Bone is a major target for metastases in the most frequent solid tumors, which result in severe complications and are a major cause of pain. A bone metastasis gene expression signature was identified using human breast cancer cells in a mouse model. The bone metastasis-related genes encode secretory and cell surface proteins implicated in bone-homing (CXCR4), angiogenesis (CTGF and FGF5), invasion (MMP-1 and ADAMTS1), and osteoclast recruitment (IL11). This signature superimposes on the 70-gene poor prognosis gene expression signature for breast cancer, and only ADAMTS1, CTGF and IL11 were found to be overexpressed in human primary breast cancers with bone relapse. We analyzed the expression of the six bone metastasis-related genes in bone metastases from patients with different types of solid tumors, to assess its relevance in human clinical samples. MMP-1, CXCR4, FGF5 and CTGF were found to be overexpressed in tumor cells of human bone metastases when compared to a human normal epithelial cell line. All the analyzed genes were overexpressed in the tumor cells of breast cancer bone metastases when compared to normal breast tissue. We did not detect any differences between the expression of these genes in bone metastases from breast cancer or from other types of solid tumors. Importantly, there was a significant correlation between the expressions of IL11/CTGF, IL11/ADAMTS1, CTGF/CXCR4, CTGF/ADAMTS1, and MMP-1/ADAMTS1, supporting the cooperative function of these proteins in the bone microenvironment, and the potential functional role of these genes in the establishment of bone metastases in vivo.
1004 Background: Studies of checkpoint inhibitor monotherapy show only modest activity in HR+ MBC. We report data from the first randomized study comparing E plus P versus E alone in HR+/HER2- MBC. Methods: Eligible patients (pts) had HR+/HER2- MBC, ≥2 lines of hormonal therapies and 0-2 lines of chemotherapy for MBC. Pts were randomized 1:1 to E 1.4mg/m2 intravenously (IV) on d1 and d8 with P 200 mg/m2 IV on d1 of a 21-day cycle (Arm A) or E alone (Arm B). At time of progression, pts in arm B could crossover and receive P alone. Primary endpoint was progression-free survival (PFS). Key secondary endpoints were: objective response rate (ORR) and overall survival (OS). Exploratory analyses assessed the association between PFS and PD-L1 status, tumor-infiltrating lymphocytes (TILs), neutrophil-lymphocyte ratio (NLR), tumor mutation burden (TMB), and genomic alterations by next generation sequencing on archival tissue. Results: 88 pts initiated protocol therapy; the median age was 58, median prior lines of chemotherapy 1, prior lines of hormonal therapy 2. Median follow-up was 6.3 months. Median PFS and ORR were not different between Arms A and B (PFS 4.1 vs 4.2 months p = 0.38; ORR 25% and 34% respectively (p = 0.49). 14 patients initiated crossover treatment with pembrolizumab; 1 patient experienced a PR (ORR 7%). All-cause AEs occurred in 100% of pts (G3-4, 54.6%) including 2 treatment related deaths on Arm A, both from known AEs attributed to both drugs. PD-L1 assay was performed in 65 pts: 24 (36.9%) had PD-L1 positive ( > 1% with 22C3, centrally tested) tumors. PD-L1 status, TILs, NLR, TMB, and genomic alterations were not associated with PFS (Table). Updated data, including OS and genomic results, will be presented. Conclusions: Among pts with HR+/HER2- MBC, the combination of E and P was not associated with longer PFS than E alone in the ITT or PD-L1+ population, though the PD-L1+ subgroup had very limited power to assess P benefit. Clinical trial information: NCT03051659. [Table: see text]
561 Background: Cognitive impairment has been reported among breast cancer (BC) patients (pts) after adjuvant chemotherapy. However, very few studies focused on cognitive function at diagnosis. Here we aimed to describe cognitive impairment among recently diagnosed BC before any treatment. Methods: A predefined sub-study of the French national prospective cohort of cancer and toxicities performed extensive objective and subjective cognitive assessment before any BC treatment (surgery or neo-adjuvant treatment). This study included a group of pts with newly diagnosed invasive Stage I-III BC and a group of healthy control (HC) women matched on age and education level. Episodic and working memory, executive functions, processing speed, attention, cognitive complaints (FACT-COG), anxiety and depression (HADS) and fatigue dimensions (FA12) were assessed with neuropsychological tests and the referred self-report questionnaires. Objective and cognitive impairment were defined according to International Cognition and Cancer Task Force recommendations. Results: 264 women (median age 54±11 years) recently diagnosed (average of 37 days after initial diagnosis) with invasive BC (stage I-II, 69%) and 132 matched HC participated in this study. Impaired working memory (20% vs 4%), information processing speed (36% vs 17%), attention (16% vs 1%) and executive function (21% vs 8%) were higher among pts than in HC (p < 0.001). In addition, 24% (n = 64) of pts reported cognitive complaints versus 12% of HC (n = 16, p < 0.01). Emotional and cognitive fatigue were higher in pts than HC (mean 24 vs 15 and 18 vs 11, p < 0.01). Similarly, higher levels of anxiety and depression were observed in patients when compared with HC (respectively in 41% and 3% of patients vs 10 and 1% for HC, p < 0.001). Objective cognitive impairment was not associated with cognitive complains. Both objective and subjective cognitive impairment were not associated with anxiety or depression. However cognitive complain was associated with fatigue (p < 0.001). Conclusions: In this large study, compared to HC, patients recently diagnosed with a localized BC reported more cognitive complains and objective cognitive impairment before surgery, without link with emotional status, but with fatigue. Further understanding of the biology and correlates of cognitive dysfunction at BC diagnosis is needed (CANTO-NCT01993498).
10069 Background: A substantial proportion of breast, colo-rectal and prostate cancer patients (pts) can expect long term disease free survival after their primary treatment. Among those, fatigue commonly persists after diagnosis (dx) and can be debilitating. In this study, we evaluated the incidence of fatigue 2 years (y) after cancer dx and its association with health behaviors. Methods: We used a French population based cross-sectional study, which included a representative sample of pts from 12 cancer types (VICAN2). VICAN2 surveyed 4347 pts 2 y after dx. There is a 99% completion rate of fatigue related questions. For this study, we included 2017 pts with breast (1237), colo-rectal (348) and prostate (432) cancer without evidence of metastases at dx or relapse 2y after dx and with fatigue information. Severe fatigue was defined as average score of EORTC QLQC30 fatigue subscale ≥40 at 2y after dx. There were <1% of missing values in the evaluated covariates. Multivariate logistic regression models looked at associations of fatigue with heatlh behaviors (Δ in exercise since dx, exercise at diagnosis, body mass index (BMI), Δ since dx, smoking), age, gender, comorbidities, education, employment, cancer type, radiation, chemotherapy, hormonal therapy. Results: 52% of pts reported severe fatigue at 2 y after dx (median fatique score: 44, range: 0-100). 2 y after dx, 47% of pts either stopped or decrease exercise and 16% had a ≥ 10% change in BMI. Factors associated with fatigue included health behaviors (Table), but also age (adjusted odds ratio [ aOR] for severe fatigue, 95% confidence interval [95% CI]: 0.97, 0.96-0.98), gender ( aOR, 95 CI male vs. female: 0.5, 0.3-0.8), comorbidities ( aOR, 95 CI yes vs. no: 2.0, 1.6-2.4) and treatment type ( aOR, 95 CI radiation vs. no: 1.5, 1.1-2.0). Conclusions: Fatigue continues to be a substantial problem for cancer survivors 2 y after dx. Some factors that may contribute to persistent fatigue (health behaviors) may be amenable to interventions. [Table: see text]
512 Background: We recently witnessed a trend to de-escalate CT and escalate ET in adjuvant BC treatment (tx). However, there has been limited prior research investigating the differential impact on QoL of tx classes. We aimed to test the impact of CT and ET on QoL PROs 2 yrs after diagnosis (dx). Methods: CANTO (NCT01993498) is a multicenter prospective longitudinal study of stage I-III BC pts that characterizes long-term toxicities of BC tx. For this analysis we included 4262 pts recruited from 2012-14. QoL was extensively evaluated using the EORTC QLQ C30 and BR23. Linear regression modeling was performed, adjusting for demographic and clinical factors, with use of CT and/or ET as independent variables. Analyses were stratified by menopausal status due to different tx patterns and sequelae of CT. Results: Median age at dx was 56 yrs, 63% of pts were post (PostM) and 37% premenopausal (PreM), 80% had Charlson score 0, 91% stage I-II. 26% received mastectomy, 52% CT (preM 68%, postM 44%; 86% anthracycline+taxane) and 82% ET (preM 89% tamoxifen; postM 88% aromatase inhibitor). 32% preM pts had menses 1 year after ET initiation. Overall, QoL deteriorates 2 yrs after dx. ET negatively impacts more QoL domains than CT at 2 yrs. Also, young age, smoking, income, aggressive local tx and physiological distress are often associated with low QoL. In the stratified analyses, in postM pts, mostly ET (not CT) is associated with deteriorated QoL. In contrast, in preM pts, mostly CT (not ET) is associated with deteriorated QoL. Table shows eg of associations. Conclusions: In a large prospective cohort of BC survivors, detrimental QoL 2 yrs after dx is mostly associated with ET; however, negative effects of CT persist on preM. This differential effect on QOL should be considered when choosing optimal adjuvant therapy and appropriate selection of pts for ET escalation should be a research priority. [Table: see text]
11564 Background: The interplay between breast cancer (BC) late effects, psychosocial and work-related factors in return to work (RTW) is not well understood. Previous reports were retrospective and did not combine all these features. Methods: We used data of a French prospective cohort study (CANTO, NCT01993498) of stage I-III BC patients (pts) including detailed clinical data of 1,874 pts working at diagnosis (dx) and ≥5 years younger than legal retirement age. The outcome was non-RTW 2 years after dx. Multivariable regressions were conducted to identify correlates of non-RTW. First, we examined the independent effect of treatments, toxicities (Common Toxicity Criteria Adverse Events), and patient reported outcomes (EORTC BR23 and FA12; Hospital Anxiety and Depression Scale) collected shortly after end of primary treatment. Then, in a restricted sample of 1,003 pts with working conditions (WC) information available, we fitted models to account for detailed pre-dx WC including type of contract, working hours, strenuous postures, supportive environment, degree of autonomy and perception of work. All models were adjusted for age, stage, marital status, socioeconomic status and comorbidities. Results: Two years after dx, 21% of pts did not work. Adjusted odds of non-RTW were increased among pts treated with combinations of chemotherapy (CT) and trastuzumab (TR) (e.g. OR of CT-TR = 2.20 [95% CI 1.24-3.88] and OR of CT-TR-hormonotherapy (HT) = 1.72 [1.13-2.63] vs. treated only with CT-HT), who had severe arm morbidity (OR = 1.73 [1.27-2.36] vs. no), severe emotional fatigue (OR = 1.55 [1.03-2.32] vs. no), anxiety (OR = 1.51 [1.02-2.23] vs. no), or depression (OR = 2.23 [1.27-3.94] vs no). In addition, we also found that the odds of non-RTW were increased among pts who had shift working hours (OR = 2.23 [1.32-3.76] vs. no), who did not work in a supportive environment before dx (OR = 2.24 [1.44-3.50] vs. supportive) and who perceived their job as boring (OR = 3.57 [1.71-7.46] vs. not boring). Conclusions: More than 1/5 of pts did not RTW 2 years after dx, with treatment (trastuzumab), clinical, psychological and work-related factors being associated with job reintegration. Multidisciplinary strategies are needed to support BC survivors.
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