62 years (range 23 - 91). Commonest tumor types included breast 29%, gastrointestinal 19%, hematological 15%, genitourinary 15%, and lung 8%. Thirty-six percent had metastatic disease, and 54% were receiving active anticancer treatment. Eighty-four percent of respondents indicated positive intent toward COVID-19 vaccination, 10% were undecided, and 6% indicated negative attitudes. At least one vaccine dose had been received by 65% of respondents, leaving 35% unvaccinated. Fifty-eight percent of unvaccinated patients answered that they would "definitely" or "probably" take a vaccine. Higher vaccine uptake was significantly associated with older age, male gender, English as first language, longer time since cancer diagnosis, and not being on current anticancer treatment. Concerns regarding vaccine side effects, particularly thrombosis, and the desire for clear medical advice were prominent among unvaccinated respondents. CONCLUSION: Despite being eligible for COVID-19 vaccination since March 2021, a substantial minority of patients with cancer remained unvaccinated as of August 2021. Targeted communication and educational resources addressing vaccine safety in the context of cancer are key to promoting vaccine uptake in this vulnerable population.

COVID-19 Vaccine Hesitancy in Australian Patients with Solid Organ Cancers.

BACKGROUND: Vaccination is the cornerstone of the global public health response to the COVID-19 pandemic. Excess morbidity and mortality of COVID-19 infection is seen in people with cancer. COVID-19 vaccine hesitancy has been observed in this medically vulnerable population, although associated attitudes and beliefs remain poorly understood. METHODS: An online cross-sectional survey of people with solid organ cancers was conducted through nine health services across Australia. Demographics, cancer-related characteristics and vaccine uptake were collected. Perceptions and beliefs regarding COVID-19 vaccination were assessed using the Oxford COVID-19 Vaccine Hesitancy Scale, the Oxford COVID-19 Vaccine Confidence and Complacency Scale and the Disease Influenced Vaccine Acceptance Scale-6. RESULTS: Between June and October 2021, 2691 people with solid organ cancers completed the survey. The median age was 62.5 years (SD = 11.8; range 19-95), 40.9% were male, 71.3% lived in metropolitan areas and 90.3% spoke English as their first language. The commonest cancer diagnoses were breast (36.6%), genitourinary (18.6%) and gastrointestinal (18.3%); 59.2% had localized disease and 56.0% were receiving anti-cancer therapy. Most participants (79.7%) had at least one COVID-19 vaccine dose. Vaccine uptake was higher in people who were older, male, metropolitan, spoke English as a first language and had a cancer diagnosis for more than six months. Vaccine hesitancy was higher in people who were younger, female, spoke English as a non-dominant language and lived in a regional location, and lower in people with genitourinary cancer. Vaccinated respondents were more concerned about being infected with COVID-19 and less concerned about vaccine safety and efficacy. CONCLUSIONS: People with cancer have concerns about acquiring COVID-19, which they balance against vaccine-related concerns about the potential impact on their disease progress and/or treatment. Detailed exploration of concerns in cancer patients provides valuable insights, both for discussions with individual patients and public health messaging for this vulnerable population.

Serious Underlying Medical Conditions and COVID-19 Vaccine Hesitancy: A Large Cross-Sectional Analysis from Australia.

As COVID-19 vaccinations became available and were proven effective in preventing serious infection, uptake amongst individuals varied, including in medically vulnerable populations. This cross-sectional multi-site study examined vaccine uptake, hesitancy, and explanatory factors amongst people with serious and/or chronic health conditions, including the impact of underlying disease on attitudes to vaccination. A 42-item survey was distributed to people with cancer, diabetes, or multiple sclerosis across ten Australian health services from 30 June to 5 October 2021. The survey evaluated sociodemographic and disease-related characteristics and incorporated three validated scales measuring vaccine hesitancy and vaccine-related beliefs generally and specific to their disease: the Oxford COVID-19 Vaccine Hesitancy Scale, the Oxford COVID-19 Vaccine Confidence and Complacency Scale and the Disease Influenced Vaccine Acceptance Scale-Six. Among 4683 participants (2548 [54.4%] female, 2108 [45.0%] male, 27 [0.6%] other; mean [SD] age, 60.6 [13.3] years; 3560 [76.0%] cancer, 842 [18.0%] diabetes, and 281 [6.0%] multiple sclerosis), 3813 (81.5%) self-reported having at least one COVID-19 vaccine. Unvaccinated status was associated with younger age, female sex, lower education and income, English as a second language, and residence in regional areas. Unvaccinated participants were more likely to report greater vaccine hesitancy and more negative perceptions toward vaccines. Disease-related vaccine concerns were associated with unvaccinated status and hesitancy, including greater complacency about COVID-19 infection, and concerns relating to vaccine efficacy and impact on their disease and/or treatment. This highlights the need to develop targeted strategies and education about COVID-19 vaccination to support medically vulnerable populations and health professionals.

Serum thymidine kinase activity in patients with hormone receptor-positive and HER2-negative metastatic breast cancer treated with palbociclib and fulvestrant.

BACKGROUND: Biomarkers for cyclin-dependent kinase 4/6 inhibitors, such as palbociclib, for patients with hormone receptor-positive/HER2-negative metastatic breast cancer are lacking. Thymidine kinase is a proliferation marker downstream of the cyclin-dependent kinase 4/6 pathway. We prospectively investigated the prognostic role of serum thymidine kinase activity (sTKa), in patients treated with Palbociclib + fulvestrant. PATIENTS AND METHODS: PYTHIA was a phase II, single-arm, multicentre, trial that enrolled 124 post-menopausal women with endocrine-resistant hormone receptor-positive/HER2-negative metastatic breast cancer. Serum samples were collected pre-treatment (pre-trt; n = 122), at day 15 of cycle 1 (D15; n = 108), during the one week-off palbociclib before initiating cycle 2 (D28; n = 108) and at end of treatment (n = 76). sTKa was determined centrally using Divitum®, a refined ELISA-based assay with a limit of detection of 20 Divitum Units (Du)/L. The primary study endpoint was progression-free survival, assessed for its association with pre- and on-treatment sTKa. RESULTS: Data from 122 women were analysed. Pre-treatment sTKa was not associated with clinical characteristics and moderately correlated with tissue Ki-67. Palbociclib + fulvestrant markedly suppressed sTKa levels at D15, with 83% of patients recording levels below limit of detection. At D28, sTKa showed a rebound in 60% of patients. At each timepoint, higher sTKa was associated with shorter progression-free survival (each p < 0.001), with the strongest effect at D15. CONCLUSIONS: STKa is an independent prognostic biomarker in patients treated with palbociclib. High pre-treatment sTKa and its incomplete suppression during treatment may identify patients with poorer prognosis and primary resistance. This warrants validation in prospective comparative trials. CLINICALTRIALS. GOV IDENTIFIER: NCT02536742; EudraCT 2014-005387-15.

CDK4/6 inhibitors: A focus on biomarkers of response and post-treatment therapeutic strategies in hormone receptor-positive HER2-negative breast cancer.

CDK4/6 inhibitors (CDK4/6i) in combination with endocrine therapy are the mainstay of treatment for patients with hormone receptor-positive, HER2 negative (HR+/HER2neg) metastatic breast cancer. However, resistance - either de novo or acquired - invariably occurs, leading to treatment failure and cancer progression. Genomic alterations, gene expression data and circulating biomarkers have been correlated to response to treatment, but to date no biomarker has been approved to stratify patients. Treatment strategies after progression on CDK4/6i are yet to be standardized. Current approaches include endocrine therapy alone or in combination with target therapy, or chemotherapy. New agents are in clinical development based on potential mechanisms of acquired resistance. Here we will review recent advancements in biomarkers of response to CDK4/6i, and in post- treatment therapeutic strategies.

A Dose-finding Study of Metronomic Oral Vinorelbine in Combination With Oral Cyclophosphamide and Bevacizumab in Patients With Advanced Breast Cancer.

BACKGROUND: Metronomic chemotherapy can induce disease control in patients with metastatic breast cancer (MBC) and has better safety profiles than conventional chemotherapy. Evidence suggests that cytotoxics can be anti-angiogenic in pre-clinical models and may have synergistic effects when combined with anti-vascular endothelial growth factor therapies. PATIENTS AND METHODS: Patients pretreated with ≥ 1 prior line of therapy for MBC received oral cyclophosphamide 50 mg daily in combination with oral vinorelbine at escalating doses of 20 mg (V20), 30 mg (V30), and 40 mg (V40) 3 times per week, and intravenous bevacizumab 15 mg/kg every 3 weeks. Patients with human epidermal growth factor receptor 2-positive disease were given the same regimen plus standard trastuzumab. Doses were escalated when 3 patients completed 3 treatment cycles of V20 and V30, without experiencing dose-limiting toxicities. The recommended dose was then tested in a further 6 patients. Circulating tumour cells and circulating endothelial cells (CEC) were measured in 30 mL of whole blood samples at baseline, after cycle 1, and at the disease progression. RESULTS: Fifteen patients were recruited from June 2013 to October 2015. The median age was 61 years (range, 29-72 years); 80% had estrogen receptor-positive and 33% had human epidermal growth factor receptor 2-positive disease. At least 67% had visceral metastases, and 80% had received ≥ 2 lines of prior treatment. No dose-limiting toxicities were observed at the 3 dose-levels, making V40 the recommended dose. Overall 8 (53%) patients developed grade 2 adverse events (arthralgia, n = 3 [20%]; asthenia, n = 2 [13%]; diarrhea, n = 2 [13%]; leukopenia, n = 2 [13%]). Bevacizumab was associated with grade 3 hypertension (n = 3 [20%]). Stable disease as best response was observed in 11 (73.3%) patients. The clinical benefit rate was 66.6% (10/15 patients). The median time to progression was 6.9 months. At baseline, CECs were more commonly detectable than circulating tumor cells; however, no statistical correlation was found between CEC kinetics and response. CONCLUSION: A metronomic vinorelbine dose of 40 mg combined with cyclophosphamide and bevacizumab is a promising treatment regimen in pretreated patients with MBC.

A Serum Metabolomics Classifier Derived from Elderly Patients with Metastatic Colorectal Cancer Predicts Relapse in the Adjuvant Setting.

Adjuvant treatment for patients with early stage colorectal cancer (eCRC) is currently based on suboptimal risk stratification, especially for elderly patients. Metabolomics may improve the identification of patients with residual micrometastases after surgery. In this retrospective study, we hypothesized that metabolomic fingerprinting could improve risk stratification in patients with eCRC. Serum samples obtained after surgery from 94 elderly patients with eCRC (65 relapse free and 29 relapsed, after 5-years median follow up), and from 75 elderly patients with metastatic colorectal cancer (mCRC) obtained before a new line of chemotherapy, were retrospectively analyzed via proton nuclear magnetic resonance spectroscopy. The prognostic role of metabolomics in patients with eCRC was assessed using Kaplan-Meier curves. PCA-CA-kNN could discriminate the metabolomic fingerprint of patients with relapse-free eCRC and mCRC (70.0% accuracy using NOESY spectra). This model was used to classify the samples of patients with relapsed eCRC: 69% of eCRC patients with relapse were predicted as metastatic. The metabolomic classification was strongly associated with prognosis (p-value 0.0005, HR 3.64), independently of tumor stage. In conclusion, metabolomics could be an innovative tool to refine risk stratification in elderly patients with eCRC. Based on these results, a prospective trial aimed at improving risk stratification by metabolomic fingerprinting (LIBIMET) is ongoing.

Metabolomics to Assess Response to Immune Checkpoint Inhibitors in Patients with Non-Small-Cell Lung Cancer.

In the treatment of advanced non-small cell lung cancer (NSCLC), immune checkpoint inhibitors have shown remarkable results. However, not all patients with NSCLC respond to this drug treatment or receive durable benefits. Thus, patient stratification and selection, as well as the identification of predictive biomarkers, represent pivotal aspects to address. In this framework, metabolomics can be used to support the discrimination between responders and non-responders. Here, metabolomics was used to analyze the sera samples from 50 patients with NSCL treated with immune checkpoint inhibitors. All the samples were collected before the beginning of the treatment and were analyzed by NMR spectroscopy and multivariate statistical analyses. Significantly, we show that the metabolomic fingerprint of serum acts as a predictive "collective" biomarker to immune checkpoint inhibitors response, being able to predict individual therapy outcome with > 80% accuracy. Metabolomics represents a potential strategy for the real-time selection and monitoring of patients treated with immunotherapy. The prospective identification of responders and non-responders could improve NSCLC treatment and patient stratification, thus avoiding ineffective therapeutic strategies.

Plasma Thymidine Kinase Activity as a Biomarker in Patients with Luminal Metastatic Breast Cancer Treated with Palbociclib within the TREnd Trial.

PURPOSE: Thymidine kinase 1 (TK1) is downstream to the CDK4/6 pathway, and TK activity (TKa) measured in blood is a dynamic marker of outcome in patients with advanced breast cancer (ABC). This study explores TK1 as a biomarker of palbociclib response, both in vitro and in patients with ABC. EXPERIMENTAL DESIGN: Modulation of TK1 levels and activity by palbociclib were studied in seven estrogen receptor-positive breast cancer cell lines: sensitive (PDS) and with palbociclib acquired resistance (PDR). TKa was assayed in plasma obtained at baseline (T0), after one cycle (T1), and at disease progression on palbociclib (T2) in patients enrolled in the "To Reverse ENDocrine Resistance" (TREnd) trial (n = 46). RESULTS: Among E2F-dependent genes, TK1 was significantly downregulated after short-term palbociclib. Early TKa reduction by palbociclib occurred in PDS but not in PDR cells. In patients, median TKa (mTKa) at T0 was 75 DiviTum units per liter (Du/L), with baseline TKa not proving prognostic. At T1, mTKa decreased to 35 Du/L, with a minority of patients (n = 8) showing an increase-correlating with a worse outcome than those with decreased/stable TKa (n = 33; mPFS 3.0 vs 9.0 months; P = 0.002). At T2, mTKa was 251 Du/L; patients with TKa above the median had worse outcomes on post-study treatment compared with those with lower TKa (2.9 vs 8.7 months; P = 0.05). CONCLUSIONS: TK is a dynamic marker of resistance to palbociclib which may lead to early identification of patients in whom treatment escalation may be feasible. In addition, TKa may stratify prognosis in patients with acquired resistance to palbociclib.

Estimating the magnitude of clinical benefit from (neo)adjuvant chemotherapy in patients with ER-positive/HER2-negative breast cancer.

Gene-expression assays were originally validated retrospectively as tools of prognostication, with evidence emerging from more recent prospectively-conducted studies such as MINDACT and TAILORx supporting their clinical validity and utility as biomarkers in identifying patients with luminal breast cancer who might be spared chemotherapy. However, these assays still do not have the ability to identify all patients who may safely avoid chemotherapy, and may over-estimate the risk of relapse in some cases. Future studies should aim to prospectively integrate contemporary approaches that assume a theoretical risk of relapse (based on pathological and/or genomic evaluation of the primary tumour), with new tools that can detect signals of active micro-metastatic disease. Until current methods of estimating prognosis and predicting benefit from adjuvant chemotherapy are significantly refined, estimating and improving the true magnitude of benefit derived from chemotherapy remains a challenge for clinicians.