Long-Term Outcomes Using Electron IOERT APBI for Early Stage Breast Cancer: The Verona University Hospital Experience.

METHODS AND MATERIALS: From July 2006 to December 2015, 295 patients suitable for breast-conserving therapy entered a single-arm phase II study and were treated with IOERT as radical treatment. Inclusion criteria were age >50, postmenopausal status, cT1N0M0 stage, grade G1-G2, positive estrogen receptor status; unicentric and unifocal disease, histologically proven invasive ductal carcinoma no previous breast irradiation, good performance status. RESULTS: With a median follow-up of 7.1 years (95% CI, 6.5;7.4) 6 women (2.0%) experienced a true local recurrence (reappearance of the tumour in the same quadrant). Five-year overall survival and local recurrence-free survival were 96% (95% CI, 92.9;97.8) and 94.9% (95% CI, 91.6;97.0) respectively. CONCLUSION: Our trial suggests that, in highly selected early stage breast cancers, a single-dose IOERT can be safely delivered with excellent results and very low long-term recurrence rates.

Effects of Lean Thinking and Emerging Technologies on Breast Cancer Patients' Therapeutic Process During COVID-19 Pandemic: A Case-Control Matched Study.

Introduction: The advent of the COVID-19 pandemic has led to the sudden disruption of routine medical care, and the subsequent reorganization of hospital structures and therapeutic algorithms, aiming at protecting patients and health professionals. This was inevitably bound to affect our Breast Unit, dilating both pre- and post-operative times. The aim of this study was to evaluate the effect on patients' flow of organizational and logistic changes (key interventions) based on lean thinking implemented after the COVID-19 outbreak. Materials and Methods: Clinical and demographic data were retrospectively collected from patients undergoing sentinel lymph node biopsy for breast cancer at the Verona University Hospital from January 2018 to June 2020. Patients enrolled (n = 341) were divided into two groups according to date of admission: before (Group A; n = 294) and after (Group B; n = 47) the implementation of key interventions. Each case in Group B was subsequently matched 1:1 by means of case-control matching with cases from Group A for age, comorbidities, and type of surgery (Subgroup A1; N = 47). Pre-admission time (T0) and length of stay (T1) were compared between the three groups. Results: Median T0 was 312 h, whereas median T1 was 24 h. Patients in Group B had a higher frequency of comorbidities (57.4 vs. 25.2%, p = 0.001) and underwent mastectomy more often than patients in Group A (61.7 vs. 36.7%, p = 0.001). Both median T0 and T1 were higher in group B than in group A (384 vs. 300 h, p = 0.001, 48 vs. 24 h, p = 0.001, respectively). Median T0 and T1 did not significantly differ between Group B and Subgroup A1 (all p > 0.05). Conclusions: Lean thinking and new technologies could prove useful to the optimization of preoperative and postoperative times during the current pandemic, minimizing healthcare personnel and patients' exposure to SARS-CoV-2, and promoting a rational use of limited resources, while complying with oncological principles.

Male Breast Cancer: Surgical and Genetic Features and a Multidisciplinary Management Strategy.

BACKGROUND: Male breast cancer (MBC) is a rare disease with a rising incidence trend. The major risk factors related to MBC are a positive family history of breast cancer (BC) and BRCA1/2 mutations, which indicate a relevant genetic role. METHODS: In this retrospective series, we enrolled 69 male patients presenting with male breast cancer (MBC) between 01/01/1992 and 31/12/2018, and 26 high-risk not-affected men presenting between 01/01/2016 and 31/12/2018. Participants' electronic clinical records were reviewed. Patients' data reported age at diagnosis, tumor characteristics, therapeutic management, and BRCA1/2 status as well as a family history of breast, ovarian, or prostate cancer (PCa) in first-degree relatives. RESULTS: We analyzed 69 MBC patients. Median age was 64 years. The majority of tumors diagnosed were of an early TNM stage. The most frequent histological subtype was invasive ductal carcinoma (76.7%). Hormone receptors were positive in >90% of MBC cases. Nearly all patients underwent modified radical mastectomy or total mastectomy. Adjuvant endocrine therapy was delivered in 59.4%. Among MBC-affected patients, we recorded a high percentage of a positive family history of BC. Mutational analysis for the BRCA1/2 genes was performed in 17 MBC patients; 11.8% were carriers of BRCA2 pathogenic mutations. Among 26 healthy high-risk subjects included in this case series, 4 were BRCA1 mutation carriers and 9 were BRCA2 mutation carriers. DISCUSSION: We evaluated the distribution of clinicopathological characteristics in MBC subjects and assessed the frequency of mutations in the BRCA genes in affected patients and healthy high-risk subjects, with the aim of proposing a surveillance program for BC and PCa.

Multidisciplinary management of CDH1 germinal mutation and prophylactic management hereditary lobular breast cancer: A case report.

INTRODUCTION: Germline CDH1 mutations, classically associated with hereditary diffuse gastric cancer (HDGC), also imply an increased lifetime risk of developing lobular breast cancer (LBC) in a highly penetrant autosomal dominant manner. PRESENTATION OF CASE: We report a 44-year-old woman CDH1 mutation carrier with a strong family history of cancer, who previously had prophylactic total gastrectomy. We registered normal findings at the breast and axilla assessment. Mammography, ultrasonography and breast MRI scans were negative for cancer. In our Institute a bilateral prophylactic mastectomy followed by breast reconstruction was performed. Foci of atypical lobular hyperplasia(ALH) and lobular carcinoma in situ (LCIS) were histologically shown. DISCUSSION: The current consensus guidelines for women with pathogenic CDH1 mutations recommend annual mammography, ultrasound, breast MRI scans and clinical breast examination starting at the age of 35. Due to the well-documented aggressive behavior of this particular type of cancer, bilateral mastectomy and reconstruction would be more beneficial for this kind of high-risk patients. CONCLUSION: Conflicting evidences and lacking data about the benefits in terms of overall survival, disease-free survival and the long-term outcomes related to prophylactic bilateral mastectomy for CDH1 mutation carriers restrict the instruction for this type of procedure to selected cases, which should always be managed by a multidisciplinary team.

Breast cancer and neoadjuvant chemotherapy: indications for and limits of breast-conserving surgery.

AIM: The aim of our study was to determine how many and what subtypes of breast cancer could be treated with breast-conserving surgery after NACT. Another outcome was to determine the applicability of MD Anderson Cancer Center nomogram to predict it. MATERIAL OF STUDY: We reviewed the histological examinations of 86 performed mastectomies according to the indications to BCS after NACT. For 73 cases, collected all the necessary data, we could use the nomogram available on the MDACC website to calculate the probability of BCS and pCR. RESULTS: In our experience the BCS rate would increase by 34,1%, from 3,7% to 3.,8%. Patients with Triple Negative and HER2+, ER- more than ER+, show higher rates of pCR and BCS. The MDACC nomogram predicts accurately the probability of pCR and BCS after NACT in HER2 negative cancers but not in HER2 positive ones treated with Trastuzumab. This suggests that a specific nomogram for HER2 positive carcinomas has to be developed. CONCLUSION: BCS after NACT is feasible and safe in terms of LRR, DFS and OS, if patients are properly studied and selected. Indication to BCS after NACT needs of a multidisciplinary assessment considering clinical staging, biological characteristics, the radiological response pattern and the expected concordance between imaging and histology. KEY WORDS: Breast Cancer, Breast-conserving surgery, Neoadjuvant chemotherapy.

Breast cancer and gastrointestinal metastasis. A case report and review of the literature.

INTRODUCTION: Invasive lobular cancer (ILC) is the second most common type of a heterogeneous group of different histological types of invasive breast carcinoma. Breast cancer can metastatize anywhere, the most common sites are bones, liver, lungs and brain. Gastrointestinal tract (GI) metastases observed in autopsy studies account for about 6% to 18% of the overall metastases from breast cancer. OBJECTIVE: We describe a 54-year old woman with recurrent ILC in the contralateral breast. She underwent right mastectomy 16 years before. After symptomatic presentation a duodenal invasion was found and subjected to diagnostic scrutiny (FDG PET/CT, diagnostic CT, MR, EGDS). In particular, we analyse if FDG PET/CT is enough accurate in the restaging of the patient. A review of our database and of the literature of similar cases were made. RESULTS: In this patient CT and RM were suspicious for a slow developing process of the duodenum but FDG PET/CT did not show pathological uptake in the affected duodenal tract. A highly intense focus was described in a cervical lymph node, that there isn't metastatic lesion, whereas the recurrent breast lesion had only slight increased glycolytic activity. CONCLUSION: Metastatic lobular carcinoma of the breast is a rare entity with a heterogeneous range of clinical presentations. Detection of eventual gastrointestinal metastases are complicated to assess. ILC has various scale of glycolytic activity both in the primary lesion as well in the metastatic foci. When the level of suspicion is high and there is no uptake of FDG, further investigations are necessary. KEY WORD: Abdominal metastasis, FGD PET-TC, Lobular Breast Cancer.

Prognostic impact of proliferation for resected early stage 'pure' invasive lobular breast cancer: Cut-off analysis of Ki67 according to histology and clinical validation.

INTRODUCTION: The intent of this analysis was to investigate and validate the prognostic potential of Ki67 in a multi-center series of patients affected by early stage 'pure' invasive lobular carcinoma (ILC). METHODS: Clinical-pathological data of patients affected by ILC were correlated with overall survival and disease-free survival (OS/DFS); data from a parallel invasive ductal carcinoma (IDC) patients' cohort were gathered as well. The maximally selected Log-Rank statistics analysis was applied to Ki67 continuous variable to estimate the appropriate cut-off. The Subpopulation Treatment Effect Pattern Plot (STEPP) analysis was performed as well. RESULTS: Data from overall 1097 (457/222 ILC: training/validation set; 418 IDC) patients were gathered. The identified optimal Ki67 cut-offs were 4% and 14% for DFS in ILC and IDC cohort, respectively. In ILC patients, the Ki67 cut-off was an independent OS predictor. Ten-years OS and DFS were 89.9% and 77.2% (p = 0.007) and 79.4% and 69.2% (p = 0.03) for patients with Ki67 ≤ 4% and >4%, respectively. In IDC patients, 10-years OS was 93.8% and 71.7%, p = 0.02, DFS was 84.0% and 52.6%, p = 0.0003, for patients with Ki67 ≤ 14% and >14%, respectively. In the validation set, the optimal Ki67 OS cut-off was 5%. The STEPP analysis showed that in the presence of low Ki67 values, IDC patients have a better DFS than ILC patients, while with the increase of values the prognosis tends to overlap. CONCLUSIONS: Despite the retrospective design of the study, the prognostic relevance of Ki67 (as well as its optimal cut-off) seems to significantly differ according to breast cancer histology.

Clinical results of randomized trials and 'real-world' data exploring the impact of Bevacizumab for breast cancer: opportunities for clinical practice and perspectives for research.

INTRODUCTION: Angiogenesis plays a fundamental role in breast cancer (BC) growth, progression and metastatic spread. After the promising introduction of bevacizumab for the treatment of advanced BC, the initial enthusiasm decreased when the FDA withdrew its approval in 2011. Nevertheless, several clinical studies exploring the role of bevacizumab have been subsequently published. Areas covered: The aim of this study is to review the available clinical trials exploring the potential effectiveness of bevacizumab in BC, regardless of the disease setting. Expert opinion: Even if the evidence suggests that bevacizumab must be ruled out from the HER2-positive and adjuvant setting, bevacizumab's benefit remains uncertain in the neoadjuvant setting and in the advanced treatment of HER2-negative patients. In the first setting, the addition of bevacizumab to chemotherapy increased the pathological complete response (pCR) rate in most clinical trials. However, the current absence of evidence that pCR is a trial-level surrogate for survival requires waiting for long-term results. In the advanced setting, all trials showed a benefit in progression-free survival, but not in overall survival, highlighting an increase of adverse events. The lack of predictors of response represents the main unmet need in which future clinical research will undoubtedly invest.

Subpopulation Treatment Effect Pattern Plot (STEPP) analysis of Ki67 assay according to histology: prognostic relevance for resected early stage 'pure' and 'mixed' lobular breast cancer.

BACKGROUND: The aim of this analysis was to investigate the potential impact of Ki67 assay in a series of patients affected by early stage invasive lobular carcinoma (ILC) undergone surgery. METHODS: Clinical-pathological data were correlated with disease-free and overall survival (DFS/OS). The maximally selected Log-Rank statistics analysis was applied to the Ki67 continuous variable to estimate appropriate cut-offs. The Subpopulation Treatment Effect Pattern Plot (STEPP) analysis was performed to assess the interaction between 'pure' or 'mixed' histology ILC and Ki67. RESULTS: At a median follow-up of 67 months, 10-years DFS and OS of 405 patients were 67.8 and 79.8%, respectively. Standardized Log-Rank statistics identified 2 optimal cut-offs (6 and 21%); 10-years DFS and OS were 75.1, 66.5, and 30.2% (p = 0.01) and 84.3, 76.4 and 59% (p = 0.003), for patients with a Ki67 < 6%, between 6 and 21%, and >21%, respectively. Ki67 and lymph-node status were independent predictor for longer DFS and OS at the multivariate analysis, with radiotherapy (for DFS) and age (for OS). Ki67 highly replicated at the internal cross-validation analysis (DFS 85%, OS 100%). The STEPP analysis showed that DFS rate decreases as Ki67 increases and those patients with 'pure' ILC performed worse than 'mixed' histology. CONCLUSIONS: Despite the retrospective and exploratory nature of the study, Ki67 was able to significantly discriminate the prognosis of patients with ILC, and the effect was more pronounced for patients with 'pure' ILC.

Balancing activity and tolerability of neoadjuvant paclitaxel- and docetaxel-based chemotherapy for HER2-positive early stage breast cancer: sensitivity analysis of randomized trials.

Paclitaxel and docetaxel represent the most adopted taxanes in the neoadjuvant treatment of HER2-positive breast cancer. Questions still remain with regard to their difference in terms of activity and tolerability. Events for pathological complete response (pCR), severe and febrile neutropenia (FN), and severe neurotoxicity were pooled by adopting a fixed- and random-effect model. A sensitivity analysis to test for the interaction between paclitaxel and docetaxel was accomplished. Absolute differences with 95% confidence intervals (CIs) and the number of patients needed to treat/harm (NNT/NNH) were calculated to derive the Likelihood of being Helped or Harmed (LHH). Data from 15 trials (3601 patients) were included. Paclitaxel significantly increases pCR rate by 6.8% in comparison with docetaxel (43.4%, 95% CI 41.1-45.7% versus 36.6%, 95% CI 34.3-39.0%, p=0.0001), regardless of the chemotherapy backbone, with an absolute difference of 9% and 9.2% for anthracycline-based or free-regimens. Paclitaxel significantly improves pCR versus docetaxel with a single HER2-inhibition by 6.7% (p=0.0012), with no difference if combined with a dual HER2-inhibition. Severe neutropenia and FN are significantly lower with paclitaxel, with an absolute difference of 32.4% (p<0.0001) and 2.5% (p=0.0059), respectively. Conversely, severe neurotoxicity is slightly higher with paclitaxel (3%, p=0.0001). The LHH ratio calculated for pCR and severe neutropenia is 2.0 and 0.7 for paclitaxel and docetaxel. Although the activity of neoadjuvant paclitaxel and docetaxel HER2-positive breast cancer is considered similar, the slight advantage in pCR, the significantly lower neutropenia and FN, do favor paclitaxel (in the weekly fashion) over docetaxel, despite the slightly worst neurotoxicity.

Neoadjuvant strategies for triple negative breast cancer: 'state-of-the-art' and future perspectives.

Neoadjuvant therapy for triple negative breast cancer (TNBC) has recently generated growing interest given the more aggressive biologic characteristics of such subtype and the lack of approved targeted therapies. Systemic chemotherapy represents the mainstay of treatment for TNBC. Although neoadjuvant chemotherapy has consistently demonstrated higher response rates for TNBC compared to non-TNBC, and the pathological complete response predicts long-term outcome, most patient display residual disease with a higher risk of relapse. In order to improve the outcome of TNBC new chemotherapic combinations, including platinum agents, and different targeted agents such as antiangiogenetics, poly-ADP ribose polymerase (PARP) inhibitors and other small molecule inhibitors are being evaluated in neoadjuvant setting. Currently, the research is ongoing to further characterize TNBC from a phenotypical and molecular perspective, in order to identify potential new target agents and to individualize the treatment. In this regard, the neoadjuvant setting may represent the best potential scenario to assess the activity and the sensitivity of novel agents.

Human epidermal growth factor receptor 2-positive breast cancer: heat shock protein 90 overexpression, Ki67 proliferative index, and topoisomerase II-α co-amplification as predictors of pathologic complete response to neoadjuvant chemotherapy with trastuzumab and docetaxel.

BACKGROUND: The combination of trastuzumab and chemotherapy is currently considered the standard of care for patients with locally advanced/operable human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The potential correlation between the pathologic complete response (pCR) and the overexpression of heat shock protein 90 (Hsp90), Ki67, and the amplification of topoisomerase II-α (TOPO2A) was investigated in a series of patients who received neoadjuvant treatment. METHODS: HER2-amplified patients who received neoadjuvant trastuzumab-docetaxel were gathered. Baseline and postsurgical Hsp90 immunoscore, Ki67 proliferation index, and TOPO2A amplification were determined together with classic clinical-pathologic predictors and correlated with pCR and imaging data. RESULTS: A total of 24 patients were evaluated for response; pCR, clinical, and radiologic response were found in 4 patients (16.7%; 95% confidence interval [CI], 1.7-31.5), 9 patients (37.5%; 95% CI, 18.1-56.8), and 6 patients (25.0%; 95% CI, 7.6-42.3) patients, respectively. pCR was significantly higher in premenopausal (60.0% vs. 5.3%, P = .02) and negative hormonal receptor patients (50.0% vs. 5.6%, P = .03). A trend for patients with high Ki67 and TOPO2A/HER2 co-amplification was found (21.1% vs. none, P = .54; 50.0% vs. 12%, P = .16). pCR was significantly higher in patients with Hsp90 score 3+, in comparison with score 2+ and score 1+ (50.0% vs. 14.3% vs. none, P = .05). After treatment, a statistically significant lower Ki67 staining (30.0% vs. 17.5%, P = .005) and a trend for the decreased expression of high (score 3+) and moderate (score 2+) Hsp90 immunostaining (McNemar P = .25, Wilcoxon-Mann-Whitney P = .08) were found. CONCLUSIONS: Although underpowered, our data suggest that patients with HER2-positive breast cancer overexpressing Hsp90 should be investigated as a "newer" molecular subtype with a significantly higher chance of pCR when receiving anti-Her2 agents.

Comparison between invasive breast cancer with extensive peritumoral vascular invasion and inflammatory breast carcinoma: a clinicopathologic study of 161 cases.

OBJECTIVES: Extensive peritumoral neoplastic lymphovascular invasion (ePVI) is a marker of aggressiveness in invasive breast carcinoma (BC). METHODS: We explored the impact of ePVI on different BC subtypes. In a total of 2,116 BCs, 91 ePVI-BCs, 70 inflammatory breast carcinomas (IBCs), and 114 casual BCs as a control group (CG-BC) were recruited. RESULTS: Patients affected by ePVI-BC were younger, had larger tumors, higher histologic grade, elevated Ki-67 score, Her2/neu overexpressed, and more lymph node metastases compared with CG-BC (P < .001). Interestingly, only younger mean age at diagnosis differentiated patients with ePVI-BC from patients affected by IBC. ePVI-BC showed a clinical outcome intermediate between the prognoses of IBC and CG-BC. CONCLUSIONS: Results suggest that ePVI-BC and IBC may share some pathologic processes, providing a novel perspective on the heterogeneity of BC. Epidemiologic data and molecular studies on gene expression features are needed to rationally classify these tumors into their identified subtypes.

Impact of neoadjuvant single or dual HER2 inhibition and chemotherapy backbone upon pathological complete response in operable and locally advanced breast cancer: Sensitivity analysis of randomized trials.

The role of the dual HER2 inhibition, and the best chemotherapy backbone for neoadjuvant chemotherapy still represent an issue for clinical practice. A literature-based meta-analysis exploring single versus dual HER2 inhibition in terms of pathological complete response (pCR, breast plus axilla) rate and testing the interaction according to the chemotherapy (anthracyclines-taxanes or taxanes) was conducted. In addition, an event-based pooled analysis by extracting activity and safety events and deriving 95% confidence intervals (CI) was accomplished. Fourteen trials (4149 patients) were identified, with 6 trials (1820 patients) included in the meta-analysis and 31 arms (14 trials, 3580 patients) in the event-based pooled analysis. The dual HER2 inhibition significantly improves pCR rate, in the range of 16-19%, regardless of the chemotherapy backbone (relative risk 1.37, 95% CI 1.23-1.53, p<0.0001); pCR was significantly higher in the hormonal receptor negative population, regardless of the HER2 inhibition and type of chemotherapy. pCR and the rate of breast conserving surgery was higher when anthracyclines were added to taxanes, regardless of the HER2 inhibition. Severe neutropenia was higher with the addition of anthracyclines to taxanes, with an absolute difference of 19.7%, despite no differences in febrile neutropenia. While no significant differences according to the HER2 inhibition were found in terms of cardiotoxicity, a slightly difference for grade 3-4 (1.2%) against the addition of anthracyclines was calculated. The dual HER2 inhibition for the neoadjuvant treatment of HER2-positive breast cancer significantly increases pCR; the combination of anthracyclines, taxanes and anti-Her2 agents should be currently considered the standard of care.