A polymorphism at the 3'-UTR region of the aromatase gene defines a subgroup of postmenopausal breast cancer patients with poor response to neoadjuvant letrozole.

BACKGROUND: Aromatase (CYP19A1) regulates estrogen biosynthesis. Polymorphisms in CYP19A1 have been related to the pathogenesis of breast cancer (BC). Inhibition of aromatase with letrozole constitutes the best option for treating estrogen-dependent BC in postmenopausal women. We evaluate a series of polymorphisms of CYP19A1 and their effect on response to neoadjuvant letrozole in early BC. METHODS: We analyzed 95 consecutive postmenopausal women with stage II-III ER/PgR [+] BC treated with neoadjuvant letrozole. Response to treatment was measured by radiology at 4th month by World Health Organization (WHO) criteria. Three polymorphisms of CYP19A1, one in exon 7 (rs700519) and two in the 3'-UTR region (rs10046 and rs4646) were evaluated on DNA obtained from peripheral blood. RESULTS: Thirty-five women (36.8%) achieved a radiological response to letrozole. The histopathological and immunohistochemical parameters, including hormonal receptor status, were not associated with the response to letrozole. Only the genetic variants (AC/AA) of the rs4646 polymorphism were associated with poor response to letrozole (p = 0.03). Eighteen patients (18.9%) reported a progression of the disease. Those patients carrying the genetic variants (AC/AA) of rs4646 presented a lower progression-free survival than the patients homozygous for the reference variant (p = 0.0686). This effect was especially significant in the group of elderly patients not operated after letrozole induction (p = 0.009). CONCLUSIONS: Our study reveals that the rs4646 polymorphism identifies a subgroup of stage II-III ER/PgR [+] BC patients with poor response to neoadjuvant letrozole and poor prognosis. Testing for the rs4646 polymorphism could be a useful tool in order to orientate the treatment in elderly BC patients.

Effect of Breast Cancer Treatment on Dietary Vitamin Intake Levels.

Breast cancer is the most common tumor among women, representing the second cause of cancer deaths in women. Treatment with chemotherapy negatively interferes with nutritional status. The intake of vitamins before, during and after treatment in a pilot cohort of women with non-invasive breast cancer (type I, II) treated at the Valencian Institute of Oncology (IVO) is evaluated. A 3-day anthropometric and nutritional assessment was performed using the DIAL program. Nutritional intake is compared with the values of Estimated Average Requirements (EAR) and Dietary Reference Intake (DRI) provided by the United States Department of Agriculture (USDA) and the European Food Safety Authority (EFSA). There is an overall decrease in vitamin intake during treatment which worsens at the end of said treatment. The decrease is significant in the case of vitamins B2 (p = 0.006), B3 (p = 0.042), B5 (p = 0.001), and B8 (p = 0.021). The relative risk during and after treatment increases with respect to the reference timeframe, before treatment. Deficit risks are statistically significant in the case of vitamins B5 (p = 0.001), B8 (p = 0.001) and B12 (p = 0.001). Decreased vitamin intake during treatment suggests a negative change in the patients' dietary behaviors during this time. Nutritional intervention and support may be beneficial to optimize overall dietary intake and maintain compliance with EAR and DRI for patients during a time in which adequate nutrition is important.

ER+ Breast Cancers Resistant to Prolonged Neoadjuvant Letrozole Exhibit an E2F4 Transcriptional Program Sensitive to CDK4/6 Inhibitors.

Purpose: This study aimed to identify biomarkers of resistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancers treated with prolonged neoadjuvant letrozole.Experimental Design: We performed targeted DNA and RNA sequencing in 68 ER+ breast cancers from patients treated with preoperative letrozole (median, 7 months).Results: Twenty-four tumors (35%) exhibited a PEPI score ≥4 and/or recurred after a median of 58 months and were considered endocrine resistant. Integration of the 47 most upregulated genes (log FC > 1, FDR < 0.03) in letrozole-resistant tumors with transcription-binding data showed significant overlap with 20 E2F4-regulated genes (P = 2.56E-15). In patients treated with the CDK4/6 inhibitor palbociclib before surgery, treatment significantly decreased expression of 24 of the 47 most upregulated genes in letrozole-resistant tumors, including 18 of the 20 E2F4 target genes. In long-term estrogen-deprived ER+ breast cancer cells, palbociclib also downregulated all 20 E2F4 target genes and P-RB levels, whereas the ER downregulator fulvestrant or paclitaxel only partially suppressed expression of this set of genes and had no effect on P-RB. Finally, an E2F4 activation signature was strongly associated with resistance to aromatase inhibitors in the ACOSOG Z1031B neoadjuvant trial and with an increased risk of relapse in adjuvant-treated ER+ tumors in METABRIC.Conclusions: In tumors resistant to prolonged neoadjuvant letrozole, we identified a gene expression signature of E2F4 target activation. CDK4/6 inhibition suppressed E2F4 target gene expression in estrogen-deprived ER+ breast cancer cells and in patients' ER+ tumors, suggesting a potential benefit of adjuvant CDK4/6 inhibitors in patients with ER+ breast cancer who fail to respond to preoperative estrogen deprivation. Clin Cancer Res; 24(11); 2517-29. ©2018 AACR.

Predictive and prognostic impact of tumour-infiltrating lymphocytes in triple-negative breast cancer treated with neoadjuvant chemotherapy.

INTRODUCTION: In locally and locally advanced triple-negative breast cancer (TNBC), neoadjuvant chemotherapy (NAC) only induces a pCR in 30-35% of patients. Clinical and pathological factors are not enough to distinguish the patients who have no chance of a pCR or not. The tumour microenvironment is critical for cancer and tumour-infiltrating lymphocytes (TIL). Moreover, the NAC scenario is the perfect setting to study possible changes in TIL levels. MATERIAL AND METHODS: Using our prospective maintained breast cancer (BC) database, we identified 164 TNBC patients treated with NAC between 1998 and 2015 with enough samples of diagnostic biopsy and after surgery. Evaluation of TILs before and after NAC followed a standardised methodology for visual assessment on haematoxylin-eosin sections and the amounts of TILs were quantitated in deciles. We categorised lymphocyte-predominant breast cancer cutoff according to a receiver operating characteristic (ROC) analysis. We categorised LPBC as involving > 40% lymphocytic infiltration tumour stroma. The primary end point was predictive value of TILs to NAC, and the secondary end point was disease-free survival (DFS). DFS was analysed using the Kaplan-Meier method and the groups were compared with a long-rank test. Univariate and multivariate Cox models were used to generate hazard ratios for determining associations between variables such as TIL after NAC and DFS. RESULTS: A total of 164 TNBC patients were treated with NAC and surgery. The main patients' characteristics are listed in Table 1. We identify different pathological complete response to anthracycline and taxane-based NAC; LPBC subgroup 51 from 58 patients (88%) pCR versus non- lymphocyte-predominant breast cancer (LPBC) subgroup 10 from 106 (9%) pCR, p = 0.001. At a median follow-up of 78 months, LPBC was associated with better DFS; the three-year Kaplan-Meier estimates for DFS were 2% and 30 % for patients with LPBC and non-LPBC, respectively, p = 0.01. Univariate and multivariate analysis confirmed TIL to be an independent prognostic marker of DFS. CONCLUSIONS: Tumour-infiltrating lymphocytes could be routinely used in locally advanced TNBC treated with anthracycline and taxane, such as biomarker, to be enabled the identification of different two subgroups: LPBC patients have a very high response to NAC pCR 88%, meanwhile non-LPBC patients only achieve 9%. Moreover, non-LPBC patients have a worse prognosis than LPBC patients. This data verified the predictive and prognostic value of TIL.

Epirubicin Plus Cyclophosphamide Followed by Docetaxel Versus Epirubicin Plus Docetaxel Followed by Capecitabine As Adjuvant Therapy for Node-Positive Early Breast Cancer: Results From the GEICAM/2003-10 Study.

PURPOSE: Capecitabine is an active drug in metastatic breast cancer (BC). GEICAM/2003-10 is an adjuvant trial to investigate the integration of capecitabine into a regimen of epirubicin and docetaxel for node-positive early BC. PATIENTS AND METHODS: Patients with operable node-positive BC (T1-3/N1-3) were eligible. After surgery, 1,384 patients were randomly assigned to receive epirubicin plus cyclophosphamide (EC; 90 and 600 mg/m(2), respectively, × four cycles), followed by docetaxel (100 mg/m(2) × four cycles; EC-T) or epirubicin plus docetaxel (ET; 90 and 75 mg/m(2), respectively, × four cycles), followed by capecitabine (1,250 mg/m(2) twice a day on days 1 to 14, × four cycles; ET-X); all regimens were given every 3 weeks. The primary end point was invasive disease-free survival. Secondary end points included safety (with an alopecia-specific study) and overall survival (OS). RESULTS: After a median follow-up of 6.6 years and 297 events, 86% of patients who received EC-T and 82% of those who received ET-X were invasive disease free at 5 years (hazard ratio, 1.30; 95% CI, 1.03 to 1.64; log-rank P = .03). The OS difference between arms was not statistically significant (hazard ratio, 1.13; 95% CI, 0.82 to 1.55; log-rank P = .46). The most frequent grade 3 to 4 adverse events in the EC-T versus ET-X arms were neutropenia (19% v 10%), with 7% febrile neutropenia across arms; fatigue (13% v 11%); diarrhea (3% v 11%); hand-foot syndrome (2% v 20%); mucositis (6% v 5%); vomiting (both, 5%); and myalgia (4.5% v 1%). Incomplete scalp hair recovery was more frequent in the EC-T than ET-X arm (30% v 14%), and patients who received EC-T wore wigs significantly longer than those who received ET-X (8.35 v 6.03 months). CONCLUSION: Invasive disease-free survival, but not OS, was significantly superior for patients with node-positive early BC who received the adjuvant standard schedule EC-T than for those who received the experimental ET-X regimen. Toxicity profiles differed substantially across arms.

SEOM clinical guidelines for the treatment of metastatic breast cancer.

Patients with metastatic breast cancer have a wide number of treatment options, including medical, surgical, and supportive care measures. Treatment decisions are based in predictive and prognostic factors and the informed choice of the patients. SEOM has elaborated these guidelines with evidence-based recommendations for the diagnostic work-up, treatment (chemotherapy, endocrine therapy and targeted therapies) and supportive care for the management of these patients.