BackgroundAromatase (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.MethodsWe 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.ResultsThirty-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).ConclusionsOur 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.

This study aimed to identify biomarkers of resistance to endocrine therapy in estrogen receptor-positive (ER) breast cancers treated with prolonged neoadjuvant letrozole. We performed targeted DNA and RNA sequencing in 68 ER breast cancers from patients treated with preoperative letrozole (median, 7 months). 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 ( = 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. 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. .

IntroductionIn 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 methodsUsing 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.ResultsA 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.ConclusionsTumour-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.

#5117 Objective: To assess the safety and efficacy of Myocet (M), Docetaxel (T), Trastuzumab (H) with prophylactic Pegfilgrastrim (N) as neoadjuvant chemotherapy in operable breast cancer patients (pts). The primary efficacy end point was pathologic complete response in the breast. Methods: Eligible pts had pathologically confirmed stage II or IIIA untreated breast cancer and HER2 overexpression determined by FISH in a central laboratory. M 50 mg/m2 and T 60 mg/m2 were given on day 1 and N on day 2 every 3 weeks for 6 cycles (Cy); H (4mg/Kgr loading dose, then 2 mg/Kgr/week) was given intravenously for 17 weeks, recommended dose in a phase I study (Proc ASCO 2007,25:596s Abstr.# 11.032). After all chemotherapy was completed, clinical responses were assessed. After surgery, pathological responses were evaluated using the Miller Payne scoring scale (MPSS). Results: 59 pts have been evaluated. Median age was 47.6 years (range 24-71) and median clinical tumour size 47.5 mm (range, 10-80). 19 pts (32.2%) presented with stage IIIA disease and 40 pts (67.8%) with stage II, 36 pts (61.0%) were premenopausal; 50 pts (84.8%) had histological grade 2-3 tumours; and 29 (49.2%) were ER-PgR-negative. All the pts received M and T 6 Cy with medium relative doses intense of 98.9% and 99.1% respectively. Objective clinical response rate was 84.7% (CI: 75.5-93.9) with 31 (52.5%) complete responses and 19 (32.2%) partial responses. 42 pts (71.2%) underwent conservative surgery, 17 pts (28.8%) achieved a pathological complete response in breast (Grade 5 in MPSS), of these, 16 pts (27.1%) achieved a pathological complete response in breast and axilar (Grade 5A+Grade 5D). Main grades (G) toxicities during MTHN treatment: leucopenia G3/4 was present in 18 pts (30.5%); neutropenia G3/4 in 17 pts (28.8%); febrile neutropenia G3 in 3 pts (5.1%); diarrhea G3 was present in 3 pts (5.1%); G2 rash in 2 pts (3.4%); G3 asthenia in 5 pts (8.5%) and stomatitis G3 in 1 pt (1.7%). 8 pts (13.6%) experienced asymptomatic and reversible cardiac left ventricular function G2. Conclusions: Concomitant administration of M plus THN is highly effective and active regimen with little toxicity in pts with HER2+ and early stage breast cancer. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5117.

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