Davide Lombardi

Familial breast cancer: characteristics and outcome of BRCA 1-2 positive and negative cases

BackgroundThe clinical and pathological characteristics and the clinical course of patients with breast cancer and BRCA 1–2 mutation are poorly known.MethodsFrom 1997, patients with breast cancer and a family history of breast or ovarian cancer were offered BRCA testing. The clinical and pathological features of patients with known BRCA status were retrospectively assessed and comparisons were made between cancers arising in BRCA positive and BRCA wild type (WT) patients respectively. Type of treatment, pattern of relapse, event (local relapse, contralateral breast cancer, metastases) free and overall survival were also compared in the two groups. Out of the 210 patients tested, 125 had been treated and followed-up at our Institution and were evaluated in this study.ResultsBRCA positive patients tended to be more often premenopausal (79% vs 65%) and to have positive lymphnodes (63% vs 49%), poorly differentiated tumours (76% vs 40% – p = 0.002 at univariate analysis, not significant at multivariate analysis) and negative estrogen receptors (43% vs 29%). Treatment was not different in the two groups. In the 86 BRCA-WT patients, the first event was a local relapse in 3 (3%), metachronous contralateral breast cancer in 7 (8%) and distant metastases in 16 (19%). In the 39 BRCA positive patients, the corresponding figures were 3 (8%), 8 (21%) and 3 (8%). There was no difference in event free survival, with a median of 180 months in both groups of patients. At 20 years, projected survival was 85% for BRCA positive patients and 55% for BRCA-WT, but this difference was not statistically significant.ConclusionAlthough BRCA positive patients have more frequently negative prognostic factors, their prognosis appears to be equal to or better than in patients with BRCA-WT.

Combination chemotherapy with navelbine and continuous infusion of 5-fluorouracil in metastatic, chemotherapy refractory breast cancer

BACKGROUND The protracted continuous infusion (PCI) of 5-fluorouracil (5-FU) has proven in several studies an active and well tolerated treatment for advanced, pretreated breast cancer. Navelbine has also activity in this setting. PATIENTS AND METHODS Heavily pretreated patients with metastatic breast carcinoma were eligible for the study. Treatment consisted of 5-FU 250 mg/m2 given as a PCI by an elastomeric pump and navelbine 20 mg/m2 on days 1 and 8, every four weeks. Eighty-three patients (median age 54 years; range 32-82 years) entered the study. The median number of metastatic tumour sites was 2, with visceral involvement in 56 patients. Apart from five patients with contraindications, all patients had been pretreated with anthracyclines. Thirty-one patients had received taxanes and seventy-four bolus 5-FU. RESULTS A median of 5 cycles (range 1-14) per patient was administered. The median duration of 5-FU infusion was 17 weeks (range, 4-90). In the 80 evaluable patients (3 not yet evaluable) 12 complete remissions and 24 partial remissions occurred (response rate, 45%). Median duration of response was 9 months. Toxicity was mild. Median survival was 20 months. CONCLUSIONS PCI-5-FU combined with navelbine offers a reasonable chance of tumour regression with modest side effects in patients with heavily pretreated breast cancer.

A different immunologic profile characterizes patients with HER-2-overexpressing and HER-2-negative locally advanced breast cancer: implications for immune-based therapies

IntroductionThe clinical efficacy of trastuzumab and taxanes is at least partly related to their ability to mediate or promote antitumor immune responses. On these grounds, a careful analysis of basal immune profile may be capital to dissect the heterogeneity of clinical responses to these drugs in patients with locally advanced breast cancer undergoing neoadjuvant chemotherapy.MethodsBlood samples were collected from 61 locally advanced breast cancers (36 HER2- and 25 HER2+) at diagnosis and from 23 healthy women. Immunophenotypic profiling of circulating and intratumor immune cells, including regulatory T (Treg) cells, was assessed by flow cytometry and immunohistochemistry, respectively. Serum levels of 10 different cytokines were assessed by multiplex immunoassays. CD8+ T cell responses to multiple tumor-associated antigens (TAA) were evaluated by IFN-γ-enzyme-linked immunosorbent spot (ELISPOT). The Students t test for two tailed distributions and the Wilcoxon two-sample test were used for the statistical analysis of the data.ResultsThe proportion of circulating immune effectors was similar in HER2+ patients and healthy donors, whereas higher percentages of natural killer and Treg cells and a lower CD4+/CD8+ T cell ratio (with a prevalence of naïve and central memory CD8+ T cells) were observed in HER2- cases. Higher numbers of circulating CD8+ T cells specific for several HLA-A*0201-restricted TAA-derived peptides were observed in HER2+ cases, together with a higher prevalence of intratumor CD8+ T cells. Serum cytokine profile of HER2+ patients was similar to that of controls, whereas HER2- cases showed significantly lower cytokine amounts compared to healthy women (IL-2, IL-8, IL-6) and HER2+ cases (IL-2, IL-1β, IL-8, IL-6, IL-10).ConclusionsCompared to HER2- cases, patients with HER2-overexpressing locally advanced breast cancer show a more limited tumor-related immune suppression. This may account for the clinical benefit achieved in this subset of patients with the use of drugs acting through, but also promoting, immune-mediated effects.

Improved Natural Killer cell activity and retained anti-tumor CD8(+) T cell responses contribute to the induction of a pathological complete response in HER2-positive breast cancer patients undergoing neoadjuvant chemotherapy.

BackgroundLocally advanced HER2-overexpressing breast cancer (BC) patients achieve a high rate of pathological complete responses (pCR) after neoadjuvant chemotherapy (NC). The apparently unaltered immune proficiency of these patients together with the immune-modulating activities of NC drugs suggest a potential contribution of host immunity in mediating clinical responses. We thus performed an extensive immunomonitoring in locally advanced BC patients undergoing NC to identify immunological correlates of pCR induction.MethodsThe immune profile of 40 HER2-positive and 38 HER2-negative BC patients was characterized at diagnosis and throughout NC (Paclitaxel and Trastuzumab, or Docetaxel and Epirubicin, respectively). The percentages of circulating immune cell subsets including T and B lymphocytes, Natural Killer (NK) cells, regulatory T cells, T helper 17 lymphocytes, were quantified by multiparametric flow cytometry. NK cells functional activity was evaluated through the analysis of NF-kB nuclear translocation by Multispectral flow cytometry, and with the in vitro monitoring of Trastuzumab-mediated antibody-dependent cell cytotoxicity (ADCC). CD8+ T cell responses against six different tumor-associated antigens (TAA) were characterized by IFN-γ ELISPOT and IFN-γ/IL-2 DualSpot assays.ResultsAfter NC, HER2-positive patients showed a significant increase in the number of NK cells and regulatory T cells irrespective of the pathological response, whereas patients undergoing a pCR disclosed higher percentages of T helper 17 cells. Notably, a significant increase in the number of activated NK cells was observed only in HER2-positive patients achieving a pCR. Characterization of anti-tumor T cell responses highlighted sustained levels of CD8+ T cells specific for survivin and mammaglobin-A throughout NC in patients undergoing a pCR in both arms. Moreover, HER2-positive patients achieving a pCR were characterized by a multi-epitopic and polyfunctional anti-tumor T cell response, markedly reduced in case of partial response.ConclusionsThese results indicate that maintenance of functional T cell responses against selected antigens and improvement of NK cell proficiency during NC are probably critical requirements for pCR induction, especially in HER2-positive BC patients.Trail registration: Trial registration number: NCT02307227, registered on ClinicalTrials.gov (http://www.clinicaltrials.gov, November 26, 2014).

Therapeutic management of breast cancer in the elderly

Introduction: Over the last few decades, the population of developed countries has aged. Breast cancer is the most common cancer among the increased numbers of older women. The choice of adjuvant treatment is particularly difficult in older women because the oncologist has to balance reduction of the risk of recurrence with patient-related comorbidities that may increase the risk of treatment-related toxicity and influence patient survival. Areas covered: This article describes the concept of a comprehensive geriatric assessment and reviews the current literature on biological and pathological characteristics of breast cancer in the elderly, including genomic assays recently available in the clinic. Endocrine, targeted and chemotherapy treatments both in adjuvant and metastatic setting are also covered. Expert opinion: A new generation of studies aimed to re-evaluate treatments in the various subtypes of breast cancer is needed. Whether this will be possible through prospective studies (especially in the adjuvant setting) is unknown. An alternative direction for further research in the elderly could be a reappraisal of old studies with carefully planned subtype analyses. Whatever the direction, the management of elderly breast-cancer patients is inherently multidisciplinary: the contribution of medical and allied health professionals is essential to the provision of optimal care.

Late tamoxifen in patients previously operated for breast cancer without postoperative tamoxifen: 5-year results of a single institution randomised study

BackgroundA population of breast cancer patients exists who, for various reasons, never received adjuvant post-operative tamoxifen (TAM). This study was aimed to evaluate the role of late TAM in these patients.MethodsFrom 1997 to 2003, patients aged 35 to 75 years, operated more than 2 years previously for monolateral breast cancer without adjuvant TAM, with no signs of metastases and no contraindication to TAM were randomized to TAM 20 mg/day orally for 2 years or follow-up alone. Events were categorized as locoregional relapse, distant metastases, metachronous breast cancer, tumours other than breast cancer and death from any causes, whichever occurred first. The sample size (197 patients per arm, plus 10% allowance) was based on the assumption of a 30% decrease in the number of events occurring at a rate of 5% annually in the 10 years following randomization. Four hundred and thirty-three patients were randomized in the study (TAM 217, follow-up 216). Patients characteristics (TAM/follow-up) included: median age 55/55 years, median time from surgery 25/25 months (range, 25-288/25-294), in situ carcinoma 18/24, oestrogen receptor (ER) positive in 75/68, negative in 70/57, unknown in 72/91 patients. Previous adjuvant treatment included chemotherapy in 131/120 and an LHRH analogue in 11/13 patients.ResultsThirty-six patients prematurely discontinued TAM after a median of 1 month, mostly because of subjective intolerance. Eighty-three events (TAM 39, follow-up 44) occurred: locoregional relapse in 10/8, distant metastases in 14/16, metachronous breast cancer in 4/10, other tumours in 11/10 patients. Less ER-positive secondary breast cancers occurred in the TAM treated patients than in follow-up patients (1 vs 10, p = 0.005). Event-free survival was similar in both groups of patients.ConclusionsThis 5-year analysis revealed significantly less metachronous ER-positive breast cancers in the TAM treated patients. No other statistically significant differences have emerged thus far.

Selecting for BRCA1 testing using a combination of homogeneous selection criteria and immunohistochemical characteristics of breast cancers

BackgroundBRCA1 gene-related tumours are more frequently estrogen receptor (ER) and progesterone receptor (PR) negative with a lower prevalence of human epidermal growth factor receptor 2 (HER2) overexpression or amplification. We evaluated the effectiveness of a combination of homogeneously selected criteria and immunohistochemical (IHC) characteristics of Familial Breast Cancers (FBCs) in detecting BRCA1 mutation carriers.MethodsPrimary breast tumours from 93 FBC patients defined by specific eligibility criteria, based on personal and familial tumour history, were evaluated by Allreds method. The BRCA1 molecular analysis, including Multiplex Ligation-dependent Probe Amplification (MLPA), was considered as the gold standard assay.ResultsA total of 10 BRCA1 pathogenetic mutations was found. With the exclusion of the tumours characterized by double positive receptorial status and/or strong HER2 positivity (3+), we identified 22 patients, 10 of whom resulted as BRCA1 mutation carriers. The sensitivity, specificity, positive and negative predictive values were 100%, 83.3%, 45.4% and 100% respectively.ConclusionOur findings suggest that the IHC analysis by Allreds method improves our ability to select patients for BRCA1 testing.

HER2 guided neoadjuvant treatment of advanced breast cancer: Clinico-biological correlations

11559 Background: Tailoring neoadjuvant chemotherapy (NACT) ± trastuzumab (T) according to tumor/host features remains an open issue, with special reference to anthracycline omission in HER2+ cases. Methods: Patients (pts) with breast cancer (BC), NACT candidate, were eligible. HER2+ pts (n=12) received 24 wks of weekly T 4mg/kg loading dose d1 then 2mg/kg and Paclitaxel (P) 80 mg/m2 before surgery, followed by additional 12 wks of TP and T for 1 year. HER2- pts (n=21) received 8 cycles of epirubicin (E) and docetaxel (D) (90 and 75mg/m2 respectively, q3 wks) before surgery, followed by 3 CMF cycles. Hormone therapy was suggested in all hormone sensitive cases. The primary endpoint was pCR and its correlation with Topo2α expression and the extent of spontaneous T cell responses to HER2 and other BC-associated antigens. Results: The TP regimen gave a clinical response in all 8 evaluable pts (clinical complete remission (CR) in 3 pts, partial remission (PR) in 5). Radical mastectomy (RM and quadrantectomy (...

Final results of a phase II clinical and pharmacokinetical trial with oral idarubicin (IDA) in elderly patients (pts) with metastatic breast cancer (MBC)

727 Background: Anthracyclines are among the most active agents in the treatment of MBC. There is a concern in their use in elderly pts due to possible cardiotoxicity Methods: Pts with MBC, measura...

Combined chemo-immunotherapy for metastatic melanoma. A monoinstitutional experience

7569 Background: The combination of Interferon α-2b (INF) and intravenous Interleukin-2 (IL-2) with chemotherapy (CT) has produced encouraging results in metastatic melanoma, as shown in phase II and III trials, but toxicity remains of concern. We report on our experience with a chemo-immunotherapy regimen with subcutaneous administration of IL-2. PATIENTS AND METHODS 28 patients (pts) with advanced melanoma, median age 47.5 years (range 29-70) and male/female ratio 19/9, received CT plus immunotherapy with subcutaneous IL-2 and INF. Doses were as follows: Cisplatinum 20 mg/m2 iv days 1-4, Vinblastine 1.6 mg/m2 iv days 1-4, Dacarbazine 800 mg/m2 iv day 1, Interferon α-2b 5M IU/m2 sc days 1-5, IL-2 9M IU sc days 1-5 and 8-12. Treatment was repeated every three weeks up to a maximum of six cycles. Response was assessed every two cycles and toxicity every cycle, according to WHO and NCI criteria respectively. RESULTS The overall response rate was 33% with 3 (11%) complete responses, lasting for 17, 14 and 24+ months respectively. There were 6 (22%) partial responses and 3 stable disease. 3 responders progressed in the central nervous system (CNS). For the whole population, median time to progression and survival were 3.5 and 9 months respectively. The most common G3-4 toxicity was neutropenia, reported in 25/28 (92%) pts. Only 2 pts (7%) experienced neutropenic fever. Less frequent was G3-4 thrombocytopenia, observed in 6/28 (21%) pts, with only 1 pt needing platelet support. G1-2 nausea and vomiting as well as fever following cytokine injections were reported in all pts. 1 toxic death occurred, due to neutropenic fever. CONCLUSIONS This schedule with sc IL-2 had an acceptable level of toxicity and although the response rate was lower, TTP and OS were comparable to those reported with more intensive regimens. Several pts progressed in the CNS, suggesting that new combinations able to prevent this event are needed. No significant financial relationships to disclose.