Exemestane plus everolimus and palbociclib in metastatic breast cancer: clinical response and genomic/transcriptomic determinants of resistance in a phase I/II trial.

The landscape of cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) resistance is still being elucidated and the optimal subsequent therapy to overcome resistance remains uncertain. Here we present the final results of a phase Ib/IIa, open-label trial (NCT02871791) of exemestane plus everolimus and palbociclib for CDK4/6i-resistant metastatic breast cancer. The primary objective of phase Ib was to evaluate safety and tolerability and determine the maximum tolerated dose/recommended phase II dose (100 mg palbociclib, 5 mg everolimus, 25 mg exemestane). The primary objective of phase IIa was to determine the clinical benefit rate (18.8%, n = 6/32), which did not meet the predefined endpoint (65%). Secondary objectives included pharmacokinetic profiling (phase Ib), objective response rate, disease control rate, duration of response, and progression free survival (phase IIa), and correlative multi-omics analysis to investigate biomarkers of resistance to CDK4/6i. All participants were female. Multi-omics data from the phase IIa patients (n = 24 tumor/17 blood biopsy exomes; n = 27 tumor transcriptomes) showed potential mechanisms of resistance (convergent evolution of HER2 activation, BRAFV600E), identified joint genomic/transcriptomic resistance features (ESR1 mutations, high estrogen receptor pathway activity, and a Luminal A/B subtype; ERBB2/BRAF mutations, high RTK/MAPK pathway activity, and a HER2-E subtype), and provided hypothesis-generating results suggesting that mTOR pathway activation correlates with response to the trial's therapy. Our results illustrate how genome and transcriptome sequencing may help better identify patients likely to respond to CDK4/6i therapies.

Surgery of the primary tumor in patients with de novo metastatic breast cancer: a nationwide population-based retrospective cohort study in Belgium.

PURPOSE: We aimed to assess the impact of surgery of primary tumor in overall survival (OS) of women with de novo metastatic breast cancer. METHODS: Nationwide, population-based retrospective cohort study of women diagnosed with de novo metastatic breast cancer in Belgium, between Jan/2010-Dec/2014. Data was obtained from the Belgian Cancer Registry and administrative databases. "Surgery" group was defined by surgery of primary tumor up to nine months after diagnosis. We excluded women who did not receive systemic treatment or did not complete nine months follow-up after diagnosis. All the subsequent analyses reporting on overall survival and the stratified outcome analyses were performed based on this nine-month landmark cohort. OS was estimated using Kaplan-Meier method and compared using adjusted Cox proportional hazards models controlling for confounders with 95% confidence intervals (CI). We performed a stratified analysis according to surgery timing and a propensity score matching analysis. RESULTS: 1985 patients, 534 (26.9%) in the "Surgery" and 1451 (73.1%) in the "No Surgery" group. Patients undergoing surgery were younger (p < 0.001), had better performance status (PS) (p < 0.001), and higher proportion of HER2-positive and triple-negative breast cancer (p = 0.012). Median follow-up was 86.0 months (82.6-88.5). Median OS was 60.1 months (57.1-68.2) in the "Surgery" vs. 41.9 months (39.8-44.2) in the "No Surgery" group (adjusted HR 0.56; 0.49-0.64). OS was similar when surgery was performed upfront or after systemic treatment. Propensity score matching analysis confirmed the same findings. CONCLUSION: Among patients receiving systemic treatment for de novo metastatic breast cancer and surviving nine months or more, those who received surgery of the primary tumor within nine months of diagnosis have longer subsequent survival than those who did not.

Effectiveness of palbociclib with aromatase inhibitors for the treatment of advanced breast cancer in an exposure retrospective cohort study: implications for clinical practice.

BACKGROUND: New drugs for locally advanced or metastatic breast cancer have led to clinical benefits, aside with increasing costs to healthcare systems. The current financing model for health technology assessment (HTA) privileges real-world data. As part of the ongoing HTA, this study aimed to evaluate the effectiveness of palbociclib with aromatase inhibitors (AI) and compare it with the efficacy reported in PALOMA-2. METHODS: A population-based retrospective exposure cohort study was conducted including all patients initiating treatment in Portugal with palbociclib under early access use and registered in the National Oncology Registry. The primary outcome was progression free survival (PFS). Secondary outcomes considered included time to palbociclib failure (TPF), overall survival (OS), time to next treatment (TTNT), and proportion of patients discontinuing treatment due to  adverse events (AEs). The Kaplan-Meier method was used and median, 1- and 2-year survival rates were computed, with two-sided 95% confidence intervals (95%CI). STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) guidelines for reporting observational studies were used. RESULTS: There were 131 patients included. Median follow-up was 28.3 months (IQR: 22.7-35.2) and median duration of treatment was 17.5 months (IQR: 7.8-29.1). Median PFS was 19.5 months (95%CI 14.2-24.2), corresponding to a 1-year PFS rate of 67.9% (95%CI 59.2-75.2) and a 2-year PFS rate of 42.0% (95%CI 33.5-50.3). Sensitivity analysis showed median PFS would increase slightly when excluding those not initiating treatment with the recommended dose, raising to 19.8 months (95%CI 14.4-28.9). By considering only patients meeting PALOMA-2 criteria, we could observe a major difference in treatment outcomes, with a mean PFS of 28.8 months (95%CI 19.4-36.0). TPF was 19.8 months (95%CI 14.2-24.9). Median OS was not reached. Median TTNT was 22.5 months (95%CI 18.0-29.8). A total of 14 patients discontinued palbociclib because of AEs (10.7%). CONCLUSIONS: Data suggest palbociclib with AI to have an effectiveness of 28.8 months, when used in patients with overlapping characteristics to those used in PALOMA-2. However, when used outside of these eligibility criteria, namely in patients with less favorable prognosis (e.g., presence of visceral disease), the benefits are inferior, even though still favorable.

PET/CT in Patients with Breast Cancer Treated with Immunotherapy.

Significant advances in breast cancer (BC) treatment have been made in the last decade, including the use of immunotherapy and, in particular, immune checkpoint inhibitors that have been shown to improve the survival of patients with triple negative BC. This narrative review summarizes the studies supporting the use of immunotherapy in BC. Furthermore, the usefulness of 2-deoxy-2-[18F]fluoro-D-glucose (2-[18F]FDG) positron emission/computerized tomography (PET/CT) to image the tumor heterogeneity and to assess treatment response is explored, including the different criteria to interpret 2-[18F]FDG PET/CT imaging. The concept of immuno-PET is also described, by explaining the advantages of mapping treatment targets with a non-invasive and whole-body tool. Several radiopharmaceuticals in the preclinical phase are referred too, and, considering their promising results, translation to human studies is needed to support their use in clinical practice. Overall, this is an evolving field in BC treatment, despite PET imaging developments, the future trends also include expanding immunotherapy to early-stage BC and using other biomarkers.

Real-world effectiveness of palbociclib plus fulvestrant in advanced breast cancer: Results from a population-based cohort study.

BACKGROUND: Real-world (RW) data may provide valuable information on the effectiveness and safety of medicines, which is particularly relevant for clinicians, patients and third-party payers. Evidence on the effectiveness of palbociclib plus fulvestrant is scarce, which highlights the need of additional studies. The aim of this study was to evaluate the effectiveness of palbociclib plus fulvestrant in advanced breast cancer (ABC). MATERIALS AND METHODS: We conducted a population-based retrospective cohort study and cases of interest were identified through the Portuguese National Cancer Registry database and additional data sources. Patients aged≥18 years, diagnosed with ABC and exposed to palbociclib plus fulvestrant between May 31, 2017 and March 31, 2019 were included. Patients were followed-up until death or cut-off date (February 28, 2021). Primary outcome was rw-progression-free survival (rwPFS). Secondary outcomes were rw-overall survival (rwOS), rw-time to palbociclib failure (rwTPF) and rw-time to next treatment (rwTTNT). RESULTS: A total of 210 patients were included. Median age was 58 years (range 29-83) and 99.05% were female. Median follow-up time was 23.22 months and, at cut-off date, treatment had been discontinued in 189 patients, mainly due to disease progression (n = 152). Median rwPFS was 7.43 months (95% confidence interval [CI] 6.28-9.05) and 2-year rwPFS was 16.65% (95%CI 11.97-22.00). Median rwOS was 24.70 months (95%CI 21.58-29.27), median rwTPF was 7.5 months (95%CI 6.51-9.08) and median rwTTNT was 11.74 months (95%CI 10.33-14.08). CONCLUSION: Palbociclib plus fulvestrant seems an effective treatment for ABC in real-world context. Compared to registrations studies, rwPFS and rwOS were shorter in real-life setting.

Breast cancer surgery with augmented reality.

INTRODUCTION: Innovations in 3D spatial technology and augmented reality imaging driven by digital high-tech industrial science have accelerated experimental advances in breast cancer imaging and the development of medical procedures aimed to reduce invasiveness. PRESENTATION OF CASE: A 57-year-old post-menopausal woman presented with screen-detected left-sided breast cancer. After undergoing all staging and pre-operative studies the patient was proposed for conservative breast surgery with tumor localization. During surgery, an experimental digital and non-invasive intra-operative localization method with augmented reality was compared with the standard pre-operative localization with carbon tattooing (institutional protocol). The breast surgeon wearing an augmented reality headset (Hololens) was able to visualize the tumor location projection inside the patient's left breast in the usual supine position. DISCUSSION: This work describes, to our knowledge, the first experimental test with a digital non-invasive method for intra-operative breast cancer localization using augmented reality to guide breast conservative surgery. In this case, a successful overlap of the previous standard pre-operative marks with carbon tattooing and tumor visualization inside the patient's breast with augmented reality was obtained. CONCLUSION: Breast cancer conservative guided surgery with augmented reality can pave the way for a digital non-invasive method for intra-operative tumor localization.

Clinical behavior and outcomes of breast cancer in young women with germline BRCA pathogenic variants.

Young breast cancer (BC) patients carrying a germline BRCA pathogenic variant (mBRCA) have similar outcomes as non-carriers. However, the impact of the type of gene (BRCA1 vs. BRCA2) and hormone receptor status (positive [HR+] vs. negative [HR-]) on clinical behavior and outcomes of mBRCA BC remains largely unknown. This is an international, multicenter, hospital-based, retrospective cohort study that included mBRCA patients diagnosed, between January 2000 and December 2012, with stage I-III invasive early BC at age ≤40 years. From 30 centers worldwide, 1236 young mBRCA BC patients were included. Among 808 and 428 patients with mBRCA1 or mBRCA2, 191 (23.6%) and 356 (83.2%) had HR+tumors, respectively (P < 0.001). Median follow-up was 7.9 years. Second primary BC (P = 0.009) and non-BC malignancies (P = 0.02) were more frequent among mBRCA1 patients while distant recurrences were less frequent (P = 0.02). Irrespective of hormone receptor status, mBRCA1 patients had worse disease-free survival (DFS; adjusted HR = 0.76, 95% CI = 0.60-0.96), with no difference in distant recurrence-free interval (DRFI) and overall survival (OS). Patients with HR+ disease had more frequent distant recurrences (P < 0.001) and less frequent second primary malignancies (BC: P = 0.005; non-BC: P = 0.18). No differences in DFS and OS were observed according to hormone receptor status, with a tendency for worse DRFI (adjusted HR = 1.39, 95% CI = 0.94-2.05) in patients with HR+ BC. Type of mBRCA gene and hormone receptor status strongly impact BC clinical behavior and outcomes in mBRCA young patients. These results provide important information for patients' counseling on treatment, prevention, and surveillance strategies.

Body weight and return to work among survivors of early-stage breast cancer.

BACKGROUND: Many breast cancer (BC) survivors are employed at diagnosis and are expected to return to work after treatment. Among them, around 50% are overweight or obese. There are limited data about the impact of body weight on their ability to return to work. METHODS: We used data from CANcer TOxicity (NCT01993498), a prospective, multicentre cohort of women with stage I-III BC. Professionally active women who were ≥5 years younger than retirement age were identified. Multivariable logistic regression models examined associations of body mass index (BMI) at diagnosis and subsequent weight changes with non-return to work 2 years after diagnosis, adjusting for psychosocial, treatment and behavioural characteristics. RESULTS: Among 1869 women, 689 were overweight or obese. Overall, 398 patients (21.3%) had not returned to work 2 years after diagnosis. Non-return to work was more likely for overweight or obese than underweight or normal weight patients (adjusted OR (aOR) 1.32; 95% CI, 1.01 to 1.75; p=0.045). Weight loss (≥5%) was observed in 15.7% overweight or obese and 8.7% underweight or normal weight patients and was associated with significant increases in physical activity only among overweight or obese patients (mean change, +4.7 metabolic-equivalent-of-task-hour/week; 95% CI +1.9 to +7.5). Overweight or obese patients who lost weight were more likely to return to work compared with those who did not lose weight (aOR of non-return-to-work, 0.48; 95% CI 0.24 to 0.97, p=0.0418), whereas weight loss was associated with increased odds of non-return to work among underweight or normal weight women (aOR 2.07; 95% CI 1.20 to 3.56, p=0.0086) (pinteractionBMI×weight changes=0.0002). The continuous trend of weight gain on non-return to work was significant for overweight or obese patients (aOR for one-percent-unit difference, 1.03; 95% CI 1.01 to 1.06, p=0.030). CONCLUSIONS: Excess weight may be a barrier to return to work. Among overweight or obese BC survivors, weight loss was associated with higher rates of return to work, whereas further weight gain was associated with lower likelihood of return to work. Employment outcomes should be evaluated in randomised studies of weight management.

Clinical outcomes of patients with breast cancer relapsing after (neo)adjuvant trastuzumab and receiving trastuzumab rechallenge or lapatinib-based therapy: a multicentre retrospective cohort study.

BACKGROUND: In the prepertuzumab era, we evaluated the clinical outcomes of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer who underwent first-line trastuzumab-based or lapatinib-based therapy according to prior exposure to (neo)adjuvant trastuzumab. MATERIALS AND METHODS: In this multicentre retrospective cohort study conducted in 14 Italian centres of the Gruppo Italiano Mammella, consecutive patients undergoing first-line trastuzumab or lapatinib-based therapy were included. Analyses were performed according to the type of first-line therapy for metastatic disease (trastuzumab or lapatinib). Dichotomous clinical outcomes were analysed using logistic regression and time-to-event outcomes using Cox proportional hazard models controlling for relevant demographic, clinicopathological and therapy characteristics. RESULTS: Out of 450 patients included in the study, 416 (92%) received trastuzumab and 34 (7.5%) lapatinib. As compared with the trastuzumab cohort, more patients in the lapatinib cohort had a trastuzumab-free interval <1 month (37% vs 13.9%; p=0.017) and brain metastasis as first site of relapse (38.2% vs 9.4%; p<0.001). Among the 128 patients who relapsed after prior (neo)adjuvant trastuzumab, 101 (78.9%) received first-line trastuzumab and 27 (21.1%) first-line lapatinib. The following outcomes were observed with first-line lapatinib or trastuzumab, respectively: overall response rate 45.5% vs 61.3% (p=0.184), clinical benefit rate 68.2% vs 72.5% (p=0.691), median progression-free survival (PFS) 11.4 vs 12.0 months (p=0.814) and median overall survival (OS) 34.7 vs 48.2 months (p=0.722). In patients with brain metastasis as first site of relapse, median PFS was 12.2 vs 9.9 months (p=0.093) and median OS 33.7 vs 28.5 months (p=0.280), respectively. CONCLUSIONS: In patients with HER2-positive breast cancer relapsing after prior (neo)adjuvant trastuzumab, first-line treatment with trastuzumab or lapatinib was not associated with a significant difference in the clinical outcomes. A non-significant trend favouring the use of lapatinib was observed in patients with brain metastasis as the first site of relapse.

Impact of Extraskeletal Metastases on Skeletal-Related Events in Metastatic Castration-Resistant Prostate Cancer with Bone Metastases.

The therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC) has substantially evolved over the last decade. Nonetheless, a better understanding of bone-targeted agents (BTAs) action in mCRPC remains an unmet need. Theuse of BTAs aims to reduce the incidence of skeletal-related events (SREs) in patients with mCRPC. Less frequent BTA schedules are currently being studied to minimize adverse events. In this study, the impact of metastatic compartment (bone and extraskeletal metastases (BESM) vs. bone-only metastases (BOM)) on bone biomarker kinetics, time to first on-study SRE, and symptomatic skeletal events (SSEs) is evaluated. This is a retrospective analysis of the prospective, randomized, multicenter clinical trial of denosumab vs. zoledronic acid in patients with mCRPC and bone metastases. A total of 1901 patients were included, 1559 (82.0%) with BOM and 342 with BESM (18.0%). Bone metastases burden was balanced between groups. Baseline levels and normalization rates of corrected urinary N-terminal telopeptide and bone alkaline phosphatase did not differ between groups. However, BESM patients had a higher risk of SREs (adjusted HR 1.21; 95% CI 1.01-1.46; p = 0.043) and SSEs (adjusted HR 1.30; 95% CI 1.06-1.61; p = 0.014). This difference was more pronounced in the first 12 months of BTA treatment.In mCRPC, strategies of BTA schedule de-escalation may take into account presence of extraskeletal metastases.

Serum Detection of Nonadherence to Adjuvant Tamoxifen and Breast Cancer Recurrence Risk.

PURPOSE: Nonadherence to long-term treatments is often under-recognized by physicians and there is no gold standard for its assessment. In breast cancer, nonadherence to tamoxifen therapy after surgery constitutes a major obstacle to optimal outcomes. We sought to evaluate the rate of biochemical nonadherence to adjuvant tamoxifen using serum assessment and to examine its effects on short-term, distant disease-free survival (DDFS). PATIENTS AND METHODS: We studied 1,177 premenopausal women enrolled in a large prospective study (CANTO/NCT01993498). Definition of biochemical nonadherence was based on a tamoxifen serum level < 60 ng/mL, assessed 1 year after prescription. Self-reported nonadherence to tamoxifen therapy was collected at the same time through semistructured interviews. Survival analyses were conducted using an inverse probability weighted Cox proportional hazards model, using a propensity score based on age, staging, surgery, chemotherapy, and center size. RESULTS: Serum assessment of tamoxifen identified 16.0% of patients (n = 188) below the set adherence threshold. Patient-reported rate of nonadherence was lower (12.3%). Of 188 patients who did not adhere to the tamoxifen prescription, 55% self-reported adherence to tamoxifen. After a median follow-up of 24.2 months since tamoxifen serum assessment, patients who were biochemically nonadherent had significantly shorter DDFS (for distant recurrence or death, adjusted hazard ratio, 2.31; 95% CI, 1.05 to 5.06; P = .036), with 89.5% of patients alive without distant recurrence at 3 years in the nonadherent cohort versus 95.4% in the adherent cohort. CONCLUSION: Therapeutic drug monitoring may be a useful method to promptly identify patients who do not take adjuvant tamoxifen as prescribed and are at risk for poorer outcomes. Targeted interventions facilitating patient adherence are needed and have the potential to improve short-term breast cancer outcomes.

Changes in weight, physical and psychosocial patient-reported outcomes among obese women receiving treatment for early-stage breast cancer: A nationwide clinical study.

BACKGROUND: Evidence on how weight loss correlates to health-related quality-of-life (HRQOL) among obese breast cancer (BC) patients is limited. We aimed to evaluate associations between weight changes and HRQOL. METHODS: We included 993 obese women with stage I-II-III BC from CANTO, a multicenter, prospective cohort collecting longitudinal, objectively-assessed anthropometric measures and HRQOL data (NCT01993498). Associations between weight changes (±5% between diagnosis and post-treatment [shortly after completion of surgery, adjuvant chemo- or radiation-therapy]) and patient-reported HRQOL (EORTC QLQ-C30/B23) were comprehensively evaluated. Changes in HRQOL and odds of severely impaired HRQOL were assessed using multivariable generalized estimating equations and logistic regression, respectively. RESULTS: 14.1% women gained weight, 67.3% remained stable and 18.6% lost weight. Significant decreases in functional status and exacerbation of symptoms were observed overall post-treatment. Compared to gaining weight or remaining stable, obese women who lost weight experienced less of a decline in HRQOL, reporting better physical function (mean change [95%CI] for gain, stability and loss: -12.9 [-16.5,-9.3], -6.9 [-8.2,-5.5] and -6.2 [-8.7,-3.7]; pinteraction[weight-change-by-time] = 0.006), less dyspnea (+18.9 [+12.3,+25.6], +9.2 [+6.5,+11.9] and +3.2 [-1.0,+7.3]; pinteraction = 0.0003), and fewer breast symptoms (+22.1 [+16.8,+27.3], +18.0 [+15.7,+20.3] and +13.4 [+9.0,+17.2]; pinteraction = 0.044). Weight loss was also significantly associated with reduced odds of severe pain compared with weight gain (OR [95%CI] = 0.51 [0.31-0.86], p = 0.011) or stability (OR [95%CI] = 0.62 [0.41-0.95], p = 0.029). No associations between weight loss and worsening of other physical or psychosocial parameters were found. CONCLUSIONS: This large contemporary study suggests that weight loss among obese BC patients during early survivorship was associated with better patient-reported outcomes, without evidence of worsened functionality or symptomatology in any domain of HRQOL.

Effectiveness of Adjuvant Ovarian Function Suppression in Premenopausal Women With Early Breast Cancer: A Multicenter Cohort Study.

BACKGROUND: Ovarian function suppression (OFS) with tamoxifen or aromatase inhibitors (AIs) improves disease-free survival in premenopausal women with breast cancer, mostly in those at higher risk of recurrence. However, its real-world use and impact remain poorly understood. PATIENTS AND METHODS: This is a multicenter retrospective cohort study of premenopausal women with stage I to III hormone receptor-positive breast cancer diagnosed from 2006 to 2015 that aimed to look at the uptake and effectiveness of the addition of OFS to backbone endocrine therapy (tamoxifen or AI). To deal with confounding, we used both multivariate modeling and propensity score matching. RESULTS: Of 1717 eligible patients, 17.1% were treated with OFS. There was a substantial increase of use of OFS over time, especially from 2014 onward (16% vs. 25% after 2014), particularly for the combination with AI (0.4% vs. 8% after 2014). In a multivariate model, only younger age and year of diagnosis ≥ 2014 were associated with OFS utilization (both P < .001). With a median follow-up of 38 months (P25-P75, 19.6-66.4 months), patients receiving OFS had a better overall survival than those not receiving OFS (adjusted hazard ratio, 0.44; 95% confidence interval, 0.19-0.96; absolute benefit at 5 years, 2.1% [95.3% vs. 93.2% in those not receiving OFS]). A similar benefit was identified using propensity score matching. CONCLUSIONS: In the real-world setting, there was an increase in the use of OFS after 2014. After 2014, one-quarter of premenopausal women received adjuvant OFS, of which more than 30% received it in combination with an AI. In this study, the use of adjuvant OFS was associated with an overall survival benefit.

Dissecting the effect of hormone receptor status in patients with HER2-positive early breast cancer: exploratory analysis from the ALTTO (BIG 2-06) randomized clinical trial.

PURPOSE: Limited evidence exists on the impact of hormone receptor (HR) status to counsel HER2-positive early breast cancer patients receiving adjuvant anti-HER2 therapy. METHODS: ALTTO (BIG 2-06) was an international, intergroup, open-label, randomized phase III trial in HER2-positive early breast cancer patients randomized to receive 1 year of trastuzumab and/or lapatinib. HER2, estrogen and progesterone receptors were centrally tested for all patients. We investigated the impact of HR status on prognosis, risk of disease-free survival (DFS) events over time, patterns of first DFS events, and factors associated with risk of DFS events overall, in years 0-5 and 6-8. RESULTS: Out of 6273 patients included in this analysis, 3603 (57.4%) had HR-positive tumors. Median follow-up was 6.93 years. Five-year and 8-year DFS were 86% and 80% in patients with HR-positive disease, and 83% and 79% in those with HR-negative tumors, respectively. Mean annual hazards of recurrence in years 0-5 were 3% in patients with HR-positive disease and 4% in those with HR-negative tumors, while in years 6-8 they were 3% and 2%, respectively. Distribution of first DFS event in years 6-8 (P = 0.005) and type of first distant recurrence (P < 0.001) were significantly different between the two groups. Risk factors for DFS events overall, in years 0-5, and 6-8 were different in patients with HR-positive and HR-negative tumors. CONCLUSIONS: HER2-positive early breast cancer is characterized by the presence of two diseases with distinct natural history based on HR status requiring the development of different follow-up strategies and future de-escalation and escalation clinical trials.

Levels of Circulating Fibroblast Growth Factor 23 (FGF23) and Prognosis in Cancer Patients with Bone Metastases.

The fibroblast growth factor (FGF) signaling pathway plays a key role in tumorigenesis and is recognized as a potential therapeutic target. In this study, the authors aimed to assess the impact of serum FGF23 levels in the prognosis of patients with cancer and bone metastases from solid tumors. A cohort of 112 patients with cancer and metastatic bone disease were treated with bone-targeted agents (BTA). Serum baseline FGF23 was quantified by ELISA and dichotomized in FGF23high and FGF23low groups. Additionally, the association between FGF23 and overall survival (OS) and time to skeletal-related events (TTSRE) was investigated. Baseline characteristics were balanced between groups, except for the median urinary N-terminal telopeptide (uNTX) level. After a median follow-up of 26.0 months, a median OS of 34.4 and 12.2 months was found in the FGF23low and FGF23high groups, respectively (multivariate HR 0.18, 95% CI 0.07⁻0.44, p = 0.001; univariate HR 0.27, p = 0.001). Additionally, TTSRE was significantly longer for patients with FGF23low (13.0 vs 2.0 months, p = 0.04). Overall, this study found that patients with FGF23low at baseline had longer OS and TTSRE. Further studies are warranted to define its role as a prognostic biomarker and in the use of drugs targeting the FGF axis.

Modelling cancer outcomes of bone metastatic patients: combining survival data with N-Telopeptide of type I collagen (NTX) dynamics through joint models.

BACKGROUND: Joint models (JM) have emerged as a promising statistical framework to concurrently analyse survival data and multiple longitudinal responses. This is particularly relevant in clinical studies where the goal is to estimate the association between time-to-event data and the biomarkers evolution. In the context of oncological data, JM can indeed provide interesting prognostic markers for the event under study and thus support clinical decisions and treatment choices. However, several problems arise when dealing with this type of data, such as the high-dimensionality of the covariates space, the lack of knowledge about the function structure of the time series and the presence of missing data, facts that may hamper the accurate estimation of the JM. METHODS: We propose to apply JM for the analysis of bone metastatic patients and infer the association of their survival with several covariates, in particular the N-Telopeptide of Type I Collagen (NTX) dynamics. This biomarker has been identified as a relevant prognostic factor in patients with metastatic cancer, but only using static information in some specific time points. RESULTS: We extended this analysis using the full NTX time series for a larger cohort of patients with bone metastasis, and compared the results obtained by the JM and the extended Cox regression model. Imputation based on fuzzy clustering was used to deal with missing values and several functions for NTX evolution were compared, such as rational, exponential and cubic splines. CONCLUSIONS: The JM obtained confirm the association between NTX values and patients' response, attesting the importance of this time series, and additionally provide a deep understanding of the key survival covariates.

Mixed Invasive Ductal and Lobular Carcinoma of the Breast: Prognosis and the Importance of Histologic Grade.

BACKGROUND: The diagnosis of mixed invasive ductal and lobular carcinoma (IDC-L) in clinical practice is often associated with uncertainty related to its prognosis and response to systemic therapies. With the increasing recognition of invasive lobular carcinoma (ILC) as a distinct disease subtype, questions surrounding IDC-L become even more relevant. In this study, we took advantage of a detailed clinical database to compare IDC-L and ILC regarding clinicopathologic and treatment characteristics, prognostic power of histologic grade, and survival outcomes. MATERIALS AND METHODS: In this retrospective cohort study, we identified 811 patients diagnosed with early-stage breast cancer with IDC-L or ILC. Descriptive statistics were performed to compare baseline clinicopathologic characteristics and treatments. Survival rates were subsequently analyzed using the Kaplan-Meier method and compared using the Cox proportional hazards model. RESULTS: Patients with ILC had more commonly multifocal disease, low to intermediate histologic grade, and HER2-negative disease. Histologic grade was prognostic for patients with IDC-L but had no significant discriminatory power in patients with ILC. Among postmenopausal women, those with IDC-L had significantly better outcomes when compared with those with ILC: disease-free survival (DFS) and overall survival (OS; adjusted hazard ratio [HR], 0.54; 95% confidence interval [CI] 0.31-0.95). Finally, postmenopausal women treated with an aromatase inhibitor had more favorable DFS and OS than those treated with tamoxifen only (OS adjusted HR, 0.50; 95% CI, 0.29-0.87), which was similar for both histologic types (p = .212). CONCLUSION: IDC-L tumors have a better prognosis than ILC tumors, particularly among postmenopausal women. Histologic grade is an important prognostic factor in IDC-L but not in ILC. IMPLICATIONS FOR PRACTICE: This study compared mixed invasive ductal and lobular carcinoma (IDC-L) with invasive lobular carcinomas (ILCs) to assess the overall prognosis, the prognostic role of histologic grade, and response to systemic therapy. It was found that patients with IDC-L tumors have a better prognosis than ILC, particularly among postmenopausal women, which may impact follow-up strategies. Moreover, although histologic grade failed to stratify the risk of ILC, it showed an important prognostic power in IDC-L, thus highlighting its clinical utility to guide treatment decisions of IDC-L. Finally, the disease-free survival advantage of adjuvant aromatase inhibitors over tamoxifen in ILC was consistent in IDC-L.

Chemoradiotherapy completion and neutropenia risk in HIV patients with cervical cancer.

Cervical cancer (CC) is one of the acquired immunodeficiency syndrome (AIDS) defining diseases and the human immunodeficiency virus (HIV) infection is thought to relate with increased acute toxicity of chemoradiotherapy (CRT).We investigated the effect of HIV status in the incidence of neutropenia associated with cisplatin-based CRT for CC and its impact in treatment completion.This is a single-center retrospective cohort study. Data collection was performed for all the consecutive stage Ib-IV CC women treated with cisplatin-based CRT from 2012 to 2016, and with known HIV status.Sixty-one patients were included, 6 were HIV+. HIV+ patients had a higher risk of neutropenia at any cycle during cisplatin CRT [adjusted odds ratio (OR) 7.3, 95% confidence interval (95% CI) 1.02-52.3; P = .05]. Despite the absolute differences, mean neutrophil count was nonsignificantly lower in HIV+ women, both at baseline [4455/µL (interquartile range, IQR: 1830-6689) vs 6340 (IQR: 1720-18,970) for HIV-, P = .98] and at the end of treatment [1752/µL (IQR: 1100-2930) vs 3147/µL (IQR: 920-18,390) in HIV-; P = .06]. Moreover, when considering the effect of time, CRT seems to induce a consistent drop of neutrophils in both groups (P = .229). No febrile neutropenia events occurred.In HIV+ women, there were more CT cycle delays (P = .013), patients were more prone to use granulocyte colony-stimulating factor (G-CSF; HIV+ 40.0% vs HIV- 4.0%; P = .04) and less likely to complete at least 5 cycles of cisplatin (P = .02). All patients received adequate dose of pelvic RT, regardless of HIV status.HIV+ patients have a significantly increased risk of neutropenia during CRT treatment for CC and are less likely to complete chemotherapy with cisplatin.

Endocrine therapy and palbociclib within a compassionate use program in heavily pretreated hormone receptor-positive, HER2-negative metastatic breast cancer.

This is a single center retrospective analysis of patients with hormone receptor-positive, HER2-negative metastatic breast cancer progressing after ≥ 4 treatment lines treated with palbociclib in combination with endocrine therapy within a compassionate use program. Thirty-four patients were included between 10/2015 and 02/2017, the majority (82.4%) being previously treated with mTOR inhibitors. Disease control rate was 52.9% and 24.4% at week 12 and 24. Overall progression-free survival was 3.1 months with no difference between mTOR inhibitor-pretreated (3.5 months) and -naïve patients (2.7 months; hazard ratio, 0.83). Toxicity profile in this population was comparable to that seen in previous trials.