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Background: Few data exist in literature regarding oncoplastic surgery (ONC) and ductal carcinoma in situ (DCIS). The role of ONC in the treatment of DCIS has not been elucidated yet: no case-control study has yet been published on the issue and no long-term oncologic results are reported., Methods: Using the European Institute of Oncology (IEO) institutional breast cancer data base we investigated the oncologic safety of ONC for DCIS comparing a consecutive series of 44 patients who have underwent ONC followed by external irradiation for DCIS (Group A-study group) with 375 patients who received conservation alone followed by external irradiation for DCIS (Group B control group) in the same period. We excluded patients presenting with secondary tumors or local relapses and those requiring re-excision or completion mastectomy for positive margins. Primary endpoints were disease-free survival (DFS) and ipsilateral breast tumor recurrence (IBTR) within the study group and comparison with the control group., Results: Events rates and death rates were similar in the two groups. The average annual rate of invasive IBTR in group A and B was 1.6% and 1.0% respectively. No difference in the rate of lymphnode metastasis, distant metastasis, contralateral breast cancer, other primary cancer or death was observed across the two groups., Conclusions: Our findings suggest the safety of ONC and irradiation for the management of DCIS extending the indications for conservation in DCIS patients otherwise treated with mastectomy. It provides the best available evidence supporting ONC as a valid treatment option for the management of DCIS., (Copyright © 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Tumor-infiltrating lymphocytes (TILs) are a robust prognostic adjunct in invasive breast cancer, but their clinical role in ductal carcinoma in situ (DCIS) has not been ascertained., Patients and Methods: We evaluated the prevalence and clinical relevance of TILs in a well annotated series of 1488 consecutive DCIS women with a median follow-up of 8.2 years. Detailed criteria for TILs evaluation were pre-defined involving the International Immuno-Oncology Biomarker Working Group. TILs percentage was considered both as a continuous and categorical variable. Levels of TILs were examined for their associations with ipsilateral breast event (IBE), whether in situ or invasive., Results: Of the 1488 patients with DCIS under study, 35.1% had <1%, 58.3% 1-49% and 6.5% ≥50% peri-ductal stromal lymphocytes. The interobserver agreement in TILs evaluation, measured by the intraclass correlation coefficient (ICC) was 0.96 (95% CI 0.95-0.97). At univariable analysis, clinical factors significantly associated with TILs (P ≤0.001) were intrinsic subtype, grade, necrosis, type of surgery. Her-2 positive DCIS were more frequently associated with TILs (24% of patients with TILs ≥50%), followed by the triple negative (11%), Luminal B/Her-2 positive (9%) and Luminal A/B subtypes (1%) (P < 0.0001). We did not find any association between TILs as a continuous variable and the risk of IBEs. Likewise, when patients were stratified by TILs percentage (<1%, between 1% and 49.9%, and ≥50%), no statistically significant association was observed (10-year cumulative incidence of IBEs: 19%, 17.3%, and 18.7% respectively, P = 0.767)., Conclusion: TILs occur more frequently in the Her-2 positive DCIS. Although we did not find a significant association between TILs and the 10-year risk of IBE, our data suggest that immunotherapies might be considered in subsets of DCIS patients., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Purpose: It is controversial whether sentinel node biopsy (SNB) without axillary dissection (AD) should be performed in cN1/2 breast cancer patients who become cN0 after neoadjuvant treatment, since the false negative rate (FNR) may be unacceptably high. We assessed outcomes to address this issue., Methods: We retrospectively assessed 396 cT1-4, cN0/1/2 patients, who became or remained cN0 after neoadjuvant treatment and underwent SNB with at least one sentinel node (SN) found, and AD not performed if the SN was negative., Results: After a median follow-up of 61 months (interquartile range 38-82), five-year overall survival was 90.7% (95% CI, 87.7-93.7) in the whole cohort, 93.3% (95% CI, 90.0-96.6) in those initially cN0, and 86.3% (95% CI, 80.6-92.1) in those initially cN1/2 (P = 0.12). Axillary failure occurred in only 1 (0.7%) initially cN1/2 patient who became cN0. In initially cN0 patients, and also initially cN1/2 patients who responded well to neoadjuvant treatment (ypT0/ypTx), SN-negativity was a significant predictor of good outcome, consistent with the known prognostic significance of axillary status, and suggesting that SN status accurately reflected axillary status. By contrast, in initially cN1/2 patients found to be ypT1/2/3, SN status (and whether or not AD was performed) had no influence on survival., Conclusions: These findings suggest that SNB is acceptable in cN1/2 patients who become cN0 after neoadjuvant therapy., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Although tumor-infiltrating lymphocytes (TILs) have been associated with a favorable prognosis in triple-negative breast cancer (TNBC) patients, this marker is not currently considered robust enough for entering the clinical practice. In the present study, we assessed the clinical validity of the guidelines recently issued by the International TIL Working Group in a large retrospective series of well-annotated TNBC patients., Patients and Methods: TILs were evaluated in all the full-face H&E sections from 897 consecutive TNBC (i.e. tumors with <1% of ER and PgR immunoreactivity and absence of HER2 overexpression or amplification) patients diagnosed and treated at the European Institute of Oncology between 1995 and 2010 (median follow-up 8.2 years, range 6 months to 18 years). All mononuclear cells were evaluated in the stromal area within the borders of the invasive tumor, reported as a percentage value and treated as a continuous variable in survival analysis., Results: The median percentage of TILs was 20%, and 21.9% of the cases had ≥50% (lymphocyte predominant breast cancer, LPBC) TILs. At univariable survival analysis, TILs were a significant predictor of better disease-free survival (DFS), distant disease-free survival (DDFS) and overall survival (OS) (P < 0.0001). Multivariable analysis confirmed that each 10% increase in TILs strongly predicted better survival, independent of patients' age, lymph node status, tumor size, histological grade, peritumoral vascular invasion and Ki-67 labeling index. Patients with LPBC had a 10-year survival rate of 71%, 84% and 96% for DFS, DDFS and OS, respectively. Stratified analysis revealed a positive correlation between TILs and OS across all the subgroups analyzed., Conclusion: Our data support the analytical validity of the recently issued TILs evaluation guidelines in the clinical practice., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: Oncoplastic surgery is a well-established discipline that combines conserving treatment for breast cancer with immediate plastic reconstruction. Although widely practiced, the oncologic outcomes of this combined approach are reported only in small series. The aim of the present paper is to assess the safety of oncoplastic surgery for invasive primary breast cancer., Methods: We compared 454 consecutive patients who underwent an oncoplastic approach between 2000 and 2008 for primary invasive breast tumors (study group) with twice the number of patients who received conservation alone in the same interval time (control group). Disease free survival and overall survival were estimated using the Kaplan-Meier method. The log-rank test was used to assess differences between groups., Results: The median follow-up was 7.2 years. The overall survival is similar within the two groups, being 91.4% and 91.3% at 10-yr in the study group and in the control group respectively. The disease free survival is slightly lower in the oncoplastic group (69 vs.73.1% at 10-yr). The difference is not statistically significant., Discussion: We have compared a large series of primary breast cancer patients that have undergone oncoplastic surgery (454) with a control group (908) and they were followed for a prolonged period of time. It provides the best available evidence to suggest that oncoplastic surgery is a safe and reliable treatment option for the managing of invasive breast cancer., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: No analyses have investigated the prognostic role of medial presentation in breast cancer patients on disease-free survival (DFS) and overall survival according to immunohistochemically-defined subtypes., Patients and Methods: We collected information from the institutional clinical database on consecutive breast cancer patients who underwent conservative surgery at the European Institute of Oncology, Milan, Italy, between 1994 and 2008. We compared the outcomes of patients with medial breast cancer with those of patients with nonmedial tumors observed at the institution during the same period., Results: Among 7369 evaluable patients, 2254 (24%) had their primary tumors in medial quadrants and 7015 (76%) in other areas. Five-year DFS was 84.7% and 86.6% (P = .008) in patients with medial and nonmedial disease, respectively. In multivariate analysis, medial location was correlated with greater risk of recurrence (hazard ratio [HR], 1.23; 95% confidence interval [CI], 1.11-1.35; P < .0001) and death (HR, 1.27; 95% CI, 1.09-1.49; P = .0028)., Conclusion: Medial presentation is an adverse prognostic factor for breast cancer patients., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: The long-term prognostic relevance of immediate breast reconstruction (IBR) for patients with estrogen receptor (ER)-negative breast cancer (BC) has not been fully elucidated., Patients and Methods: The study population included 444 patients with ER-negative BC who underwent total mastectomy with complete axillary dissection between 1995 and 2006, 339 patients with and 105 patients without IBR. The median follow-up was 8.6 years., Results: Patients treated with IBR were younger (P < .001) and received surgery more recently (2003-2006: 53.1% vs. 39%; P = .0003), and had a lower number of metastatic lymph nodes (>4 lymph nodes involvement: 29.5% vs. 45.7%; P = .0026), smaller tumors (pT1/2: 15% vs. 26.7%; P = .0007), and lower extent of peritumoral vascular invasion (15.9% vs. 21%; P = .032). The 5-year cumulative incidence of locoregional recurrence was 7.1% in the IBR group and 11.7% in the no IBR group (hazard ratio [HR], 0.81; P = .63). The 5-year cumulative incidence of distant metastases were similar in the 2 groups (P = .79). The 5-year overall and disease-free survival proportions were 79.9% versus 69.5% (HR, 1.11; P = .67) and 66.6% versus 54.1% (HR, 1.04; P = .83) in the IBR group and no IBR group, respectively., Conclusion: IBR intervention does not significantly affect prognosis of ER-negative BC patients., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: To assess the prognostic role of human epidermal growth factor receptor 2 (HER2) overexpression in patients with ductal carcinoma in situ (DCIS)., Patients and Methods: We identified patients with HER2-positive DCIS among a population of 1667 cases, prospectively diagnosed and surgically treated at the European Institute of Oncology from 1996 to 2008. Rates of subsequent DCIS or invasive cancer in HER2-positive disease were estimated. We evaluated Cumulative Incidence of In Situ Breast Cancer Recurrence (isBCR), INvasive Breast Cancer Recurrence (IBCR) and any Breast Cancer Recurrence (BCR). isBCR, IBCR and BCR were defined as the time from surgery to breast cancer recurrence as first event (in situ, invasive or both, respectively) or last visit in case of no events., Results: We identified 560 (33.5%) patients with HER2-positive DCIS. The median follow-up was 7.6 years (interquartile range 5.9-9.5). We observed 422 events out of 1667 patients, with 141 in situ recurrences, 201 invasive recurrences and 80 other events (64 second primaries and 16 deaths). The 10-year isBCR proportions were 11.8% [95% confidence interval (CI) 9.0% to 15.4%] in the HER2-positive group and 8.8% (95% CI 6.9% to 11.0%) in the HER2-negative group (Gray test, P = 0.010). At multivariable analysis, the adjusted risk of isBCR was higher in the HER2-positive group than in the HER2-negative group [hazard ratio (HR) HER2 positive versus negative: 1.59 (95% CI 1.06-2.39)]. We observed significant differences both in BCR and isBCR for patients treated by quadrantectomy without radiotherapy versus patients treated with radiotherapy [adjusted HR HER2 positive versus negative: 1.53 (95% CI 1.07-2.18) and adjusted HR HER2 positive versus negative: 2.18 (95% CI 2.18-3.69), respectively]., Conclusion: HER2 overexpression predicts an increased risk of isBCR. Radiotherapy reduces local failure rates in HER2-positive DCIS., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Limited data are available on the prognostic value of changes in the biological features of residual tumours following neoadjuvant therapies in breast cancer patients., Patients and Methods: We collected information through the institutional clinical database on all consecutive breast cancer patients treated with neoadjuvant chemotherapy at the European Institute of Oncology (IEO), Milan, Italy, between 1999 and 2011. We selected patients who did not achieve pathological complete response at final surgery. All patients had a pathological evaluation, including ER, PgR, HER2 protein and Ki-67 expression carried out at the IEO both at diagnostic core biopsy and at final surgery., Results: We identified a total of 904 patients. The 5% of patients who were ER positive at diagnostic biopsy had ER-negative residual tumour at final surgery. For PgR expression, 67% of the patients, whose tumours had a PgR >20% at diagnostic biopsy had a PgR <20% at final surgery. The Ki-67 expression changed from >20% to <20% in 40% of the patients. At the multivariate analysis, the decrease of PgR-immunoreactive cells correlated with improved outcome in terms of disease-free survival (DFS) [hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.54-1.00, P 0.046]. In addition, the decrease of Ki-67 expression to <20% of the cells at final surgery was found to be associated with better outcome both in terms of DFS (HR 0.52; 95% CI 0.40-0.68 P < 0.0001) and overall survival (HR 0.45; 95% CI 0.32-0.64, P < 0.0001)., Conclusion: The decrease of PgR and Ki-67 expression after preoperative chemotherapy has a prognostic role in breast cancer patients with residual disease., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Rational: We retrospectively analyzed 232 patients affected by well differentiated ductal intraepithelial neoplasia (DIN1c or DCIS G1) treated with conservative surgery without adjuvant radiotherapy., Results: 25 invasive and 18 non-invasive local recurrences were observed (median follow-up 80 months; 5-year cumulative incidence: 12.2%). Seven of the 15 young patients (<40 y) developed local recurrence (2 in situ, 5 invasive). Age <50 (HR 1.89, 95% C.I. 1.01-3.45), multifocality (HR 3.21, 95% C.I. 1.46-7.06), Ki-67 > 7% (HR 2.33, 95% C.I. 1.20-4.55) and surgical margins <10 mm (HR 2.00, 95% C.I. 1.06-3.76) were significantly associated with an increased risk of local recurrence., Conclusions: Young age, multifocality and small margins appeared as clear risk factors of local recurrence in DIN1c (DCIS G1) population. The presence of multiple poor prognostic features warrant a thorough discussion regarding local treatment., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Aim: It is established that axillary dissection (AD) can be safely avoided in breast cancer patients with a negative sentinel node (SN). In the present study we assessed whether the rate of axillary disease was sufficiently low on long term follow-up to consolidate the policy of AD avoidance., Methods: We retrospectively analysed data on 5262 consecutive primary breast cancer patients with clinically negative axilla and negative SN, treated from 1996 to 2006, who did not receive AD. We used univariate and multivariate analyses to assess the influence of patient and tumour characteristics on first events and survival. The primary endpoint was the development of axillary disease as first event., Results: After a median follow-up of 7.0 years (interquartile range 5.4-8.9 years) survival for the series was high (91.3%; 95% CI 90.3-92.3 at 10 years) and only 91 (1.7%) patients developed axillary disease as first event. Axillary disease was significantly more frequent in patients with the following characteristics: <35 years at diagnosis, tumour >1 cm, multifocality/multicentricity, G3, ductal histotype, Ki67 ≥ 30%, peritumoral vascular invasion, luminal B-like subtype, HER2 positivity, mastectomy, and not receiving radiotherapy., Conclusion: Long-term follow-up of our large series confirms that axillary metastasis is infrequent when AD is omitted in SN-negative breast cancer patients, and has low impact on overall survival., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Breast cancer occurs rarely in men, accounting for approximately 1% of all breast carcinomas. Data on prognosis principally derive from retrospective studies and from extrapolation of female breast cancer series., Patients and Methods: A total of 99 men with invasive breast cancer were matched with 198 women with breast cancer who had surgery at the same institution from 1999 to 2010. Matching variables were year of surgery, age, primary tumor size, nodal involvement, hormone receptor status, status of HER2 (human epidermal growth factor receptor 2 [ERBB2]), Ki-67, and grade. Median follow-up was 8.6 years., Results: Disease-free survival (DFS) was significantly poorer in the men (10-year DFS, 51.7% vs. 66.5%; hazard ratio [HR], 1.79; 95% CI, 1.19-2.68; P = .004). Similar results were observed for overall survival (OS) (10-year OS, 70.7% vs. 84.2%; HR, 1.79; 95% CI, 1.01-3.15; P = .043). The cumulative incidence of death for causes not related to the primary breast cancer was significantly higher for men than for women (HR, 2.87; 95% CI, 1.58-5.22; P = .001), whereas the breast cancer-specific survival (BCSS) was similar between the 2 groups (10-year BCSS, 81.5% vs. 88%; HR, 1.27; 95% CI, 0.62-2.59; P = .517)., Conclusion: This comparative series found that men with breast cancer had a poorer DFS and OS when compared with women. The men also had a higher risk of contralateral tumors and second primaries. Appropriate counseling, surveillance, and prevention are recommended to improve survival for these individuals., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Introduction: The prognostic value of low estrogen and progesterone receptors expression (ER/PgR 1%-10%) in early breast cancer patients is still unclear., Patients and Methods: We retrospectively analyzed 1424 consecutive patients with HER2/neu-negative and low endocrine receptors expression early breast cancer, submitted to surgery at the European Institute of Oncology between January 1995 and December 2009. Patients were classified according to the percentage of ER/PgR expression using immunohistochemistry. Group 1 with ER/PgR < 1%, and group 2 with ER/PgR 1% to 10%., Results: Group 1 (ER/PgR < 1%) included 1300 patients, and group 2 (ER/PgR 1%-10%) 124 patients. Median follow-up time was 74 months (range, 3-192 months). The 5-year disease-free survival (DFS) rate was 74% (95% confidence interval [CI], 72%-77%) for group 1, and 79% (95% CI, 70%-86%) for group 2 (P = .16). The 5-year overall survival (OS) rate was 86% (95% CI, 84%-88%) in group 1 and 90% (95% CI, 83%-95%) in group 2 (P = .13). In patients without lymph node involvement, the 5-year OS rate was 92% (95% CI, 89.5%-93.6%) for group 1 and 98% (95% CI, 90.2%-99.8%) for group 2 (P = .061). One hundred ten patients received endocrine therapy with no significant effect on DFS (P = .36) and OS (P = .30)., Conclusion: The ER/PgR 1%-10% group had a slight, but not statistically significant, better prognosis than the ER/PgR <1% group. Further studies are needed to identify the appropriate clinical approach in this subset of patients with low ER/PgR expression (ER/PgR 1%-10%), HER2-negative early breast cancer., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: The indication of adjuvant chemotherapy for patients with highly proliferative estrogen receptor-positive breast cancer is controversial. We analyzed the predictive value of Ki67 for the efficacy of adjuvant chemotherapy in patients with estrogen receptor-positive, node-positive breast cancer., Patients and Methods: We identified 1241 patients with Luminal B early stage breast cancer with 1-3 axillary positive nodes who underwent surgery between 1995 and 2005 at the European Institute of Oncology and received adjuvant hormonotherapy and/or chemotherapy. Differences in the distribution of characteristics according to treatment were evaluated by the Chi-square test. To evaluate the effect of adding chemotherapy to hormonotherapy, the propensity score method was used to match patients' characteristics minimizing bias related to the non-random assignment of treatment., Results: The probability of receiving chemotherapy was significantly associated with age, tumor grade, degree of hormone responsiveness, tumor size and peripheral vascular invasion. The propensity score distribution was statistically different between the two treatment groups (p < 0.0001). The 5-year OS percentages were 95.8% (95% CI, 93.5-97.2) in the hormonotherapy group and 96.2% (95%CI, 94.4-97.4%) in the hormonotherapy/chemotherapy group (log-rank test p-value 0.663). The 5-year DFS percentages were 84.6% (95% CI, 81.0-87.6%) in the hormonotherapy group and 84.2% (95% CI, 81.3-86.7%) in the hormonotherapy/chemotherapy group (log-rank test p-value 0.388). However, when analyzing the 5-year DFS by Ki-67 distribution, Subpopulation Treatment Effect Pattern Plot (STEPP) analysis showed a beneficial effect of chemotherapy in patients with highly proliferative tumor (Ki-67 ≥ 32%). The interaction between Ki-67 and treatment was statistically significant (p = 0.027)., Conclusions: Ki67 expression identifies a subset of patients with Luminal B and node-positive breast cancer who could benefit from addition of adjuvant chemotherapy to hormonotherapy. Dichotomy was observed for Ki67 at 32% level., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: The prognostic implications of internal mammary (IM) and supraclavicular (SC) node involvement in locally advanced breast cancer is still unclear., Patients and Methods: We evaluated 107 patients with IM (n = 65) or SC (n = 42) node involvement who underwent operation at the European Institute of Oncology between 1997 and 2009 to assess their prognostic features. We subsequently analyzed matched cohorts, using the 107 patients as cases and another group of patients as a control cohort, to evaluate prognostic differences between patients with and those without IM or SC node involvement., Results: Five-year disease-free survival (DFS) was 84% in IM vs. 38.8% in SC node involvement (P < .0001), and 5-year overall survival (OS) was 96.9% in IM node vs. 57.1% in SC node involvement (P < .0001). No difference in outcome was found between patients with and controls without IM node involvement. Conversely, a statistically significant difference in DFS and locoregional recurrence was observed in patients with SC node involvement compared with controls without SC node involvement., Conclusion: SC node involvement correlated with a significantly poorer outcome in patients with locally advanced breast cancer. Adequate staging, including biopsy of suspicious locoregional ipsilateral lymph nodes, is mandatory in these patients. Patients with IM or SC node involvement should be treated with curative intent using combined-modality treatments., (Copyright © 2014 Elsevier Inc. All rights reserved.)

We collected information on 497 consecutive breast cancer patients aged less than 35 years operated at the European Institute of Oncology. The main aim of the study is to compare biological and clinical features dividing the population by age: <25 years, 25-29 and 30-34 years old. Pattern of recurrence and survival were also analyzed. Patients aged <25 years had 81.8% poorly differentiated tumors compared with 66.7% and 56.5% in the 25-29 and 30-34 groups, respectively; no other significant difference were found in the distribution of clinical and immunohistochemical features The distribution of Luminal A and B, Triple Negative and HER2 subtypes (immunohistochemically defined) was not statistically different among the three age groups. No difference was found in the incidence of loco-regional relapses, distant metastases, disease-free survival (p = 0.79) and overall survival (p = 0.99) between the three age groups. This latter findings was confirmed using age as a continuous variable assuming a linear association between age and the outcomes considered, too. In conclusion, our data indicate that the group of patients with breast cancer below 35 years is essentially a homogenous group when classical clinical and immunohistochemical features were considered., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Postmenopausal hormone replacement therapy (HRT) relieves menopausal symptoms and may decrease mortality in recently postmenopausal women, but increases breast cancer risk. Low-dose tamoxifen has shown retained activity in phase-II studies., Methods: We conducted a phase-III trial in 1884 recently postmenopausal women on HRT who were randomly assigned to either tamoxifen, 5 mg/day, or placebo for 5 years. The primary end point was breast cancer incidence., Results: After 6.2 ± 1.9 years mean follow-up, there were 24 breast cancers on placebo and 19 on tamoxifen (risk ratio, RR, 0.80; 95% CI 0.44-1.46). Tamoxifen showed favorable trends in luminal-A tumors (RR, 0.32; 95% CI 0.12-0.86), in HRT users <5 years (RR, 0.35; 95% CI 0.15-0.82) and in women completing at least 12 months of treatment (RR, 0.49; 95% CI 0.23-1.02). Serious adverse events did not differ between placebo and tamoxifen, including, respectively, coronary heart syndrome (6 versus 4), cerebrovascular events (2 versus 5), VTE (2 versus 5) and uterine cancers (3 versus 1). Vasomotor symptoms were 50% more frequent on tamoxifen., Conclusions: The addition of low-dose tamoxifen to HRT did not significantly reduce breast cancer risk and increased climacteric symptoms in recently postmenopausal women. However, we noted beneficial trends in some subgroups which may deserve a larger study.

Literature shows that HER2/neu positive breast cancer cells are more sensitive to radiation-induced apoptosis by targeting the epidermal growth factor receptor family tyrosine kinase. We selected 466 patients with pT1-2 HER2/neu positive tumors who received adjuvant trastuzumab for primary invasive breast cancer. Patients were divided into three groups [Quadrantectomy followed by conventional radiotherapy vs Quadrantectomy followed by Intra-operative radiotherapy with electrons vs Mastectomy without radiotherapy]. After a median follow-up of 52 months, the 5-year cumulative incidence of locoregional recurrence (LRR) was 1.9%, 11.5% and 5.0% respectively (p < 0.01). At the multivariate analysis, extensive perivascular invasion, Luminal B HER2/Progesterone Receptor (PgR) negative status and Quadrantectomy followed by Intra-operative radiotherapy with electrons have significantly increased the risk of LRR. Our results suggest that HER2/neu positive breast cancer might have better outcomes when treated simultaneously with external radiotherapy and trastuzumab. Moreover, we underline the importance of PgR and further new stratification of risk among luminal subtypes., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Breast reconstruction after mastectomy is currently considered an essential component in managing breast cancer patients, particularly those diagnosed at a young age. However, no studies have been published on the feasibility of immediate breast reconstruction in patients diagnosed and operated during the course of gestation., Method: We retrospectively identified all breast cancer patients who were subjected to mastectomy and immediate breast reconstruction during pregnancy at the European Institute of Oncology between 2002 and 2012. Patient demographics, gestational age at surgery, tumor stage, adjuvant treatment, details of the surgical procedures, surgical outcomes and fetal outcomes were analyzed., Results: A total of 78 patients with breast cancer diagnosed during pregnancy were subjected to a surgical procedure during the course of gestation. Twenty-two patients had mastectomy; of whom 13 were subjected to immediate breast reconstruction. Twelve out of 13 patients had a two-stage procedure with tissue expander insertion. Median gestational age at surgery was 16 weeks. No major surgical complications were encountered. Only one patient elected to have an abortion, otherwise, no spontaneous abortions or pregnancy complications were reported. Median gestational age at delivery was 35 weeks (range: 32-40 weeks). No major congenital malformations were reported. At a median follow-up of 32 months, all patients are alive with no long-term surgical complications., Conclusions: This is the first study of immediate breast reconstruction in pregnant breast cancer patients. Tissue expander insertion appears to ensure a short operative time, and does not seem to be associated with considerable morbidity to the patient or the fetus. Hence, it could be considered in the multidisciplinary management of women diagnosed with breast cancer during pregnancy., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Postsurgical treatment of ductal intraepithelial neoplasia (DIN) with standard doses of tamoxifen has not reached a consensus yet. Given positive results of low-dose tamoxifen on breast cancer biomarkers modulation, we analyzed a large cohort of DIN patients treated with low-dose tamoxifen or no treatment as per institutional guidelines., Patients and Methods: All consecutive women operated on at the European Institute of Oncology for estrogen receptor (ER)-positive DIN (474 treated with low-dose tamoxifen and 509 untreated patients) were followed up for a median of 7 years., Results: Compared with untreated patients, a significant 30% reduction in breast cancer risk was observed on low-dose tamoxifen with an adjusted hazard ratio (HR) = 0.70 [95% confidence interval (CI) 0.51-0.94], with a greater benefit in postmenopausal (HR = 0.57; 95% CI 0.34-0.94) than in premenopausal women (HR = 0.79; 95% CI 0.54-1.17). Treated patients with ER and progesterone receptor (PgR) >50% DIN had a lower incidence of breast events than untreated ones (HR = 0.61; 95% CI 0.40-0.94), whereas no protective effect has been observed in patients with ER or PgR <50% DIN. Drug discontinuation resulted in a doubled risk of recurrence in premenopausal women only (HR = 1.95; 95% CI 0.98-3.89). No excess of endometrial cancer occurred., Conclusions: Low-dose tamoxifen is a promising and safe strategy for highly endocrine responsive DIN. Treatment adherence is crucial in premenopausal women. A definitive trial is ongoing.

Background: Fat grafting is widely carried out in breast cancer patients to improve quality in breast reconstruction. Recently, in vitro and animal studies have questioned the role of adipose tissues in cancer development., Designs: Matched-cohort study. We analysed: (i) 59 intraepithelial neoplasia patients who had undergone lipofilling, with no recurrence between primary surgery and lipofilling. (ii) A control group of 118 matched patients (two controls per lipofilling patient) with the corresponding recurrence-free intervals. Both groups were also matched for main cancer criteria. A local event (LE) was the primary end point, with follow-up starting from the baseline., Results: Median follow-up was 63 and 66 months from surgery, and 38 and 42 from baseline, for the lipofilling and control groups, respectively; the 5-year cumulative incidence of LE was 18% and 3% (P = 0.02). Ki-67 was the significant factor in univariate survival analysis. A subgroup analysis showed that lipofilling increased the risk of LE in women <50 years, with high grade neoplasia, Ki-67 ≥ 14 or who had undergone quadrantectomy., Conclusion: Higher risk of LE was observed in intraepithelial neoplasia patients following lipofilling. Although further studies are required to validate our conclusions, patients belonging to this subgroup should be informed of these results and the potential risks.

Background: Conflicting data are available in the literature on the outcome of invasive apocrine carcinoma (IAC), possibly related to a heterogeneous classification of these tumors., Patients and Methods: A series of 6899 consecutive patients with invasive ductal carcinoma (IDC) not otherwise specified and 72 patients with immunohistochemically defined IAC who received surgery at the European Institute of Oncology between 1997 and 2005 were included. We then explored patterns of recurrence of IAC according to 2 immunohistochemically defined tumor subtypes: pure apocrine carcinoma (estrogen [ER] and progesterone [PgR] receptor negative, and AR positive) and apocrine-like carcinoma (ER or PgR positive and AR negative)., Results: The diagnosis of pure apocrine carcinoma was correlated with a worse outcome in terms of DFS (hazard ratio [HR] 1.7; 95% confidence interval [CI], 1.01-2.86; P = .0010) if compared with IDC, whereas IDC and apocrine-like breast cancers showed a similar outcome in terms of DFS and overall survival. Patients with pure apocrine carcinoma had an increased risk in contralateral breast cancer (HR, 4.12; 95% CI, 1.22-14; P = .02)., Conclusion: Pure apocrine carcinoma represents a distinct subtype of breast cancer with a significantly worse DFS as compared with IDC. AR determination might have an important prognostic implication in IAC. Moreover, AR-targeted therapy should be further explored within these tumors., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: The immunohistochemical (IHC) evaluation of estrogen receptor (ER), progesterone receptor (PgR), Ki-67 and HER2 is considered a surrogate means for identifying the molecular subtypes of breast cancer with different prognosis., Patients and Methods: We explored patterns of recurrence in 4837 women with breast cancer defined as Luminal B (ER-positive and/or PgR-positive, HER2 positive and/or Ki-67≥14%) by IHC classification. We evaluated four subgroups within the Luminal B subtype according to HER2 expression and PgR status., Results: Patients within the ER+/PgR+/HER2- subgroup presented a 5-year breast cancer-related survival (BCS) of 97% (95% confidence interval (CI), 96-97) and overall survival (OS) of 95% [95% CI, 95-96], the best survivals of the Luminal B subgroups. In the multivariate analysis, the ER+/PgR-/HER2- subgroup was associated with a reduced BCS (HR 1.71; 95%CI, 1.25-2.35) and OS (HR 1.47; 95%CI, 1.10-1.96) when compared with the ER+/PgR+/HER2- subgroup. Also patients within the ER+/PgR-/HER2+ subgroup had a reduced BCS (HR 1.93; 95%CI, 1.32-2.83) and OS (HR 1.62; 95%CI, 1.14-2.30) when compared with ER+/PgR+/HER2- subgroup. On the other hand, no statistically significant differences were found with regard to BCS and OS among patients with ER+/PgR+/HER2+ and patients with ER+/PgR+/HER2- disease., Conclusions: PgR loss identifies Luminal B breast cancer subgroups at higher risk of relapse and death, both with HER-2-positive and HER-2-negative disease.

Background: A small but significant proportion of patients with breast cancer (BC) will develop loco-regional recurrence (LRR) after immediate breast reconstruction (IBR). The LRR also varies according to breast cancer subtypes and clinicopathological features., Methods: We studied 1742 consecutive BC patients with IBR between 1997 and 2006. According to St Gallen conference consensus 2011, its BC approximations were applied to classify BC into five subtypes: estrogen receptor (ER) and/or progesterone receptor (PgR) positive, HER2 negative, and low Ki67 (<14%) [luminal A]; ER and/or PgR positive, HER2 negative and high Ki67(≥ 14%) [luminal B/HER2 negative]; ER and/or PgR positive, any Ki67 and HER2 positive [luminal B/HER2 positive]; ER negative, PgR negative and HER2 positive [HER2 positive/nonluminal]; and ER negative, PgR negative and HER2 negative [triple negative]. Cumulative incidences of LRR were compared across different subgroups by means of the Gray test. Multivariable Cox regression models were applied., Results: Median follow up time was 74 months (range 3-165). The cumulative incidence of LRR was 5.5% (121 events). The 5-year cumulative incidence of LRR was 2.5% for luminal A; 5.0% for luminal B/HER2 negative; 9.8% for luminal B/HER2 positive; 3.8% for HER2 non luminal; and 10.9% for triple negative. On multivariable analysis, tumor size (pT) >2 cm, body mass index (BMI) ≥ 25, triple negative and luminal B/HER2 positive subtypes were associated with increased risk of LRR., Conclusion: Luminal B/HER2 positive, triple negative subtypes and BMI ≥ 25 are independent prognostic factors for risk of LRR after IBR., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: We retrospectively investigated (18)F-FDG uptake by the primary breast tumor as a predictor for relapse and survival., Patients and Methods: We studied 203 patients with cT1-T3N0 breast cancer. Standardized uptake value (SUVmax), was measured on the primary tumor. After a median follow-up of 68 months (range 22-80), the relation between SUVmax and tumor factors, disease free-survival (DFS) and overall survival (OS) was investigated., Results: In the PET-positive patients, the median FDG uptake by the tumor was 4.7. FDG uptake was significantly related to tumor size, number of involved axillary nodes, grade, negative ER, high Ki-67 and HER2 overexpression. No distant metastases or deaths occurred in the PET-negative group. Five-year DFS was 97% and 83%, respectively in the PET-negative and PET-positive groups (P = 0.096). At univariate analysis, DFS was significantly lower in patients with SUVmax >4.7 compared to the patients with negative PET (P = 0.042), but not to the patients with SUVmax ≤4.7 (P = 0.106). At multivariable analysis, among PET-positive patients, SUVmax was not an independent prognostic factor for DFS (HR(>4.7 vs ≤4.7): 1.02 (95% CI 0.45-2.31)). Five-year OS was 100% and 93%, respectively, in the PET-negative and PET-positive groups (P = 0.126)., Conclusion: FDG uptake by the primary lesion was significantly associated with several prognostic variables, but it was not an independent prognostic factor., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: This study assesses outcome in terms of disease-free survival (DFS) and overall survival (OS) of special types of triple-negative breast cancer (TNBC)., Patients and Methods: We identified 8801 women with first primary nonmetastatic breast cancer operated on at the European Institute of Oncology between 1997 and 2005. Of these patients, 781 consecutive patients with immunohistochemically defined TNBC were selected for the analyses. We explored patterns of recurrence by histologic type. Median follow-up was 5.7 years (range 0-13 years)., Results: The 5-year DFS was 77% for TNBC, 68% for human epidermal growth factor receptor 2 (HER2)-positive breast cancer, and 84% and 95% for luminal B and luminal A breast cancer, respectively. From 781 TNBC subtypes, 693 cases (89%) were classified as ductal not otherwise specified (NOS) (invasive ductal carcinoma [IDC]), 29 were classified as apocrine (3.7%), 18 (2.3%) were classified as lobular, 10 (1.2%) were classified as adenoid cystic, and 10 (1.2%) were classified as metaplastic. Five-year DFS and OS were 77% and 84% for patients with ductal carcinoma, 56% and 89% for patients with metaplastic carcinoma, and both 5-year DFS and OS were 100% for patients with adenoid cystic and medullary carcinomas, respectively., Conclusion: Distinct prognostic implications may derive from the specific histotype of TNBC. The identification of these special types has a significant clinical utility and should be considered in therapeutic algorithms., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Patients with metastatic breast cancer to the ovary, without tumor debulking and after systemic therapy, have a 5-year survival rate < 10%., Patients and Methods: We analyzed a series of 37 patients, operated in one institution over 10 years, for both the primary tumor (PT) and ovarian/pelvic metastases (OPM). Estrogen receptors (ER), progesterone receptors (PgR), HER-2 and Ki-67 were determined., Results: Patients were predominantly young: 27 (73%) patients were < 50 years. Average ER/PgR expression did not change significantly between PT (mean ER = 66%, PgR = 35%) and OPM (mean ER = 67%, PgR = 28%). Median time to OPM was 42 months (range 0-176); 5-year OS after OPM was 51% (95% confidence interval 32% to 67%). When combining ER and PgR status, patients with ER > 50% on both PT and OPM and with PgR > 50% on PT and/or OPM (good prognosis, 11 patients) had a better outcome versus0 patients with ER and PgR ≤ 50% on both PT and OPM (bad prognosis, eight patients) and also versus the remaining patients (intermediate prognosis, 18 patients), P value = 0.010., Conclusion: Patients with OPM from breast cancer show a favorable prognosis after tumor debulking, whether it was radical or not, especially when a high expression of ER and PgR is present in both PT and OPM.

Purpose: To develop a Risk Score (RS) to predict distant recurrence among premenopausal women with node-negative endocrine-responsive early breast cancer., Methods: The Cox model was used to develop the RS using clinical and histopathological features from 378 women participating in the IBCSG Trial VIII who received endocrine therapy alone or following chemotherapy. The performance of the resulting model was validated on a cohort of 1005 patients from a single institution who received endocrine therapy alone., Results: In a multivariable analysis, the risk of distant recurrence was associated with tumor size, ER, Ki-67 and peritumoral vascular invasion. In the validation cohort, patients with high RS were at greater risk of distant recurrence compared to patients with low RS (HR, 17.41; 95% CI, 5.72-52.95)., Conclusion: In premenopausal women with node-negative endocrine-responsive early breast cancer, the RS identifies patients at higher risk of distant recurrence., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Breast cancer is a heterogeneous disease. Circulating tumor cell (CTC) enumeration might be useful to identify different risk categories within each molecular subtype., Methods: We retrospectively analyzed 203 consecutive patients with metastatic breast cancer with baseline CTC enumeration performed with CellSearch (Veridex Corp, Warren, NJ) between March 2005 and July 2011. Patients were categorized into 3 prognostic groups based on the number of CTCs (0, 1-4, and ≥ 5) and into 5 categories based on tumor biological characteristics: luminal-A (estrogen receptor [ER] and progesterone receptor [PR] > 1%, grade 1/2, human epidermal growth factor 2 [HER2]-negative [HER2(-)], Ki67 value < 14%); luminal-B (ER and/or PR > 1%, grade 3, HER2(-), Ki67 value > 14%); luminal-B HER2-positive [HER2(+)] (ER and/or PR > 1%, any grade, HER2(+), Ki-67 value any); HER2(+) (HER2 overexpressed/fluorescence in situ hybridization [FISH] amplified, ER and PR absent); triple negative (TN) (ER and PR 0%, HER2 not overexpressed/FISH not amplified)., Results: Median age was 57 years (range 31-78 years). Twenty-seven patients (13.3%) had luminal-A category, 105 (51.7%) patients had luminal-B, 29 (14.3%) patients had luminal-B HER2(+), 24 patients (11.8%) had HER2(+), and 18 patients (8.9%) had TN. CTCs were mostly found in patients with luminal-A/luminal-B HER2(-) subtype. At multivariable analysis, CTC count was a significant predictive factor for overall survival (OS) in all molecular subtypes (log-rank P < .01). Patients with 0 CTCs/7.5 mL blood and all subtypes, except HER2(+), seem to perform better compared with other categories., Conclusion: These findings confirm CTCs as an important prognostic factor for metastatic breast cancer in all molecular subtypes. Larger studies could help identify metastatic breast cancer subgroups in which CTC analysis would be particularly useful., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: To identify risk factors of recurrence in a large series of patients with breast cancer who underwent a nipple-sparing mastectomy (NSM)., Patients and Methods: Breast-related recurrences and local recurrences (LR) in the breast and the nipple areola complex (NAC) were studied. Cumulative incidences of events were estimated through competing risk analysis. Multivariate Cox regression models were also applied., Results: We identified 934 consecutive NSM patients during 2002-2007. Median follow-up was 50 months. In 772 invasive carcinoma patients, the rate of LR in the breast and in the NAC was 3.6% and 0.8%, respectively. In the 162 patients with intraepithelial neoplasia, the rate of LR in the breast and in the NAC was 4.9% and 2.9%, respectively. The significant risk factors of LR in the breast for the group A were grade, overexpression/amplification of HER2/neu and breast cancer molecular subtype Luminal B. In group B, the risk factors of LR in the breast and in the NAC were age (<45 years), absence of estrogen receptors, grade, HER2/neu overexpression and high Ki-67., Conclusions: The LR rate after NSM in our series was low. Biological features of disease and young age should be taken into account when considering NSM in breast cancer patients.

Background: Biopsy of metastatic site of disease can influence treatment decisions, but its impact on survival remains uncertain., Patients and Methods: One-hundred patients with first metachronous liver metastases (LM) from breast cancer (BC) who underwent liver biopsy between 1999 and 2009 were identified. One-hundred matched control patients with LM from BC and no biopsy were selected., Results: Liver biopsy had no statistically significant impact on survival when comparing biopsied patients to controls [HR 0.82 (95% CI 0.58-1.16)]. Patients with early metastasis (within 3 years) undergoing liver biopsy had a better survival [HR 0.60 (95% CI 0.38-0.97)] compared to those who did not. Liver biopsy had no statistically significant impact on survival in patients with late LM (after 3 years) [HR 1.09 (95% CI 0.69-1.74)]. We observed that 18 out of 100 biopsied patients (18.0%) had a conversion of predictive factors which allowed adjusting for therapy, specifically new expression of ER (n=5), overexpression of HER2 (n=12) or both (n=1). Fourteen out of 18 (77.8%) received anti-HER2 treatment for the first time at the time of metastasis and 3 others (16.7%) received hormone therapy. Those 18 patients showed a better survival compared to the other 82 biopsied patients [HR 0.55 (95% CI 0.28-1.10)] and compared to the 13 biopsied patients with disappearance of features which predicted responsiveness to a given treatment [HR 0.19 (95% CI 0.06-0.62)]., Conclusions: Liver biopsy can impact survival of patients with early metastases from BC. Discordance between primary and distant lesions can offer the patients new treatment options., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: The identification of special types of breast cancer might be of value in assessing prognosis and predicting response to therapy., Methods: A total of 7372 consecutive patients with immunohistochemically defined luminal invasive breast cancer operated at the European Institute of Oncology between 1997 and 2005 were included. We then explored patterns of recurrence by histological type. Median follow-up was 5.8 years., Results: Tumors from 5707 patients were classified as invasive ductal cancer (IDC) not otherwise specified (NOS), 851 lobular, 338 mixed ductal and lobular, 250 cribriform, 143 mucinous and 83 tubular carcinomas. Compared with IDC NOS disease-free survival (DFS) was significantly longer in patients with cribriform tumors [5-year DFS 97.9% versus 87.4%; hazard ratio (HR) = 0.48; P = 0.015) and in pooled cribriform plus tubular carcinomas (5-year DFS 98.7% versus 87.4%; HR = 0.45; P = 0.005). Mucinous tumors presented similar DFS if compared with IDC (5-year DFS 93 % versus 87.4%; HR = 1.03; P = 0.91). Conversely, DFS was poorer for patients with lobular carcinoma (5-year DFS 86.8% versus 87.4%; HR = 1.27; P = 0.01)., Conclusions: The diagnosis of tubular, cribriform and lobular carcinomas carry distinct prognostic implications. The identification of these special types has a significant utility in luminal breast cancer and should be considered in therapeutic algorithms.

Background: Lipofilling has been indicated for postmastectomy and postlumpectomy breast reconstruction. The clinical literatures underline its technical efficacy but experimental studies raise important questions about the potential detrimental effect of adipocytes on the stimulation of cancer growth and reappearance., Design: We collected 321 consecutive patients operated for a primary breast cancer between 1997 and 2008 who subsequently underwent lipofilling for reconstructive purpose. For each patient, we selected two matched patients with similar characteristics who did not undergo a lipofilling., Results: Eighty-nine percent of the tumors were invasive. Median follow-up was 56 months from the primary surgery and 26 months from the lipofilling. Eight and 19 patients had a local event in the lipofilling and control group, respectively, leading to comparable cumulative incidence curves [P = 0.792; Hazard Ratio(Lipo vs No lipo) = 1.11 (95% confidence interval 0.47-2.64)]. These results were confirmed when patients undergoing quadrantectomy and mastectomy were analyzed separately and when the analysis was limited to invasive tumors. Based on 37 cases, the lipofilling group resulted at higher risk of local events when the analysis was limited to intraepithelial neoplasia., Conclusions: Lipofilling seems to be a safe procedure in breast cancer patients. Longer follow-up and further experiences from oncological series are urgently required to confirm these findings.

Background: To evaluate the outcome of breast cancer patients after locoregional recurrence (LRR) according to tumor biological features evaluated at first diagnosis and at the time of recurrence., Patients and Methods: We collected information on all consecutive breast cancer patients operated at the European Institute of Oncology between 1994 and 2005. The tumor characteristics and subsequent outcome of patients who experienced LRR were analyzed., Results: Two hundred and seventy nine patients with LRR were identified, 197 and 82 patients with local and regional recurrence respectively. The overall discordance rate between primary cancer and LRR was 9% for estrogen receptor expression, 22% for progesterone receptor and 4% for human epidermal growth factor receptor 2. For patients with regional recurrence, the risk of distant metastasis was significantly higher compared with local relapse in case of late recurrence (hazard ratio [HR] = 2.76; 95% CI 1.31-5.85). Patients with triple-negative breast cancer at LRR experienced a higher risk of subsequent relapse (HR 2.87 [1.67-4.91]) and death (HR 2.00 [1.25-3.19])., Conclusion: LRR correlates with a high risk of subsequent events and death in particular in patients with triple-negative subtype.

Background: Currently, the acquisition of tissue from metastatic deposits is not recommended as a routine practice. Our aim was to evaluate the discordance rate of estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2) receptor status between primary tumor and liver metastases and its potential impact on treatment choice., Patients and Methods: We retrospectively analyzed a database including 1250 ultrasound-guided liver biopsies carried out at the European Institute of Oncology from August 1999 to March 2009. ER, PgR, and HER2 status were determined by immunohistochemistry and/or FISH. Differences between proportions were evaluated using Fisher's exact test., Results: We identified 255 consecutive patients with matched primary and liver tissue samples. Changes in ER status were observed in 37 of 255 patients (14.5%). Changes in PgR status were observed in 124 of 255 patients (48.6%). Changes in HER2 status were observed in 24 of 172 assessable patients (13.9%). We observed a discordance in receptor status (ER, PgR, and HER2) between primary tumor and liver metastases, which led to change in therapy for 31 of 255 of patients (12.1%)., Conclusions: Biopsy of metastases for reassessment of biological features should be considered in all patients, when safe and easy to carry out, since it is likely to impact treatment choice.

Aims: Breast cancer is the most frequent secondary tumor in young women previously treated with mantle radiation for Hodgkin's disease. Prior therapeutic radiation to the breast region is considered an absolute contraindication to breast conservative surgery, and mastectomy is considered the treatment of choice. We performed a retrospective review to assess the potential of performing breast conservative surgery and intraoperative radiotherapy with electrons (ELIOT), in these patients., Methods and Results: Forty-three patients affected by early breast cancer, previously treated with mantle radiation for malignant lymphoma, who underwent breast conservative surgery and ELIOT, were identified in our institution. Median age at diagnosis of lymphoma was 26 years (49% were less than 25). Median interval between lymphoma and breast cancer occurrence was 19 years. A total dose of 21 Gy (prescribed at 90% isodose) in 39 patients (91%), of 17 Gy (prescribed at 100% isodose) in 1 patient and 18 Gy (prescribed at 90% isodose), was delivered. ELIOT was well tolerated in all patients without any unusual acute or late reactions. After a median follow-up of 52 months, local recurrence occurred in 9% of the patients and metastases in 7% patients., Conclusion: In patients previously treated for lymphoma, partial breast irradiation, and in particular ELIOT, permits breast conservative surgery without acute local complications, decreasing the number of avoidable mastectomies., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Purpose: This study was designed to establish whether the number of lymph nodes removed has an effect on prognosis in patients with node-negative gastric cancer., Patients and Methods: We retrospectively analysed data of 114 consecutive patients who underwent gastrectomy and extended lymph node dissection for node-negative adenocarcinoma of the stomach between 2000 and 2005. Standard survival methods and restricted cubic spline multivariable Cox regression models were applied., Results: Median age was 63 years and 67 patients out of 114 (59%) were males. Median number of dissected LNs was 22 (range 2-73). Median follow-up was 76 months. Patients who had ≤15 nodes removed had significantly worse distant disease-free survival, disease-free survival and overall survival at multivariable analysis than other patients. The results did not change when pT1 and pT2-3 cancer patients were analysed separately. The risk of distant metastases decreased as the number of dissected lymph nodes increased (>15)., Conclusions: More extended lymph node resection offered survival benefit even in the subgroup of patients with early stage disease. Lymphadenectomy involving more than 15 lymph nodes should be performed for the treatment of node-negative gastric cancer., Synopsis: The impact on survival of the number of lymph nodes removed in patients with node-negative gastric cancer has not been established. This study suggests that more extended lymph node resection offers protection, as patients who had ≤15 nodes removed had significantly worse disease-free survival and overall survival at multivariate analysis than patients in whom >15 nodes were removed., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: cancer-testis (CT) antigens, frequently expressed in human germline cells but not in somatic tissues, may become aberrantly reexpressed in different cancer types. The aim of this study was to investigate the expression of CT antigens in breast cancer., Patients and Methods: a total of 100 selected invasive breast cancers, including 50 estrogen receptor (ER) positive/HER2 negative and 50 triple negative (TN), were examined for NY-ESO-1 and MAGE-A expression by immunohistochemistry., Results: a significantly higher expression of MAGE-A and NY-ESO-1 was detected in TN breast cancers compared with ER-positive tumors (P = 0.04). MAGE-A expression was detected in 13 (26%) TN cancers compared with 5 (10%) ER-positive tumors (P = 0.07). NY-ESO-1 expression was confirmed in nine (18%) TN tumor samples compared with two (4%) ER-positive tumors., Conclusions: MAGE-A and NY-ESO-1 CT antigens are expressed in a substantial proportion of TN breast cancers. Because of the limited therapeutic options for this group of patients, CT antigen-based vaccines might prove to be useful for patients with this phenotype of breast cancer.

Background: There is limited knowledge about prognosis of selected breast cancer subtypes among very young women., Patients and Methods: We explored patterns of recurrence by age according to four immunohistochemically defined tumor subtypes: Luminal A and Luminal B (estrogen receptor positive and/or progesterone receptor positive and either human epidermal growth factor receptor 2 (HER2) positive and/or high Ki-67), HER2-positive (and) endocrine receptor absent and Triple Negative, in 2970 premenopausal patients with pT1-3, pN0-3 and M0 breast cancer., Results: Patients <35 years of age (315, 11%) presented a significantly increased risk of recurrence and death [hazards ratio (HR) = 1.65, 95% confidence interval (CI) 1.30-2.10 and HR = 1.78, 95% CI 1.12-2.85, respectively] when compared with older patients (2655, 89%) with similar characteristics of disease. This was true considering patients with Luminal B [HR = 1.62, 95% CI 1.21-2.18 for disease-free survival (DFS) and HR = 2.09, 95% CI 0.96-4.53 for overall survival (OS)] and with Triple Negative (HR = 2.04, 95% CI 1.11-3.72 for DFS and HR = 2.20, 95% CI 1.10-4.41 for OS) breast cancer, observing the highest risk of recurrence in the younger patients with HER2-positive breast cancer (HR = 2.37, 95% CI 1.12-5.02) when compared with older patients., Conclusions: Very young patients with Triple Negative, Luminal B or HER2-positive breast cancer have a worse prognosis when compared with older patients with similar characteristics of disease.

Introduction: Despite the reduced aggressiveness of breast cancer with older age, elderly patients are diagnosed with larger and more advanced tumors compared with younger patients. We studied the specific relationship between lymph node (LN) involvement and age., Patients and Methods: Data were analyzed on 12,152 consecutive breast cancer patients who were operated on between 1995 and 2006 in a single institution. Cubic spline logistic models were used., Results: LN involvement was present in 5409 patients (44.5%). Median age was 52 years; median tumor diameter was 1.7 cm; 83.4% had positive estrogen receptors; and 15.3% had human epidermal growth factor receptor (HER)2/neu overexpression. At the univariate analysis, the probability of LN involvement decreased with increasing age up to approximately 65 years, but it increased thereafter. However, when investigating the relationship in pT strata, after adjusting for other prognostic factors, we observed no increase of LN involvement probability in elderly patients., Conclusion: Increasing risk of LN involvement in the elderly can be explained by delayed diagnosis in this age group. Lack of systematic screening programs for this subpopulation and tendency of the elderly to wait longer before consulting a physician might be blamed. Aging per se does not increase the risk of LN involvement.

Background: Tamoxifen's cost-benefit ratio for breast ductal intraepithelial neoplasia (DIN) is unclear. Since low-dose tamoxifen showed a favorable modulation of breast cancer biomarkers in phase II trials, a monoinstitutional cohort of women with DIN treated with low-dose tamoxifen or no systemic treatment was analyzed., Patients and Methods: A total of 309 patients with DIN received low-dose tamoxifen as part of institutional guidelines and were compared with 371 patients with DIN who received no systemic treatment after surgery., Results: Women with estrogen receptor (ER)/progesterone receptor (PgR) >50% DIN who were not treated had a higher incidence of breast events than women on tamoxifen [hazard ratio (HR) 1.76; 95% confidence interval (CI) 1.00-3.12] or women with ER/PgR <50% DIN (HR 1.72; 95% CI 1.14-2.58). Among untreated patients with ER >50% DIN, recurrence was higher in PgR > or =50% DIN than in PgR <50% DIN, whereas it was similar among low PgR (<50%) DIN against which tamoxifen had no effect. No difference in endometrial cancer incidence was noted., Conclusions: High ER and especially high PgR expression is a significant adverse prognostic indicator of DIN, and low-dose tamoxifen appears to be an active treatment. Women with low-expression ER or PgR DIN do not seem to benefit from tamoxifen. A definitive clinical trial is warranted.

Background: A minority of patients treated conservatively for breast cancer will develop local or regional recurrences. Our aim was to determine how their occurrence may be linked to the evolution of the disease., Patients and Methods: We analyzed 2784 women treated for early-stage breast cancer by quadrantectomy and whole-breast irradiation in a single institution. We evaluated the prognostic factors associated with local, regional and distant recurrences and the prognostic value of local and regional recurrences on systemic progression., Results: After a median follow-up of 72 months, we observed 33 local events, 35 regional events and 222 metastases or deaths as first events (5-year cumulative incidence 1.1%, 1.2% and 7.6%, respectively). Size, estrogen receptor status, Her2/Neu and Ki-67 were associated with all three types of events, while axillary status and vascular invasion were associated only with the occurrence of metastases or death. Young age increased the risk of local recurrence. Local and regional recurrences were associated with an increased risk of systemic progression: hazard ratios 2.5 [95% confidence interval (CI) 1.1-5.8] and 5.3 (95% CI 3.0-9.5), respectively., Conclusions: Local and regional recurrences after breast-conserving surgery are rare events. They are markers of tumor aggressiveness and indicators of an increased likelihood of distant metastases.

Introduction: Surgical treatment of breast cancer in very young patients (<35 years) is still a matter of debate, since age is a predictive factor of local recurrence after breast conservation., Patients and Methods: We retrospectively evaluated outcome and prognostic factors of 201 consecutive patients treated with breast conservation followed by whole breast irradiation between 1997 and 2004 with special attention paid to local control. The average follow up was 72 months (range 13-133 months)., Results: The mean age was 32 years (Range 20-34). Invasive ductal carcinoma was found in 175 (87.1%) patients. Two (1%) patients had invasive lobular carcinoma. One-hundred and eighteen patients (58.7%) had tumors of 2 cm or smaller. Sentinel lymph node biopsy was performed in 105 (52.2%) patients. One-hundred and ten (54.7%) patients had node-negative disease, 68 (33.8%) patients had 1-3 positive nodes and 23 (11.4%) +4 positive nodes. Eighteen patients (9.0%) developed a local recurrence, 25 (12.5%) developed distant metastases and 23 patients (11.4%) died during follow up. The 5- and 10-year cumulative incidence of local events were 8.2% and 12,3% respectively. The univariate analysis did not identify any variables affecting local disease-free survival., Conclusions: Breast conservation in very young patients achieves an acceptable local control rate. No prognostic factors were associated with local events., (Copyright (c) 2009. Published by Elsevier Ltd.)

Background: We aimed to predict disease-free survival (DFS) in patients who failed to achieve a pathologic complete remission (pCR) after preoperative chemotherapy (PC)., Patients and Methods: Data from 577 patients treated with PC and operated at the European Institute of Oncology (EIO) were used to develop a nomogram using Cox proportional hazards regression model based on both categorical (pT, positive nodes, human epidermal growth factor receptor 2 (HER2) status, vascular invasion) and continuous histological variables (estrogen receptors and Ki-67 expression) at surgery. The nomogram was tested on a second patient cohort (343 patients) treated in other institutions and subsequently operated at the EIO., Results: The nomogram for DFS based on both categorical and continuous variables had good discrimination in the training and the validation sets (concordance indices 0.73, 0.67)., Conclusion: The use of a nomogram based on the degree of selected histopathological variables can predict DFS and might help in the adjuvant therapeutic algorithm design.

Background: In the case of ipsilateral breast tumour recurrence (IBTR) after breast-conserving surgery (BCS), a second conservative surgical approach maybe considered in some motivated patients whereas in others mastectomy is unavoidable., Patients and Methods: From 1997 to 2004, 282 patients presented at the European Institute of Oncology with an operable invasive IBTR after BCS. One hundred and sixty-one (57%) underwent a second conservative surgery, whereas 121 patients (43%) were given a mastectomy and represent the study population. We investigated the prognosis and determined predictive factors of outcome., Results: Median time from primary breast cancer to IBTR was 41 months (range 5-213). Recurrences were T2-T4 and/or multifocal in 83 cases (68.6%). With a median follow-up of 5 years after mastectomy, 5-year overall survival (OS) and disease-free survival (DFS) were 73.3% [95% confidence interval (CI) 65.0% to 81.6%] and 50.4% (95% CI 40.9% to 59.8%), respectively. At the multivariate analysis, early onset of IBTR, presence of vascular invasion and Ki67 >or=20 of the recurrent tumour were found to significantly affect both DFS and OS., Conclusions: In women who need mastectomy for IBTR, early onset of the relapse, high proliferation index and presence of vascular invasion represent the worst prognostic factors.