Characteristics and outcome of BRCA mutated epithelial ovarian cancer patients in Italy: A retrospective multicenter study (MITO 21).

OBJECTIVE: Around 15% of epithelial ovarian cancer (EOC) patients (pts) harbor a germline BRCA1 or 2 mutation, showing different features than BRCA wild-type pts. The clinical and pathological features of an Italian BRCA mutated EOC cohort were described. METHODS: We retrospectively analyzed clinical, pathological and mutational data from a cohort of Italian BRCA mutated EOC pts. treated in 15 MITO centers between 1995 and 2017. RESULTS: Three-hundred thirty-one pts. were recorded. Two-hundred forty (72%) and 91 (27.5%) pts. harbored a BRCA1 and BRCA2 mutation, respectively. Median age at diagnosis was 52 years. The most frequent diagnosis was a high grade serous FIGO III or IV EOC and platinum doublet in first-line was administered to almost all pts. Fifty-three % of them had no residual disease (R = 0) at surgery. Median progression-free-survival (mPFS) after first-line chemotherapy was 29 months. Expected percentage of pts. alive at 5 years was 72.5% (CI 60.2-80.8%) and R = 0 predicted a significantly longer overall survival (OS). Sixty-six pts. (19,9%) had both an EOC and a breast cancer (BC) diagnosis. The first diagnosis was BC in 81,8% of cases with a mean interval between the two diagnoses (IBTDs) of 132.4 months. Mutational data show that the founder mutation c.5266dupC in BRCA1 was the most frequently recorded. CONCLUSIONS: This is the largest Italian BRCA mutEOC cohort. The only predictor of longer OS was R = 0. EOC pts. that developed subsequently a BC are long-term survivors.

MiR-100 is a predictor of endocrine responsiveness and prognosis in patients with operable luminal breast cancer.

PURPOSE: Overexpression of miR-100 in stem cells derived from basal-like breast cancers causes loss of stemness, induction of luminal breast cancer markers and response to endocrine therapy. We, therefore, explored miR-100 as a novel biomarker in patients with luminal breast cancer. METHODS: miR-100 expression was studied in 90 patients with oestrogen-receptor-positive/human-epidermal growth factor receptor 2-negative breast cancer enrolled in a prospective study of endocrine therapy given either preoperatively, or for the treatment of de novo metastatic disease. Response was defined as a Ki67 ≤2.7% after 21±3 days of treatment. The prognostic role of miR-100 expression was evaluated in the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and The Cancer Genome Atlas (TCGA) breast cancer datasets. Additionally, we explored the correlation between miR-100 and the expression its targets reported as being associated with endocrine resistance. Finally, we evaluated whether a signature based on miR-100 and its target genes could predict the luminal A molecular subtype. RESULTS: Baseline miR-100 was significantly anticorrelated with baseline and post-treatment Ki67 (p<0.001 and 0.004, respectively), and independently associated with response to treatment (OR 3.329, p=0.047). In the METABRIC dataset, high expression of miR-100 identified women with luminal A tumours treated with adjuvant endocrine therapy with improved overall survival (HR 0.55, p<0.001). miR-100 was negatively correlated with PLK1, FOXA1, mTOR and IGF1R expression, potentially explaining its prognostic effect. Finally, a miR-100-based signature developed in patients enrolled in the prospective study outperformed Ki67 alone in predicting the luminal A phenotype. CONCLUSIONS: Our findings suggest that miR-100 should be further explored as a biomarker in patients with luminal breast cancer.

Reoperation rate after breast conserving surgery as quality indicator in breast cancer treatment: A reappraisal.

AIM: To analyse the role of repeated breast surgery (RBS) after breast conserving surgery (BCS) as a quality indicator in a consecutive series of breast cancer patients. METHODS: Data from 1233 breast cancer patients submitted to BCS from 2015 to 2019 were reviewed. The influence of several variables on RBS rate (182/1232; 14.8%) was examined. Univariate and multivariate analyses were conducted to look for significant associations with the risk of RBS. RESULTS: Surgical workload, BCS rate and clinicopathological variables were consistent over the study period, while RBS rate decreased after the introduction of shaving of cavity margins (from 17.9% to 9.5%). Tumor persistence at RBS was higher for mastectomy vs. re-excision (87.3% vs. 37.8%; p = 0.05), inconclusive vs. positive diagnostic biopsy (48.2% vs. 69.4%; p = 0.003), ductal carcinoma in situ vs. invasive carcinoma (69.0% vs. 51.3%; p = 0.046) and lower after neoadjuvant therapy (14.3% vs. 57.8%; p = 0.044). Several clinicopathological variables were associated with the risk of RBS, but only multifocality [Odds Ratio (OR): 1.8; p = 0.009], microcalcifications (OR: 2.0, p = 0.000), neoadjuvant therapy (OR: 0.4; p = 0.014), pathological intraoperative assessment (OR: 0.6; p = 0.010) and shaving of cavity margins (OR: 0.3; p = 0.000) retained independent value at multivariate analysis. CONCLUSIONS: RBS rate can be reduced by shaving of cavity margins. Current standards for RBS should not be made more stringent due to the existence of non-actionable risk factors. The value of RBS as a quality indicator should be scrutinzed.

Cytoreductive Surgery for Heavily Pre-Treated, Platinum-Resistant Epithelial Ovarian Carcinoma: A Two-Center Retrospective Experience.

Few retrospective studies have shown a benefit in selected patients affected by heavily pre-treated, platinum-resistant ovarian carcinomas (PROCs) who have undergone cytoreduction at relapse. However, the role of tertiary and quaternary cytoreductive surgery is not fully defined. Our aim was to evaluate survival and surgical morbidity and mortality after maximal cytoreduction in this setting. We evaluated all consecutive patients undergoing cytoreduction for platinum-resistance over an 8-year period (2010-2018) in two different centers. Fifty patients (median age 52.5 years, range 34-75) were included; the median number of previous chemotherapy lines was three (range 1-7) and the median number of previous surgeries was one (range 1-4). Completeness of cytoreduction (CC = 0) was achieved in 22 patients (44%). Rates of major operative morbidity and 30-day mortality were 38% and 8%, respectively. Median follow-up was 35 months. The absence of tumor residual (CC = 0) was associated with a significantly better overall survival (OS) compared to the CC > 0 subgroup (median OS 32.9 months (95% CI 21.6-44.2) vs. 4.8 months (95% CI n.a.-9.8), hazard ratio (HR) 4.21 (95% CI 2.07-8.60), p < 0.001). Optimal cytoreduction is feasible and associated with promising OS in selected, heavily pre-treated PROCs. Further prospective studies are required to better define the role of surgery in platinum-resistant disease.

Validation of Androgen Receptor loss as a risk factor for the development of brain metastases from ovarian cancers.

BACKGROUND: Central nervous system (CNS) spreading from epithelial ovarian carcinoma (EOC) is an uncommon but increasing phenomenon. We previously reported in a small series of 11 patients a correlation between Androgen Receptor (AR) loss and localization to CNS. Aims of this study were: to confirm a predictive role of AR loss in an independent validation cohort; to evaluate if AR status impacts on EOC survival. RESULTS: We collected an additional 29 cases and 19 controls as validation cohort. In this independent cohort at univariate analysis, cases exhibited lower expression of AR, considered both as continuous (p <  0.001) and as discrete variable (10% cut-off: p <  0.003; Immunoreactive score: p <  0.001). AR negative EOC showed an odds ratio (OR) = 8.33 for CNS dissemination compared with AR positive EOC. Kaplan-Meier curves of the combined dataset, combining data of new validation cohort with the previously published cohort, showed that AR <  10% significantly correlates with worse outcomes (p = 0.005 for Progression Free Survival (PFS) and p = 0.002 for brain PFS (bPFS) respectively). Comparison of AR expression between primary tissue and paired brain metastases in the combined dataset did not show any statistically significant difference. CONCLUSIONS: We confirmed AR loss as predictive role for CNS involvement from EOC in an independent cohort of cases and controls. Early assessment of AR status could improve clinical management and patients' prognosis.

Concerns and Expectations of Risk-Reducing Surgery in Women with Hereditary Breast and Ovarian Cancer Syndrome.

Hereditary Breast and Ovarian Cancer syndrome (HBOC) carriers face complex decisions, which might affect their fertility and body image. Using an anonymous 40-items questionnaire we evaluated the expectations and concerns about Risk-Reducing Surgery (RRS) in 204 carriers. Participants are well-informed about the options to manage cancer risk, and women with previous cancer are more concerned with screening failure. Satisfaction with RR Mastectomy is high, even if many carriers are unsatisfied with reconstructed breast feel and nipple-areola complex tactile sensation and those with previous breast cancer report a change in their sexual habits. The decrease of libido and vaginal dryness are the most complained symptoms after RR Salpingo-Oophorectomy. Nevertheless, most carriers would choose RRS again, due to cancer risk or screening-related stress reduction. Women who deferred RRS are more afraid of menopausal symptoms and cancer risk than those who had undergone or declined surgery. Women who declined RRS feel well-informed and trust screening procedures. In conclusion, HBOC carriers consider themselves well-informed and able to choose the best option for their condition, would choose RRS again because of cancer risk and screening-related stress reduction, and those who delay RRS face a higher preoperative level of concern and need support.

TOP2A as marker of response to pegylated lyposomal doxorubicin (PLD) in epithelial ovarian cancers.

OBJECTIVE: Relapsed epithelial ovarian cancer (EOC) is frequently treated with pegylated liposomal doxorubicin (PLD). Unfortunately, most patients do not benefit from treatment. Prediction of response is crucial to optimize PLD use and avoid unnecessary toxicities. We aimed at assessing the value of topoisomerase II alpha (TOP2A) expression as predictive marker of response to PLD-based therapy in patients with relapsed EOCs. METHODS: We retrospectively analyzed Formalin Fixed Paraffin Embedded (FFPE) tissues from 101 patients with platinum resistant (PR) or partially platinum-sensitive (PPS) EOCs treated with PLD-based chemotherapy beyond second line in three referral cancer centers between January 2010 and June 2018. TOP2A expression was measured by immunohistochemistry (IHC): images of each sample were acquired by optical microscope and analyzed by using automatic counter software. Correlation between TOP2A expression and response to PLD was assessed. Since no cut-off for positivity has been validated yet, we dichotomized TOP2A expression based on a cut-off of 18% (mean value in this study). RESULTS: TOP2A expression beyond cut-off was not prognostic for primary platinum-free interval in our series (p = 0.77) neither for optimal cytoreduction (p = 0.9). TOP2A > 18% was associated with a longer time to progression (TTP) following PLD-treatment, although not statistically significant (p = 0.394). No difference was observed between PR and PPS patients' groups (p = 0.445 and p = 0.185, respectively). Not unexpectedly, patients with TOP2A expression > 18% treated with PLD monotherapy achieved a longer TTP compared with PLD-doublet therapy (p = 0.05). CONCLUSIONS: Our data suggest that TOP2A status might predict activity of PLD in patients with PR/PPS EOCs.

A predictive score for optimal cytoreduction at interval debulking surgery in epithelial ovarian cancer: a two- centers experience.

BACKGROUND: Optimal cytoreduction (macroscopic Residual Tumor, RT = 0) is the best survival predictor factor in epithelial ovarian cancer (EOC). It doesn't exist a consolidated criteria to predict optimal surgical resection at interval debulking surgery (IDS). The aim of this study is to develop a predictive model of complete cytoreduction at IDS. METHODS: We, retrospectively, analyzed 93 out of 432 patients, with advanced EOC, underwent neoadjuvant chemotherapy (NACT) and IDS from January 2010 to December 2016 in two referral cancer centers. The correlation between clinical-pathological variables and residual disease at IDS has been investigated with univariate and multivariate analysis. A predictive score of cytoreduction (PSC) has been created by combining all significant variables. The performance of each single variable and PSC has been reported and the correlation of all significant variables with progression free survival (PFS) has been assessed. RESULTS: At IDS, 65 patients (69,8%) had complete cytoreduction with no residual disease (R = 0). Three criteria independently predicted R > 0: age ≥ 60 years (p = 0.014), CA-125 before NACT > 550 UI/dl (p = 0.044), and Peritoneal Cancer Index (PCI) > 16 (p < 0.001). A PSC ≥ 3 has been associated with a better accuracy (85,8%), limiting the number of incomplete surgeries to 16,5%. Moreover, a PCI > 16, a PSC ≥ 3 and the presence of R > 0 after IDS were all significantly associated with shorter PFS (p < 0.001, p < 0.001 and p = 0.004 respectively). CONCLUSIONS: Our PSC predicts, in a large number of patients, complete cytoreduction at IDS, limiting the rate of futile extensive surgeries in case of presence of residual tumor (R > 0). The PSC should be prospectively validated in a larger series of EOC patients undergoing NACT-IDS.

MRI to predict nipple-areola complex (NAC) involvement: An automatic method to compute the 3D distance between the NAC and tumor.

OBJECTIVES: To assess the role in predicting nipple-areola complex (NAC) involvement of a newly developed automatic method which computes the 3D tumor-NAC distance. PATIENTS AND METHODS: Ninety-nine patients scheduled to nipple sparing mastectomy (NSM) underwent magnetic resonance (MR) examination at 1.5 T, including sagittal T2w and dynamic contrast enhanced (DCE)-MR imaging. An automatic method was developed to segment the NAC and the tumor and to compute the 3D distance between them. The automatic measurement was compared with manual axial and sagittal 2D measurements. NAC involvement was defined by the presence of invasive ductal or lobular carcinoma and/or ductal carcinoma in situ or ductal intraepithelial neoplasia (DIN1c - DIN3). RESULTS: Tumor-NAC distance was computed on 95/99 patients (25 NAC+), as three tumors were not correctly segmented (sensitivity = 97%), and 1 NAC was not detected (sensitivity = 99%). The automatic 3D distance reached the highest area under the receiver operating characteristic (ROC) curve (0.830) with respect to the manual axial (0.676), sagittal (0.664), and minimum distances (0.664). At the best cut-off point of 21 mm, the 3D distance obtained sensitivity = 72%, specificity = 80%, positive predictive value = 56%, and negative predictive value = 89%. CONCLUSIONS: This method could provide a reproducible biomarker to preoperatively select breast cancer patients candidates to NSM, thus helping surgical planning and intraoperative management of patients.

Androgen receptor status predicts development of brain metastases in ovarian cancers.

Brain metastases are uncommon localizations in epithelial ovarian cancer (EOC), their reported incidence is increasing and no predictive biomarkers have been identified yet. Goals of this study were: i) to define a possible association between Estrogen Receptor (ER), Progesterone Receptor (PR), Androgen Receptor (AR),human EGF receptor 2 (HER2) and brain progression in EOC patients, and ii) to identify differences in ER, PR, AR and HER2 protein expression from primary EOC and its matched resected brain metastasis. A retrospective series of 11 EOC with matched brain metastasis surgically removed was collected. For comparison, a "Control dataset" of 22 patients, without evidence of brain involvement after an adequate follow up was matched. ER, PR, AR and HER2 status were analyzed by means of immunohistochemistry forCases (both primary and metastatic lesions) and Controls.Univariate analysis showed that AR status was significantly associated with brain localization, both considered as discrete variable (cut-off: 10%, p=0.013) and as continuous one (p=0.035). Multivariate analysis confirmed this trend (p=0.053). When considered as continuous variables, ER and AR showed greater expression in primary tumors in comparison with brain metastases (p=0.013 and p=0.032, respectively).In our series, AR predicts brain involvement, with a 9.5 times higher propensity for AR-negative EOC. Moreover, brain dissemination is probably the result of progressive dedifferentiation of primary tumor, shown by reduction of ER and AR expression in metastases. Further studies are required, in order to anticipate and improve multimodal treatment of brain metastases.

Primary tumor location predicts the site of local relapse after nipple-areola complex (NAC) sparing mastectomy.

PURPOSE: To assess the oncological safety of nipple-areola complex (NAC) sparing mastectomy in breast cancer patients. METHODS: From 2010 to 2015, 518 breast cancer patients were submitted to NAC sparing mastectomy. Breast MRI and intraoperative assessment of the subareolar (SD) and proximal (ND) nipple ducts were performed to predict NAC involvement. Significant associations between pre- and postoperative variables with SD/ND involvement and with the risk of local recurrence were retrospectively investigated. RESULTS: SD/ND were involved in 26.1% of the cases. Final pathology of SD/ND was predicted by tumor-NAC distance at MRI and intraoperative pathology with 75 and 93% accuracy, respectively. NAC involvement was more frequent in case of positive ND than positive SD (68.3 vs. 38.3%; p = 0.003). Fourteen (2.7%) local relapses developed over a mean follow-up of 33 months. Ki-67 ≥25% (p = 0.002) and high tumor grade (p = 0.027) correlated with local recurrence. Most relapses developed in the subcutaneous tissue of the quadrant where the primary tumor was located (12/14; 85.7%). No local relapses occurred in patients who received post-mastectomy radiotherapy as compared to patients who did not, although they had a higher rate of positive surgical margins (40.5 vs. 16.2%; p = 0.000). CONCLUSIONS: NAC involvement can be predicted by MRI and intraoperative pathology of ND/SD. Local recurrences after NAC sparing mastectomy almost invariably develop in the same quadrant where the primary tumor was located and in highly proliferative tumors.

Ovarian cancer in BRCA1 and BRCA2 gene mutation carriers: analysis of prognostic factors and survival.

OBJECTIVES: To compare clinical-pathological characteristics and outcome between sporadic ovarian cancer and ovarian cancer in patents with hereditary breast and ovarian cancer syndrome (HBOC). METHODS: Twenty-four patients with ovarian cancer treated between 2000 and 2009 who tested positive for BRCA1/2 mutation (BRCA+) and a control group of 64 age-matched patients with no family history of breast/ovarian cancer (controls) were enrolled. Clinical-pathological characteristics, surgical outcome, overall (OS), and progression-free survival (PFS) were compared between the two groups. RESULTS: The high-grade serous histotype was more represented in BRCA+ than in controls (70.8% versus 53.1%) (p > 0.05). BRCA+ cancers were more frequently diagnosed at stage II than controls (20.83% versus 4.69%) (p = 0.024). Radical primary surgery was performed in 70% of women in both groups, with no difference in debulking results. In patients undergoing surgery after neoadjuvant chemotherapy, in all BRCA+ patients, optimal cytoreduction was achieved (versus 70% of the controls). PFS was significantly longer for BRCA+ patients compared to controls (60 months versus 22 months; p = 0.039). No significant difference was observed in OS between BRCA+ patients and controls. CONCLUSIONS: At a median follow-up time of 46 months, BRCA+ patients have a better prognosis than controls in terms of PFS. Higher chemosensitivity of BRCA+ tumours was observed.

MRI and intraoperative pathology to predict nipple-areola complex (NAC) involvement in patients undergoing NAC-sparing mastectomy.

BACKGROUND: Nipple-areola sparing mastectomy (NSM) with immediate implant reconstruction is an option for patients with non-locally advanced breast cancer. The prediction of occult tumour involvement of the nipple-areola complex (NAC) may help select candidates to NSM. PATIENTS AND METHODS: We prospectively recorded clinical and pathological data, magnetic resonance imaging (MRI) results and intraoperative pathological assessments of the subareolar (SD) and proximal nipple ducts (ND) of 112 consecutive breast cancer patients scheduled for NSM. All parameters were correlated with final pathological NAC assessment by univariate and multivariate analysis. RESULTS: Thirty-one patients (27.7%) had tumour involvement of the NAC. At univariate analysis, age (p=0.001), post-menopausal status (0.003), tumour central location (p=0.03), tumour-NAC distance measured by MRI (p=0.000) and intraoperative pathologic assessment (SD+ND) (p=0.000) were significantly correlated with NAC involvement. At multivariate analysis, only MRI tumour-NAC distance (p=0.008) and menopausal status (p=0.039) among all preoperative variables retained statistical significance. The sensitivity and specificity of MRI tumour-NAC distance were 32.2% and 88.6% and those of intraoperative pathologic assessment were 46.7% and 100%, respectively. Sensitivity, specificity and accuracy of the double assessment (MRI plus intraoperative pathology) were 50.0%, 96.2% and 84.1%, respectively. CONCLUSION: Intraoperative pathologic assessment and tumour-NAC distance measured by MRI are the most important predictors of occult NAC involvement in breast cancer patients. A negative pathological assessment and a tumour-NAC distance ⩾ 5 mm allow optimal discrimination between NAC positive and NAC negative cases and may serve as a guide for the optimal planning of oncological and reconstructive surgery.

Suspecting malignancy in endometrial polyps: value of hysteroscopy.

AIMS AND BACKGROUND: Hysteroscopic polypectomy is the gold standard to treat endometrial polyps and obtain specimens for histological evaluation. There is continuing debate as to when to offer hysteroscopic polypectomy, especially in asymptomatic women with incidental lesions. The aims of this study were to assess the accuracy of hysteroscopy and Vabra sampling in diagnosing atypical hyperplasia and cancer growing on the surface of endometrial polyps and to investigate the association between atypical endometrial polyps and some potential clinical risk factors. METHODS AND STUDY DESIGN: This was a retrospective study. We assessed 1039 hysteroscopies and we identified 345 women with endometrial polyps. All patients with endometrial polyps underwent hysteroscopic polypectomy. Data about age, menopausal status, abnormal uterine bleeding (AUB), hormone replacement therapy and tamoxifen use were collected. Hysteroscopic, histological and clinical data were analyzed. RESULTS: The incidence of endometrial hyperplasia or cancer growing on the surface of endometrial polyps was significantly low (1.7%). Hysteroscopy correctly excluded (negative predictive value: 100%) and accurately predicted (positive predictive value: 85.7%) preneoplastic or neoplastic lesions growing within the epithelial layer of endometrial polyps. Vabra sampling was inadequate for the histological diagnosis in 38.5% of cases. Age over 60 years and postmenopausal AUB were associated with an 8.3-fold ( P = 0.022) and 8.8-fold (P = 0.020) increased risk, respectively, of preneoplastic and neoplastic lesions growing on the surface of endometrial polyps. CONCLUSIONS: Diagnostic hysteroscopy is a good tool to predict malignancy of the epithelial layer of endometrial polyps. Age over 60 years and AUB are associated with an increased risk of malignant polyps. Few suspicious endometrial polyps should undergo surgical resection.

Body mass index (BMI) and breast cancer: impact on tumor histopathologic features, cancer subtypes and recurrence rate in pre and postmenopausal women.

The study aims to analyze the association between body mass index (BMI) at time of diagnosis, breast cancer histopathologic features (tumor size, nuclear grade, estrogen and progesterone receptor (ER and PgR) and HER-2/neu expression, histological subtypes, Ki-67 index, lymphatic/vascular invasion, axillary nodes involvement) and incidence of different subtypes defined using hormone receptors and HER2/neu expression, according to menopausal status; to evaluate the impact of BMI on disease free survival (DFS) at multivariate analysis. A total of 2148 patients (592 premenopausal, 1556 postmenopausal) were classified into subgroups according to BMI distribution. High BMI was significantly associated with larger size tumor both in pre (p = 0.01) and postmenopausal women (p = 0.00). Obese premenopausal women showed worse histopathologic features (more metastatic axillary lymphnodes, p = 0.017 and presence of vascular invasion, p = 0.006) compared to under/normal weight group. Postmenopausal patients with BMI > 25 developed more frequently ER/PgR positive cancers (87% versus 75%, p 0.017), while no association was found in premenopausal women. We could not found any statistically significant correlation between breast cancer subtypes (luminal A, B, HER-2 and basal-like) and BMI both in pre and postmenopause. Higher BMI was significantly associated with a shorter DR-FS in postmenopausal women but the independent prognostic role of obesity was not confirmed in our analysis.

Moderate immunohistochemical expression of HER-2 (2+) without HER-2 gene amplification is a negative prognostic factor in early breast cancer.

BACKGROUND: Human epidermal growth factor receptor (HER)-2 testing in patients with operable breast cancer is aimed at identifying candidates for adjuvant anti-HER-2 treatment. However, commonly defined "HER-2(-)" tumors express variable levels of the HER-2 protein, which can influence prognosis. We compared the clinical outcomes of operable breast cancer patients stratified according to a common HER-2 testing algorithm. METHODS: We studied 1,150 women (median age, 58 years; range, 22-94 years) undergoing surgery for early breast cancer at our institution. HER-2 status was determined using the HercepTest™ (Dako, Glostrup, Denmark) and, when needed, by fluorescence in situ hybridization (FISH). Patients receiving adjuvant trastuzumab were excluded. The impact of HER-2 status on the disease-free survival (DFS) time was studied using multivariate Cox proportional regression analysis. RESULTS: Four hundred-fifty seven (40%), 454 (39%), 116 (10%), and 123 (11%) patients were considered HER-2 0+, HER-2 1+, HER-2 2+/HER-2(-) by FISH, and HER-2(+) (3+ or HER-2(+) by FISH), respectively. Compared with a HER-2 0 or 1+ status, a HER-2 2+/HER-2(-) by FISH status was associated with a worse DFS outcome on multivariate analysis. Compared with a HER-2(+) status, a HER-2 2+/HER-2(-) status showed a time-dependent effect on the DFS probability, with an initial advantage that worsened every year by a factor of 1.649. CONCLUSION: A HER-2 2+/HER-2(-) status is an adverse prognostic factor in patients with operable breast cancer. Because of suggestions from randomized trials that the benefits of adjuvant trastuzumab may not be limited to patients with HER-2(+) tumors, patients with a HER-2 2+/HER-2(-) status are ideal candidates for studies testing this hypothesis.

Omission of axillary dissection after a positive sentinel node dissection may influence adjuvant chemotherapy indications in operable breast cancer patients.

BACKGROUND: This study was designed to evaluate how the omission of axillary dissection would have altered the indication for adjuvant chemotherapy (ACT) in patients with early breast cancer submitted to conservative surgery with one or two positive sentinel lymph nodes (SLNs). METHODS: We identified 321 women in our institutional database who fulfilled the characteristics. All underwent completion axillary lymph node dissection (AD). Each case was blindly reviewed by our breast team in two rounds, and the total number of positive lymph nodes was disclosed only in the second. At each round, the panel chose between: (1) recommend, (2) discuss, (3) do not recommend ACT. Changes between round 1 and 2 were studied by the marginal homogeneity test. Exploratory logistic regression analyses were performed to study predictors of non-SLN involvement and of changes in the indication for ACT. RESULTS: AD revealed non-SLNs metastases in 96 patients (30 %). Fifty-two patients (16 %) had their initial indication changed at round 2 (p < 0.001). Most of the changes were toward ACT (83 %), and all except two occurred in patients with immunohistochemically defined luminal A and luminal B/HER2-negative tumors. In these two subgroups, a Ki67 above the median value (21 %) was the only independent predictor of no change in the indication to ACT at round 2. CONCLUSIONS: Omission of AD in patients with one or two positive SLNs may change the indication to ACT in a significant proportion of patients with hormone receptor-positive/HER2-negative tumors. All implications should be taken into account before abandoning AD, including a possible biologically tailored surgical approach.

Clinical and radiological predictors of nipple-areola complex involvement in breast cancer patients.

INTRODUCTION: Nipple-areola sparing mastectomy (NSM) is increasingly used in patients with non-locally advanced breast carcinoma. Literature data on the preoperative assessment of the nipple-areola complex (NAC) are inconsistent. PATIENTS AND METHODS: Out of 1359 patients submitted to total mastectomy between 2001 and 2010, we selected 61 patients whose pre-operative mammogram (MX) was available (MX group) and 39 patients who underwent preoperative breast magnetic resonance imaging (magnetic resonance imaging (MRI) group). The rate of NAC involvement, the value of MX and MRI to predict NAC involvement and the performance of the Schecter's and Loewn's algorithms for the prediction of NAC involvement were evaluated. RESULTS: In the combined MX and MRI groups, NAC involvement was found in 14% of the cases. At univariate analysis, tumour stage (p value: 0.03), central tumour location (p value: 0.004), presence of NAC retraction (p value: 0.001) and tumour-NAC distance (p value: 0.006) were associated with NAC involvement, but only the latter parameter retained statistical significance at multivariate analysis (p value: 0.05). Tumour-NAC distance was a key predictor of NAC involvement, with a negative predictive value of 94% for MX and of 100% for MRI when the cut-off was set at 10mm. Overall, the performance of Schecter's and Loewn's algorithms was respectively lower and similar as compared to the original series. CONCLUSIONS: Occult tumour involvement of the NAC is detected in a minority of breast cancer patients submitted to mastectomy. A tumour-NAC distance ≥ 10 mm by MRI may help select patients candidate to NSM.

Nipple-areola complex sparing mastectomy with periareolar pexy for breast cancer patients with moderately ptotic breasts.

BACKGROUND: Nipple-areola complex sparing mastectomy (NSM) with immediate implant reconstruction has been recently introduced for breast cancer patients who are not candidates for breast preserving surgery. As the cosmetic results in moderately ptotic breasts may not be optimal, a modified NSM with a periareolar pexy (PP-NSM) was introduced at our Institution. Patients selection criteria and complication rates of PP-NSM were prospectively recorded and compared with those of the classical NSM. RESULTS: Over a period of 11 months, 22 PP-NSMs and 35 NSMs were performed. The mean jugular-nipple distance was significantly longer in the PP-NSM as compared with the NSM (22.6 vs. 19.6 cm; p=0.000), whereas the mean inframammary fold-areola distance was superimposable (5.4 cm). The periareolar mastopexy led to a mean cranial transposition of the nipple-areola complex (NAC) of 2.2 cm (range 1.5-4 cm). Mean breast weight was significantly higher in the PP-NSM as compared with the NSM cohort (336 vs. 236 g; p=0.003). The only case of total NAC necrosis occurred in the PP-NSM group. Partial NAC necrosis was slightly more frequent in the PP-NSM than in the NSM group (13.6% vs. 2.9%%; p=n.s.), possibly due to the higher percentage of smokers (41.0% vs. 14.0%; p=0.05). Early cosmetic results were good to excellent from the surgeon's and the patient's point of view in over 80% of the cases. CONCLUSIONS: PP-NSM allows good cosmetic results and low complication rates in patients with moderately ptotic breasts requiring a mastectomy. In particular, PP-NSM seems to be a good option for women at high risk for developing breast cancer and for selected patients affected by non-locally advanced breast cancer.