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Hormone-receptor positive (HR+), Human-Epidermal-growth Factor negative (HER2-) breast cancer, including the Luminal A and the Luminal B subtypes, is the most common in women diagnosed with early-stage BC. Despite the advances in screening, surgery and therapies, recurrence still occurs. Therefore, it is important to identify early those factors that significantly impact the recurrence risk. Based on current evidence and their professional expertise, a Panel of oncologists discussed the definition of high risk of recurrence in early breast cancer. Histological grade, nodal involvement, genomic score, histological grade, tumor size, and Ki-67 proliferation index were rated as the most important factors to define the high risk in patients with early breast cancer. All these factors should be considered comprehensively to tailor the choice of treatment to the peculiar characteristics of each patient. [Display omitted] • Recurrence still occurs in early HR+ HER2- breast cancer. • Determination of recurrence risk is required to optimize the therapeutic approach. • Histological grade and nodal involvement are the most important factors. • Genomic score, Ki-67, and tumor size are also relevant to define the risk. [ABSTRACT FROM AUTHOR]

Nowadays, treatment of metastatic breast cancer (MBC) has been enriched with novel therapeutical strategies. Metronomic chemotherapy (mCHT) is a continuous and frequent administration of chemotherapy at a lower dose and so whit less toxicity. Thus, this strategy could be attractive for elderly MBC patients. Aim of this analysis is to provide insights into mCHT's activity in a real-life setting of elderly MBC patients. Data of patients ≥ 75 years old included in VICTOR-6 study were analyzed. VICTOR-6 is a multicentre, Italian, retrospective study, which collected data on mCHT in MBC patients treated between 2011 and 2016. A total of 112 patients were included. At the beginning of mCHT, median age was 81 years (75–98) and in 33% of the patients mCHT was the first line choice. Overall Response Rate (ORR) and Disease Control Rate (DCR) were 27.9% and 79.3%, respectively. Median PFS ranged between 7.6 and 9.1 months, OS between 14.1 and 18.5 months. The most relevant toxicity was the hematological one (24.1%); severe toxicity (grade 3–4) ranged from 0.9% for skin toxicity up to 8% for hematologic one. This is a large study about mCHT in elderly MBC patients, providing insights to be further investigated in this subgroup of frail patients. [ABSTRACT FROM AUTHOR]

Background: Calcium is an important intracellular messenger that mediates many biological processes that are relevant to the malignant process. Calcium ion channels are key in controlling the intracellular calcium, and little is known about their role in human cancer.Methods: We used qPCR and pyrosequencing to investigate expression and epigenetic regulation of the calcium channel regulatory subunit α(2)δ-3 (CACNA2D3) in breast cancer cell lines, primary cancers and metastatic lesions.Results: Expression of CACNA2D3 mRNA is regulated in breast cancer cell lines by methylation in the CpG island located in the 5' regulatory region of the gene. Expression is upregulated by azacytidine (AZA) in cells with CpG island methylation but unaffected in cells lacking methylation. In primary breast carcinomas, methylation is more common in cancers, which subsequently relapse with loco-regional and, particularly, visceral metastatic disease in both oestrogen receptor-α (ER)-positive and -negative cases. Furthermore, CACNA2D3 CpG island is frequently methylated in breast cancer that has metastasised to the central nervous system.Conclusion: Methylation-dependent transcriptional silencing of CACNA2D3 may contribute to the metastatic phenotype of breast cancer. Analysis of methylation in the CACNA2D3 CpG island may have potential as a biomarker for risk of development of metastatic disease. [ABSTRACT FROM AUTHOR]

Background There is the need to identify new prognostic markers to refine risk stratification for HER2-positive early breast cancer patients. The aim of this study was to evaluate the association of tumor-infiltrating lymphocytes (TILs) with distant disease-free survival (DDFS) in patients with HER2-positive early breast cancer enrolled in the ShortHER adjuvant trial which compared 9 weeks versus 1-year trastuzumab in addition to chemotherapy, and to test the interaction between TILs and treatment arm. Patients and methods Stromal TILs were assessed for 866 cases on centralized hematoxylin and eosin-stained tumor slides. The association of TILs as 10% increments with DDFS was assessed with Cox models. Kaplan–Meier curves were estimated for patients with TILs ≥20% and TILs <20%. Median follow-up was 6.1 years. Results Median TILs was 5% (Q1–Q3 1%–15%). Increased TILs were independently associated with better DDFS in multivariable model [hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.59–0.89, P  =   0.006, for each 10% TILs increment]. Five years DDFS rates were 91.1% for patients with TILs <20% and 95.7% for patients with TILs ≥20% (P  =   0.025). The association between 10% TILs increments and DDFS was significant for patients randomized to 9 weeks of trastuzumab (HR 0.60, 95% CI 0.41–0.88) but not for patients treated with 1 year of trastuzumab (HR 0.89, 95% CI 0.71–1.12; test for interaction P  =   0.088). For patients with TILs <20%, the HR for the comparison between the short versus the long arm was 1.75 (95% CI 1.09–2.80, P =0.021); whereas, for patients with TILs ≥20% the HR for the comparison of short versus long arm was 0.23 (95% CI 0.05–1.09, P  =   0.064), resulting in a significant interaction (P  =   0.015). Conclusions TILs are an independent prognostic factor for HER2-positive early breast cancer patients treated with adjuvant chemotherapy and trastuzumab and may refine the ability to identify patients at low risk of relapse eligible for de-escalated adjuvant therapy. [ABSTRACT FROM AUTHOR]

Background Chemotherapy plus 1-year trastuzumab is the standard adjuvant treatment of HER2-positive breast cancer. The efficacy of less extended trastuzumab exposure is under investigation. The short-HER study was aimed to assess the non-inferiority of 9 weeks versus 1 year of adjuvant trastuzumab combined with chemotherapy. Patients and methods HER2-positive breast cancer patients with node-positive or, if node negative, with at least one risk factor (pT>2 cm, G3, lympho-vascular invasion, Ki-67 > 20%, age ≤35 years, or hormone receptor negativity) were randomly assigned to receive sequential anthracycline–taxane combinations plus 1-year trastuzumab (arm A, long) or plus 9 weeks trastuzumab (arm B, short). This study was designed as a non-inferiority trial with disease-free survival (DFS) as primary end point. A DFS hazard ratio (HR) <1.29 was chosen as the non-inferiority margin. Analyses according to the frequentist and Bayesian approach were planned. Secondary end points included 2-year failure rate and cardiac safety. Results A total of 1254 patients from 82 centers were randomized (arm A, long: n  = 627; arm B, short: n  = 626). Five-year DFS is 88% in the long and 85% in the short arm. The HR is 1.13 (90% CI 0.89–1.42), with the upper limit of the CI crossing the non-inferiority margin. According to the Bayesian analysis, the probability that the short arm is non-inferior to the long one is 80%. The 5-year overall survival (OS) is 95.2% in the long and 95.0% in the short arm (HR 1.07, 90% CI 0.74–1.56). Cardiac events are significantly lower in the short arm (risk-ratio 0.33, 95% CI 0.22–0.50, P  < 0.0001). Conclusions This study failed to show the non-inferiority of a shorter trastuzumab administration. One-year trastuzumab remains the standard. However, a 9-week administration decreases the risk of severe cardiac toxicity and can be an option for patients with cardiac events during treatment and for those with a low risk of relapse. Trial Registration EUDRACT number: 2007-004326-25; NCI ClinicalTrials.gov number: NCT00629278. [ABSTRACT FROM AUTHOR]

Background: The CCAAT/enhancer binding protein delta (CEBPδ) is a member of a highly conserved family of basic region leucine zipper transcription factors. It has properties consistent with a tumour suppressor; however, other data suggest that CEBPδ may be involved in the metastatic process.Methods: We analysed the expression of CEBPδ and the methylation status of the CpG island in human breast cancer cell lines, in 107 archival cases of primary breast cancer and in two series of metastatic breast cancers using qPCR and pyrosequencing.Results: Expression of CEBPδ is downregulated in primary breast cancer by site-specific methylation in the CEBPδ CpG island. Expression is also downregulated in 50% of cases during progression from primary carcinoma to metastatic lesions. The CEBPδ CpG island is methylated in 81% metastatic breast cancer lesions, while methylation in the CEBPδ CpG island in primary cancers is associated with increased risk of relapse and metastasis.Conclusion: CCAAT/enhancer binding protein delta CpG island methylation is associated with metastasis in breast cancer. Detection of methylated CEBPδ genomic DNA may have utility as an epigenetic biomarker of primary breast carcinomas at increased risk of relapse and metastasis. [ABSTRACT FROM AUTHOR]

Background:The CCAAT/enhancer binding protein delta (CEBPδ) is a member of a highly conserved family of basic region leucine zipper transcription factors. It has properties consistent with a tumour suppressor; however, other data suggest that CEBPδ may be involved in the metastatic process.Methods:We analysed the expression of CEBPδ and the methylation status of the CpG island in human breast cancer cell lines, in 107 archival cases of primary breast cancer and in two series of metastatic breast cancers using qPCR and pyrosequencing.Results:Expression of CEBPδ is downregulated in primary breast cancer by site-specific methylation in the CEBPδ CpG island. Expression is also downregulated in 50% of cases during progression from primary carcinoma to metastatic lesions. The CEBPδ CpG island is methylated in 81% metastatic breast cancer lesions, while methylation in the CEBPδ CpG island in primary cancers is associated with increased risk of relapse and metastasis.Conclusion:CCAAT/enhancer binding protein delta CpG island methylation is associated with metastasis in breast cancer. Detection of methylated CEBPδ genomic DNA may have utility as an epigenetic biomarker of primary breast carcinomas at increased risk of relapse and metastasis. [ABSTRACT FROM AUTHOR]

Background:Calcium is an important intracellular messenger that mediates many biological processes that are relevant to the malignant process. Calcium ion channels are key in controlling the intracellular calcium, and little is known about their role in human cancer.Methods:We used qPCR and pyrosequencing to investigate expression and epigenetic regulation of the calcium channel regulatory subunit α2δ-3 (CACNA2D3) in breast cancer cell lines, primary cancers and metastatic lesions.Results:Expression of CACNA2D3 mRNA is regulated in breast cancer cell lines by methylation in the CpG island located in the 5′ regulatory region of the gene. Expression is upregulated by azacytidine (AZA) in cells with CpG island methylation but unaffected in cells lacking methylation. In primary breast carcinomas, methylation is more common in cancers, which subsequently relapse with loco-regional and, particularly, visceral metastatic disease in both oestrogen receptor-α (ER)-positive and -negative cases. Furthermore, CACNA2D3 CpG island is frequently methylated in breast cancer that has metastasised to the central nervous system.Conclusion:Methylation-dependent transcriptional silencing of CACNA2D3 may contribute to the metastatic phenotype of breast cancer. Analysis of methylation in the CACNA2D3 CpG island may have potential as a biomarker for risk of development of metastatic disease. [ABSTRACT FROM AUTHOR]

Background:Relapse risk assessment and individual treatment recommendations remain suboptimal for breast cancer patients. In the light of existing preclinical and clinical data, we studied NT5E (5′-nucleotidase, ecto) expression and NT5E CpG island methylation in breast cancer.Methods:We used RT-PCR, qPCR, methylation-specific PCR and pyrosequencing to analyse NT5E in breast carcinoma cell lines and primary and breast carcinomas.Results:NT5E CpG island methylation was inversely associated with NT5E expression in breast carcinoma cell lines. In clinical series, patients whose primary tumours had NT5E CpG island methylation were less likely to develop metastasis (P=0.003, OR=0.34, 95% CI: 0.17-0.69). In 3/4 paired samples, NT5E was methylated in primary tumours and demethylated in CNS metastases. Patients progressing to non-visceral as compared with visceral metastases were more likely to have NT5E CpG island methylation in primary tumours (P=0.01, OR=11.8). Patients with tumours lacking detectable methylation had shorter disease-free survival (DFS) (P=0.001, HR=2.7) and overall survival (OS) (P=0.001, HR=3). The favourable prognostic value of NT5E methylation was confirmed in oestrogen receptor negative (P=0.011, HR=3.27, 95% CI: 1.31-8.12) and in triple negative cases (P=0.004; HR=6.2, 95% CI: 1.9-20). Moreover, we observed a more favourable outcome to adjuvant chemotherapy in patients whose tumours were positive for NT5E CpG island methylation: DFS (P=0.0016, HR=5.1, 95% CI: 1.8-14.37) and OS (P=0.0005, HR=7.4, 95% CI: 2.416-23.08).Conclusion:NT5E CpG island methylation is a promising breast cancer biomarker. [ABSTRACT FROM AUTHOR]

Background:Brain metastasis from breast cancer is usually associated with a poor prognosis and early death. Alteration of p53 may contribute to malignant progression by abrogation of apoptosis induced by oncogene activation and by acquisition of gain-of-function properties, which promote tumour aggression. Mutation in TP53 occurs at high frequency in carcinomas of the lung and gastro-intestinal tract, but is much less frequent, at 25%, in primary breast cancer. The frequency of TP53 alteration in the central nervous system (CNS) metastatic breast cancer is not known.Methods:In all, 23 cases of histologically confirmed CNS metastatic breast cancer were identified and the coding sequence of TP53 determined. TP53 was also sequenced in two control series of primary breast carcinomas from independent clinical centres.Results:We demonstrate a strikingly high frequency of TP53 mutation in the CNS metastatic lesions with an over-representation of complex mutations (non-sense/deletions/insertions). Complex mutations occur in metastatic lesions in both triple-negative breast cancer and hormone receptor/HER2-positive cases. Analysis of paired primary carcinomas and brain metastatic lesions revealed evidence for both clonal selection and generation of new mutations (missense and complex) in progression from a primary breast carcinoma to brain metastasis.Conclusion:Mutation in TP53 is the most common genetic alteration reported during metastasis to the brain in breast cancer. [ABSTRACT FROM AUTHOR]

Purpose: Survival prediction is useful in selecting patients for palliative care or active anticancer therapy. The palliative and prognostic (PaP) score was shown to predict 1-month survival in terminally ill patients. Its application to patients with less advanced disease is a subject of debate. We assessed the value of the PaP score and of other clinical parameters in predicting survival in patients admitted in an oncological ward due to acute conditions. We also evaluated the frequency of active anticancer treatment in the last weeks of life.Methods: All the 208 patients, consecutively admitted in a department of medical oncology and radiotherapy in a 9-month period, were included. Patients and disease features together with the PaP score were assessed and included in a multivariable model for survival prediction.Results: Overall, median survival was 19 weeks and 12-week survival was 59.6%. The PaP score accurately predicted 4-week survival. Among the 39 patients who died within 4 weeks, 36% were on active treatment. The reason of admission, disease control, treatment, and PaP score were independently related to 12-week survival in the multivariate analysis; however patients with a 12-week survival lower than 30% were a minority.Conclusions: Although the PaP score accurately predicts life expectancy, its use in the setting of acute conditions seems not straightforward, due to the overall good prognosis of these patients. Active treatment in the last period of life is common. The potential reversibility of acute conditions makes prognostic measures inadequate for the purpose of treatment choices. [ABSTRACT FROM AUTHOR]

Background: Intensification of chemoradiation for advanced head and neck squamous cell carcinoma (HNSCC) is unlikely due to toxicity. Cetuximab combined either with radiotherapy or with chemotherapy showed favourable toxic profile with positive results in both combinations. Therefore, cetuximab could intensify chemoradiation without worsening toxicity. We conducted a phase II study of chemoradiation and cetuximab.Patients and methods: Eligible patients had stage III–IV M0 HNSCC. Treatment consisted of three cycles of cisplatin (20 mg/m2/day × 5 days) and fluorouracil (200 mg/m2/day × 5 days) rapidly alternated to three split courses of radiotherapy up to 70 Gy and concurrent weekly cetuximab. The primary end point of the study was complete response (CR) rate. Secondary end points were toxicity, progression-free survival (PFS) and overall survival (OS).Results: Fourty-five patients were enrolled: median age was 56 years, 38 had stage IV disease and 40 nodal involvement. CR occurred in 32 patients (71%). PFS and OS was 21+ months and 32.6+, respectively. Acute grade 3–4 toxic effects were in the expected range, but grade 3 radiodermatitis occurred in 33 patients.Conclusions: The combination of cetuximab, cisplatin, fluorouracil and radiotherapy leads to a very high proportion of CR and it is feasible with toxic effects similar to those expected by radiochemotherapy. The only unexpected toxicity was skin toxicity: grade 3 radiodermatitis occurred in 73% of the patients. [ABSTRACT FROM AUTHOR]

Tumor phenotype may change during breast cancer (BC) progression and discordance between primary and metastases ranges between 16% and 21% for Hormone Receptor (HR) expression in some series. The impact of this change on patient (pts) management and outcome is not yet clear, even though preliminary data indicate that the molecular characterization of recurrent breast cancer may induce clinicians to modify the treatment choice in ∼14% of the cases and that a change in the receptor status is associated with poorer survival. This analysis evaluates the prognostic impact of receptor discordance between paired primaries and recurrences. We used data of 879 pts of the longitudinal cohort AMBRA study, identifying 3 different groups: Group A: HR+ BC remaining HR+ at relapse; Group BHR+ BC becoming TNBC; Group C:TNBC remaining TNBC. Change in HR status was evaluated on the biopsy done at the moment of relapse. Time to event was evaluated by Cox-Mantel Hazard Ratio and Logrank Test; Mean/median by Wilcoxon Rank-Sum Test. Pts who underwent biopsy at the time of relapse were 545/879 (62%), of those 462 (84.4%) were classified as Luminal tumors and 83 (15.2%) TNBC on primary. Change in tumor phenotype occurred in 31 (6.7%) of Luminal BC and 16 (19.3%) TNBC, probably due to a higher genomic instability (p = 0.021). Median DFS between Luminal BC was not different: HR+àHR+: 74.56 months (95%CI 66.8-82.1) vs HR+àTNBC: 89.73 months (95%CI:44.73-103.46). Table summarizes main data in time to event in the 3 identified groups. *PFS at 1strelapse; **PFS at 2nd relapse; ***Time to Treatment Change at 1strelapse; °OS at 1strelapse; §OS from 1stPD. Table 325P Table HR+/HR + (range) Group A HR+/TNBC (range) Group B p value Group A vs C TNBC/TNBC (range) Group C PFS1* (months) 13.65 (0,77-162,03) 9.45 (3,97-52,73) 0.36 8.13 (6.3-10.9) PFS2** (months) 6.83 (0,00-57,13) 6.12 (2,67-26,30) 0.84 4.20 (0,33-22,17) TTC1*** (months) 12.43 (0,13-163,10) 8.88 (0,00-48,40) 0.50 7.88 (0,23-27,80) TTC2**** (months) 7.45 (0,00-55,97) 6.73 (3,77-26,80) na na OS1° (months) 23.1 (20-26) 15 (8.7-26.3) 0.031 3.60 (0,60-25,38) OS (years) 8.52 (0,26-115,92) 7.86 (0,19-30,67) 0.43 3.58 (2.91-2.39) OS from PD1§ (months) 25.8 (0,00-207,53) 17.23 (2,67-104,30) 0.82 17.90 (2,37-53,57) Change in tumor phenotype has a significant impact on OS; BC pts who become TNBC at relapse should be treated in the same way as TNBC pts at diagnosis. Anyway, OS of Luminal BC who change phenotype seems to be better than TNBC. GIM - Gruppo Italiano Mammella. Celgene. All authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background: Surveys carried out in Mediterranean countries demonstrated very low rates of awareness of both diagnosis and prognosis among cancer patients. In our institution, a long-term training program aimed at improving communication skills among all physicians interacting with cancer patients was conducted. We report here the results of an extensive assessment of patients’ awareness conducted after the first training period. Patients and methods: In a 2-year period, after every first visit of patients with a histological diagnosis of cancer, oncologists elicited perception of the patients and completed a structured questionnaire focusing on the understanding of the diagnosis and prognosis. Our data are thus a photograph of the results of the informative process conducted during the diagnostic phase. Results: Among the enrolled 649 patients, 79.3% were aware of their diagnosis; factors significantly associated with higher levels of awareness were age younger than 70 and referral from surgery (versus internal medicine). Knowledge about the palliative or curative aims of future treatments (a surrogate sign of prognostic consciousness) was evident in 55.2%. Conclusions: Compared with historical data, our results show a high level of comprehension of the diagnosis of malignancy, probably due to the extensive training effort together with the method chosen for assessment. [ABSTRACT FROM AUTHOR]