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.

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.

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.

Omission of axillary dissection after a positive sentinel lymph-node: Implications in the multidisciplinary treatment of operable breast cancer.

Omission of axillary dissection in women with breast cancer and one or two positive sentinel-node biopsy is a major advancement in the management of this disease. Supported by a sound rationale and confirmed by prospective, randomized trials, omission of axillary dissection is now recommended in women who have undergone breast conserving surgery and who are candidate to adjuvant radiotherapy. Because breast cancer is best managed in the context of a multidisciplinary team, this surgical shift in the paradigm is expected to have implications that extend also to the other specialties involved in the team. In fact, the full evaluation of the axillary tumor burden has been historically considered an essential part of tumor staging and the absolute number of involved node critical information to tailor post-surgical treatments. Lack of this information in a patient with axillary involvement documented by a positive sentinel lymph-node biopsy may represent a challenge when deciding on further, post-surgical treatments. This review will address the critical aspects and the potential implications of omission of axillary dissection in the context of the multidisciplinary breast team.

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.

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.

Correlations between diffusion-weighted imaging and breast cancer biomarkers.

OBJECTIVE: We evaluated whether the apparent diffusion coefficient (ADC) provided by diffusion-weighted imaging (DWI) varies according to biological features in breast cancer. METHODS: DWI was performed in 190 patients undergoing dynamic contrast-enhanced magnetic resonance imaging (MRI) for local staging. For each of the 192 index cancers we studied the correlation between ADC and classical histopathological and immunohistochemical breast tumour features (size, histological type, grade, oestrogen receptor [ER] and Ki-67 expression, HER2 status). ADC was compared with immunohistochemical surrogates of the intrinsic subtypes (Luminal A; Luminal B; HER2-enriched; triple-negative). Correlations were analysed using the Mann-Whitney U and Kruskal-Wallis H tests. RESULTS: A weak, statistically significant correlation was observed between ADC values and the percentage of ER-positive cells (-0.168, P = 0.020). Median ADC values were significantly higher in ER-negative than in ER-positive tumours (1.110 vs 1.050 × 10(-3) mm(2)/s, P = 0.015). HER2-enriched tumours had the highest median ADC value (1.190 × 10(-3) mm(2)/s, range 0.950-2.090). Multiple comparisons showed that this value was significantly higher than that of Luminal A (1.025 × 10(-3) mm(2)/s [0.700-1.340], P = 0.004) and Luminal B/HER2-negative (1.060 × 10(-3) mm(2)/s [0.470-2.420], P = 0.008) tumours. A trend towards statistical significance (P = 0.018) was seen with Luminal B/HER2-positive tumours. CONCLUSIONS: ADC values vary significantly according to biological tumour features, suggesting that cancer heterogeneity influences imaging parameters. KEY POINTS: DWI may identify biological heterogeneity of breast neoplasms. • ADC values vary significantly according to biological features of breast cancer. • Compared with other types, HER2-enriched tumours show highest median ADC value. • Knowledge of biological heterogeneity of breast neoplasm may improve imaging interpretation.

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.

Mirtazapine for the treatment of hot flushes in breast cancer survivors: a prospective pilot trial.

The purposes of the study are to evaluate the efficacy and safety of mirtazapine 30 mg/daily for 12 weeks to reduce hot flushes (HF) in women with previous breast cancer and to assess the influence of the same treatment on sleep quality and other menopausal symptoms. A prospective pilot trial was conducted in 40 breast cancer patients with at least seven HF per day. A HF diary was completed daily; sleep quality and other menopausal symptoms were assessed with the Pittsburgh Sleep Quality Index (PSQI), the Menopause Rating Scale (MRS) and the SF-36 Health Survey. Treatment was never started by 13 out of 40 patients (32.5%) and was interrupted by 7 out of 27 patients (25%) due to of the occurrence of side effects (mostly somnolence). In the remaining 20 patients who completed the three months treatment period, there was a 55.6% (p < 0.05) reduction in HF frequency and 61.9% (p < 0.05) reduction in HF score as compared to baseline. A significant reduction in the MRS score (32.8%; p < 0.05) was observed. Mirtazapine appears to be effective in reducing HF in breast cancer survivors. The more frequent side effect was somnolence. A sizeable compiliance problem has been observed due to the reluctance to take antidepressant drugs and to side effects.

Hormonal replacement therapy after gynaecological cancer.

Thousands of women are treated each year for gynaecological cancers; many of these are already in menopause, while other younger patients will go into early menopause due to surgery, chemotherapy and/or radiotherapy to the pelvic region. The aim of this paper is to review the biological and clinical evidence in favour and against hormone replacement therapy (HRT) use after gynaecological cancers. With the exception of breast and endometrial cancer, there is no biological evidence that HRT may increase the recurrence risk. In women with previous endometrial cancer, HRT use is not supported by univocal and conclusive data to formulate specific recommendations, whereas most authors suggest that oestrogens may be used after adequate information about risks and benefits. The use of HRT in breast cancer patients is, at present, considered contra-indicated, even if results of clinical trials are not concordant. Therapeutic non-hormonal alternatives may be proposed to these patients.

Personal use of hormone therapy by postmenopausal women doctors and male doctors' wives in Italy after the publication of WHI trial.

OBJECTIVE: To describe the prevalence of hormone replacement therapy (HT) use by postmenopausal women doctors and doctors' wives in Italy and to explore the relationship between their personal characteristics and HT use. DESIGN: A total of 500 women doctors and 500 men doctors answering on behalf of their female partners were interviewed by a specialised company in the first months of 2003. Questions were meant to explore medical, behavioural and professional characteristics, personal use of HT, reasons for or against HT use and side effects of HT. The distribution of doctors' specialisation (general practitioners (GPs), gynaecologists, medical oncologists) in the sample interviewed was the same as that of the Italian medical community. RESULTS: Overall, 37% of women doctors and 39% of doctors' wives had ever used HT after menopause, of which 64 and 58%, respectively, were current users. The median duration of HT in the past users was 2.7 years for women doctors and 3.7 for doctors' wives. There were wide differences of HT use according to the type of specialisation: gynaecologists were more willing to use HT (56-59%) than GPs (30-31%) or medical oncologists (16-30%). Vasomotor symptoms (68-69%), followed by the prevention of osteoporosis (28-39%), were the main reasons for commencing HT. The main reasons not to take or to stop HT were the absence or resolution of menopausal symptoms. Only 8% of women doctors and 4% doctors' wives stopped HT after the publication of the WHI data. CONCLUSIONS: In Italy, women doctors/doctors' wives personally use HT much more than postmenopausal general population.