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Purpose. In modern breast cancer treatment, a growing role has been observed for breast reconstruction together with an increase in clinical indications for postmastectomy radiotherapy (PMRT). Choosing the optimum type of reconstructive technique is a clinical challenge. We therefore conducted a national multicenter study to analyze the impact of PMRT on breast reconstruction. Methods. We conducted a retrospective case-control multicenter study on women undergoing breast reconstruction. Data were collected from 18 Italian Breast Centres and stored in a cumulative database which included the following: autologous reconstruction, direct-to-implant (DTI), and tissue expander/immediate (TE/I). For all patients, we described complications and surgical endpoints to complications such as reconstruction failure, explant, change in type of reconstruction, and reintervention. Results. From 2001 to April 2020, 3116 patients were evaluated. The risk for any complication was significantly increased in patients receiving PMRT (aOR, 1.73; 95% CI, 1.33–2.24; p < 0.001 ). PMRT was associated with a significant increase in the risk of capsular contracture in the DTI and TE/I groups (aOR, 2.24; 95% CI, 1.57–3.20; p < 0.001 ). Comparing type of procedures, the risk of failure (aOR, 1.82; 95% CI, 1.06–3.12, p = 0.030 ), explant (aOR, 3.34; 95% CI, 3.85–7.83, p < 0.001 ), and severe complications (aOR, 2.54; 95% CI, 1.88–3.43, p < 0.001 ) were significantly higher in the group undergoing DTI reconstruction as compared to TE/I reconstruction. Conclusion. Our study confirms that autologous reconstruction is the procedure least impacted by PMRT, while DTI appears to be the most impacted by PMRT, when compared with TE/I which shows a lower rate of explant and reconstruction failure. The trial is registered with NCT04783818, and the date of registration is 1 March, 2021, retrospectively registered.

MicroRNA-27a-5p (miR-27a-5p) has been closely related to the pathogenesis of different solid tumors, showing potentials as both useful biomarker and druggable target of clinical application. In our study, we performed the expression analysis of miR-27a-5p in a retrospective cohort of 232 breast cancer (BC) patients with a median follow-up of 99.4 months enrolled according to the REMARK guidelines. Of those patients, 9 showed synchronous metastases (MTX), 45 developed metastases during the follow-up time (M0>M1), and 178 were free from metastases after a follow-up of at least 5 years (M0). As controls, 13 normal breast tissues (NBTs) from reductive mammoplasty and 11 pre-invasive breast lesions (PreBr) were also profiled. Overall, miR-27a-5p showed higher levels in NBTs (Median 2.28, IQR 1.50-5.40) and pre-invasive breast lesions (Median 3.32, IQR 1.68-4.32) compared to tumour samples. In particular, miR-27a-5p was less expressed in patients with synchronous (Median 1.03 IQR 0.83-1.58) or metachronous (Median 1.83, IQR 1.29-3.17) metastases than in patients free from metastases after a 5-year follow-up (Median 2.17, IQR 1.19-3.64). Thus, we found that miR-27a-5p expression (log values) is negatively correlated with breast pathology evolution (R= -0.13, P=0.038). Next, we assessed the potentialities of miR-27a-5p as BC-specific prognostic biomarker in the subgroup of patients without metastases at diagnosis (n=222). Moreover, increased miR-27a-5p levels were associated with reduced risk of disease progression (Progression Free Survival (PFS) HR 0.43, 95%CI 0.18-0.99, P=0.048), metastases development (Metastases Free survival (MFS) HR 0.42, 95%CI 0.18-0.96, P=0.039), and cancer-related death (Overall Survival (OS) HR 0.30, 95%CI 0.12-0.74, P=0.009) in the subgroup of HER2-amplified tumours (n=26). Then, we extended our analysis to the TCGA BRCA dataset by selecting a total of 561 cases without synchronous metastases, for whom miR-27a-5p expression levels, and clinical and follow-up data were available. Among them, 19 were HER2 amplified according to clinical guidelines (i.e. score 3+ at immunostaining or FISH-positive). Similarly to our internal cohort, high miR-27a-5p was associated to reduced risk of disease progression (PFS HR 0.61, 95%CI 0.10-3.61) and death (OS HR 0.62, 95%CI 0.08-5.05) in the subgroup of HER2-amplified cases, although the association did not reach statistical significance. Overall, our data support the tumour suppressive role of miR-27a-5p in breast cancer, and suggest miR-27a-5p as putative prognostic biomarker in HER2-amplified tumours. Citation Format: Barbara Pasculli, Andrea Fontana, Serena Barile, Morritti Maria, Luigi Ciuffreda, Paolo Graziano, Evaristo Maiello, Paola Parrella. Hsa-miR-27a-5p expression in breast cancer and its association with patient outcome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1492.

Fundació Carreras This work was supported by Italian Ministry of Health (MoH) TRANSCAN Joint Transnational Call (JTC) 2013 co-funded by the European Regional Development Fund, "A way of making Europe" RRC-2014-2354565, Italian Ministry of Health (MoH) "Ricerca Corrente 2019" and "5×1000″ voluntary contributions" and partially supported by Associazione Italiana Ricerca sul Cancro (AIRC) Project Code: 16747. While the molecular functions of miR-200 family have been deeply investigated, a role for these miRNAs as breast cancer biomarkers remains largely unexplored. In the attempt to clarify this, we profiled the miR-200 family members expression in a large cohort of breast cancer cases with a long follow-up (H-CSS cohort) and in TCGA-BRCA cohort. Overall, miR-200 family was found upregulated in breast tumors with respect to normal breast tissues while downregulated in more aggressive breast cancer molecular subtypes (i.e. Luminal B, HER2 and triple negative), consistently with their function as repressors of the epithelial-to-mesenchymal transition (EMT). In particular miR-141-3p was found differentially expressed in breast cancer molecular subtypes in both H-CSS and TCGA-BRCA cohorts, and the combined analysis of all miR-200 family members demonstrated a slight predictive accuracy on H-CSS cancer specific survival at 12 years (survival c-statistic: 0.646; 95%CI 0.538-0.754).

Autologous fat grafting (AFG), defined as the re-implant to the breast of fat tissue from different body areas, has been firstly applied to esthetic plastic surgery and then has moved to reconstructive surgery, mainly used for scar correction and opposite breast altering. Nevertheless, due to the potentially unsafe stem-like properties of adipocytes at the tumoral bed level, no clear evidence of the procedure’s oncological safety has been clearly documented at present. We retrospectively collected data of early breast cancer (BC) patients from 17 Italian Breast Units and assessed differences in terms of locoregional recurrence rate (LRR) and locoregional recurrence-free survival (LRFS) between patients who underwent AFG and patients who did not. Differences were analyzed in the entire cohort of invasive tumors and in different subgroups, according to prognostic biological subtypes. With a median follow-up time of 60 months, LRR was 5.3% (n = 71) in the matched population, 3.9% (n = 18) in the AFG group, and 6.1% (n = 53) in the non-AFG group, suggesting non-inferiority of AFG (p = 0.084). Building Kaplan–Meier curves confirmed non-inferiority of the AFG procedure for LRFS (aHR 0.73, 95% CI 0.41–1.30, p = 0.291). The same effect, in terms of LRFS, was also documented among different biological subtypes (luminal-like group, aHR 0.76, 95% CI 0.34–1.68, p = 0.493; HER2 enriched-like, aHR 0.89, 95% CI 0.19–4.22, p = 0.882; and TNBC, aHR 0.61, 95% CI 0.12–2.98, p = 0.543). Our study confirms in a very large, multicenter cohort of early BC patients that, aside the well-known benefits on the esthetic result, AFG do not interfere negatively with cancer prognosis.

Breast cancer treatment has deeply changed in the last decades, since clinical and oncological cure cannot be achieved without patient's satisfaction in term of aesthetic outcomes. Several methods have been proposed to objectively assess these results. However, Italian breast centers have not yet agreed on measurable, reproducible and validated aesthetic outcome indicators to monitor their performance.The study was designed and conducted by Senonetwork, a not-for-profit association of Italian breast centers. Ten breast centers were selected based on specific eligibility criteria. This multicentre observational prospective study recruited 6515 patients with diagnosis of in situ or invasive breast cancer who underwent breast surgery in the years 2013-2016. Thirteen indicators of aesthetic results and of related quality of care were analyzed. Data collection and analysis were conducted using a common study database.On average, seven out of ten centers were able to collect data on the proposed indicators with a proportion of missing values 25%. By expert consensus based on study results, some seven indicators have been defined as "mandatory" while the remaining six have been defined as "recommended" because they require further refinement before they can be proposed for monitoring aesthetic outcomes or because there are doubts on the feasibility of data collection. The minimum standard is reached for 5 of 13 indicators. This finding and the wide range between centers reveal that there is ample room for improvement.From the present study useful measurable aesthetic parameters have emerged, leading to the definition of target objectives that breast centers can use for benchmarking and improvement of quality of care.

This study aimed at assessing the outcomes of nipple-areola-complex-sparing mastectomy (NSM) of breast cancer in a single-centre and single-surgeon series after 5 years of experience. From June 2007 to January 2012, 58 female patients with breast cancer were admitted for NSM at our unit and 55 of these underwent NSM. All patients underwent a preoperative clinical and instrumental evaluation. The clinical evaluation consisted of physical examination by taking measurements of the prosthesis and through anamnesis. The instrumental evaluation used were mammography, chest X-ray, abdominal and breast ultrasound, blood test and, if necessary, magnetic resonance imaging. Specific inclusion criteria have been met in recruiting patients: clinically negative axillas, tumours < 3 cm in any of the quadrants, tumours more than 1 cm away from the NAC. The patients underwent a surgical and oncological follow-up. The surgical follow-up consisted in treating wounds, managing drainages and tissue expanders and then planning the replacement surgeries. The oncological follow-up consisted of periodical medical (such as blood tests including cancer markers) and radiological evaluations (such as mammography, chest X-ray, abdominal and transvaginal ultrasound scan and/or thorax-abdomen computed tomography) to assess the disease progression, and, if necessary the patients underwent chemotherapy or hormonal therapy. Out of 58 recruited patients undergoing NSM, only 3 patients (5.1 %) had an occult tumour in the NAC at intraoperative extemporaneous histological examination and required the NAC removal. The other 55 patients (94.9 %) did not have neoplastic involvement of NAC and at an average follow-up period of 21.7 months (range 3-55 months) only 4 (7.2 %) had disease progression. Nipple-Sparing Mastectomy is a highly specialized and oncologically sure procedure to be performed only in reference centres on selected patients.

The aim of the study was to assess the diagnostic contribution of hybrid SPECT/CT lymphoscintigraphy compared to planar imaging for the correct identification of sentinel lymph nodes (SLN) in breast cancer (BC) patients.73 planar and SPECT/CT lymphoscintigraphies were performed in 70 consecutive patients with BC (70 women, mean age 55.7±12.0 years, range 26-84) for pre-surgical SLNs research. Cohen'K was performed to evaluate the agreement between both techniques; their diagnostic capability was evaluated by the Student's t-test for paired data.In 54/73 (73.9%) lymphoscintigraphies, SLNs were detected both on planar and SPECT/CT images. In 19/73 (26.1%) discordant cases, planar technique showed a higher number of SLNs in 4/19 lymphoscintigraphies, while SPECT/CT in 15/19. Radio-guided surgery confirmed SPECT/CT findings. Concordance between the two techniques was poor (K=-0.095). Overall, SPECT/CT detected 13 SLNs more than planar imaging (p=0.07). Furthermore, in 17/73 (23.2%) lymphoscintigraphies, SPECT/CT defined the exact SLNs anatomical localization, equivocal on planar images.SPECT/CT demonstrated added value over planar imaging, providing more information for the best surgical approach. It is useful especially in patients with negative or doubt planar imaging.

Irradiation-induced sarcomas are a late sequelae of irradiation therapy. Most sarcomas have been reported to occur after exposure to a radiation dose of 55 Gys and above, with a dose ranging from 16 Gys to 112 Gys. These tumours are very aggressive and an early detection is needed for a timely intervention. Surgery is only effective treatment for local control instead chemotherapy is a valuable tool for systemic control of disease. Irradiation therapy use is controversial because of its side effects on a site previously irradiated. Irradiation therapy combined with hyperthermia is a new treatment that overcomes these problems without limiting the effect of radiation therapy. It may become a tool for local control of the unresectable tumours or an adjuvant treatment of the surgery. In this report we present a rare case of irradiation-induced recurrent osteosarcoma involving the chest wall that was treated with surgical resection followed by radiation therapy combined with hyperthermia as an adjuvant treatment of the surgery.

miR-9 (hsa-miR-9-5p, miR-9-5p) is a highly conserved microRNA (miRNA) primarily expressed in the central nervous system. The three promoters of miR-9 (miR-9-1 at 1q22, miR-9-2 at 5q14.3 and miR-9-3 at 15q26.1) are embedded within CpG islands, and hypermethylation in at least one of these regions has been reported in several tumor types, thus miR-9-5p has been designated as an epigenetically regulated miRNA. However, only a partial or none correlation between methylation status of miR-9 loci and miR-9-5p expression has been demonstrated so far. Furthermore, the expression levels of miR-9-5p resulted highly variable across different carcinomas and conflicting evidences also exist about its functional role within the tumor context. In light of this, we took the effort of clarifying the role of miR-9-5p in primary breast cancer tissues and of evaluating its potential as clinical relevant prognostic biomarker. We analysed miR-9-5p expression and miR-9 promoters methylation status in 129 breast cancer cases and 12 normal breast tissues (NBTs), by qRT-PCR and MSP respectively. Overall, miR-9-5p was increased in tumors compared to NBTs (P Citation Format: Raffaela Barbano, Barbara Pasculli, Michelina Rendina, Andrea Fontana, Caterina Fusilli, Massimiliano Copetti, Stefamo Castellana, Vanna Maria Valori, Maria Morritti, Paolo Graziano, Luigi Ciuffreda, Michelina Coco, Francesco Picardo, Tommaso Mazza, Ella Evron, Roberto Murgo, Evaristo Maiello, Manel Esteller, Vito Michele Fazio, Paola Parrella. miR-9-5p expression in breast cancer correlates with hormone receptor status and affects patients survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4734. doi:10.1158/1538-7445.AM2017-4734

We have recently demonstrated that the evaluation of miR10b expression relative to its normal counterparts (Relative Expression Ratio, RER) is able to predict patients risk to develop distant metastases. To confirm these results and evaluate whether other microRNAs could be predictive of outcome in breast cancer we evaluated the expression of miR10b and miR9 in paired tumors and apparently normal breast tissues 2 cm distant from tumour (NBT) on an extended cohort (n = 127) with a longer follow up (median 42 months). As control normal breast tissues from 10 healthy subjects (HBT) treated by reductive mammoplasty were analyzed. An increased expression was seen for the miR9 and miR10b in NBT samples as compared with HBT (P Citation Format: Raffaela Barbano, Barbara Pasculli, Massimiliano Copetti, Andrea Fontana, Michelina Coco, Lorenzo Vitulano, Maria Luana Poeta, Francesca Picardo, Gianfranco Marangi, Roberto Murgo, Luigi Ciuffreda, Vanna Maria Valori, Vanna Maria Valori, Maria Morritti, Evaristo Maiello, Vito Michele Fazio, Paola Parrella. Evaluation of miR10b and miR9 expression in breast cancer and correlations with distant metastases development. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3977. doi:10.1158/1538-7445.AM2015-3977

Aim: Six months FOLFOX4 or XELOX is the standard adjuvant chemotherapy in radically resected stage III colon cancer, however a shorter duration of therapy could be equally efficacious. Methods: This is an Italian, multicenter, non-inferiority phase III trial randomizing patients (pts) with stage III and high risk stage II colon cancer to receive 3 (arm 3) vs 6 (arm 6) months of FOLFOX4 or XELOX. Primary end-point is relapse free survival (RFS), and the arm 3 will be considered non-inferior if the superior margin of the 95% CI of the HR is Results: From June 2007 to March 2013, 3,759 patients were accrued and 3,738 (1860 in arm 3 and 1878 in arm 6) included in the intent-to-treat (ITT) population, since 21 pts were excluded due to major violations. The proportion of FOLFOX4 vs XELOX was 64% vs 36% in both arms. Among the ITT population, demographic factors (including gender and age) were balanced in the two arms. As expected, compliance was higher in arm 3 than in arm 6: treatment completion rate without any modification of planned dose and timing was 35% in arm 3 and 12% in arm 6, while approximately 55% pts in both arms completed treatment with modifications of dose and/or timing, resulting in 90% vs 67% pts receiving all the planned cycles. Therapy was permanently interrupted due to toxicity in 5% of pts in arm 3 and 17% in arm 6. The overall incidence of grade 3-4 toxicity (including grade 2 oxaliplatin neurotoxicity) events was 37% in arm 3 and 60% in arm 6. Grade 2+ neuropathy was more frequent in arm 6 than in arm 3: 32 % vs 9%, respectively. With a median follow-up of 30 months, 476 pts relapsed, 195 died and 520 relapsed and/or died. Conclusions: TOSCA is the first trial completing the accrual among the international initiative of comparing 3 vs 6 months of adjuvant treatment in colon cancer (IDEA). In general, reported toxicity was low, but, as expected, significantly higher in the 6-month arm compared to that of the 3-month arm; accordingly, compliance was lower in the standard 6-month arm. Data for efficacy analysis are premature. Disclosure: All authors have declared no conflicts of interest.