Evaluation of margins during radical prostatectomy: confocal microscopy vs frozen section analysis.

OBJECTIVES: To test the performance of ex vivo fluorescence confocal microscopy (FCM; Vivascope 2500M-G4), as compared to intra-operative frozen section (IFS) analysis, to evaluate surgical margins during robot-assisted radical prostatectomy (RARP), with final pathology as the reference standard. METHODS: Overall, 54 margins in 45 patients treated with RARP were analysed with: (1) ex vivo FCM; (2) IFS analysis; and (3) final pathology. FCM margins were evaluated by two different pathologists (experienced [M.I.: 10 years] vs highly experienced [G.R.: >30 years]) as strongly negative, probably negative, doubtful, probably positive, or strongly positive. First, inter-observer agreement (Cohen's κ) between pathologists was tested. Second, we reported the sensitivity, specificity, positive predictive (PPV) and negative predictive value (NPV) of ex vivo FCM. Finally, agreement between ex vivo FCM and IFS analysis (Cohen's κ) was reported. For all analyses, four combinations of FCM results were evaluated. RESULTS: At ex vivo FCM, the inter-observer agreement between pathologists ranged from moderate (κ = 0.74) to almost perfect (κ = 0.90), according to the four categories of results. Indeed, at ex vivo FCM, the highly experienced pathologist reached the best balance between sensitivity (70.5%) specificity (91.8%), PPV (80.0%) and NPV (87.1%). Conversely, on IFS analysis, the sensitivity, specificity, PPV and NPV were, respectively, 88.2% vs 100% vs 100% vs 94.8%. The agreement between the ex vivo FCM and IFS analyses ranged from moderate (κ = 0.62) to strong (κ = 0.86), according to the four categories of results. CONCLUSION: Evaluation of prostate margins at ex vivo FCM appears to be feasible and reliable. The agreement between readers encourages its widespread use in daily practice. Nevertheless, as of today, the performance of FCM seems to be sub-par when compared to the established standard of care (IFS analysis).

Standardized pathology report for HER2 testing in compliance with 2023 ASCO/CAP updates and 2023 ESMO consensus statements on HER2-low breast cancer.

Since the release of the DESTINY-Breast04 (DB-04) trial findings in June 2022, the field of pathology has seen a renaissance of HER2 as a predictive biomarker in breast cancer. The trial focused on patients with metastatic breast cancer who were classified as "HER2-low," i.e., those with immunohistochemistry (IHC) HER2 1 + or 2 + and negative in situ hybridization (ISH) results. The study revealed that treating these patients with trastuzumab deruxtecan (T-DXd) instead of the oncologist's chosen chemotherapy led to outstanding improvements in survival. This has challenged the existing binary HER2 pathological classification system, which categorized tumors as either positive (overexpression/amplification) or negative, as per the ASCO/CAP 2018 guideline reaffirmed by ASCO/CAP 2023 guideline update. Given that DB-04 excluded patients with HER2 IHC score 0 status, the results of the ongoing DB-06 trial may shed further light on the potential benefits of T-DXd therapy for these patients. Roughly half of all breast cancers are estimated to belong to the HER2-low category, which does not represent a distinct or specific subtype of cancer. Instead, it encompasses a diverse group of tumors that exhibit clinical, morphological, immunohistochemical, and molecular variations. However, HER2-low offers a distinctive biomarker status that identifies a specific therapeutic regimen (i.e., T-DXd) linked to a favorable prognosis in breast cancer. This unique association emphasizes the importance of accurately identifying these tumors. Differentiating between a HER2 IHC score 0 and score 1 + has not been clinically significant until now. To ensure accurate classification and avoid misdiagnosis, it is necessary to adopt standardized procedures, guidelines, and specialized training for pathologists in interpreting HER2 expression in the lower spectrum. Additionally, the utilization of artificial intelligence holds promise in supporting this endeavor. Here, we address the current state of the art and unresolved issues in assessing HER2-low status, with a particular emphasis on the score 0. We explore the dilemma surrounding the exclusion of HER2-zero patients from potentially beneficial therapy based on traditional HER2 testing. Additionally, we examine the clinical context, considering that DB-04 primarily involved heavily pretreated late-stage metastatic breast cancers. We also delve into emerging evidence suggesting that extrapolating HER2-low status from the original diagnosis may lead to misleading results. Finally, we provide recommendations for conducting high-quality testing and propose a standardized pathology report in compliance with 2023 ASCO/CAP updates and 2023 ESMO consensus statements on HER2-low breast cancer.

Pathological identification of HER2-low breast cancer: Tips, tricks, and troubleshooting for the optimal test.

The introduction of novel anti-HER2 antibody-drug conjugates (ADC) for the treatment of HER2-low breast cancers has transformed the traditional dichotomy of HER2 status to an expanded spectrum. However, the identification of HER2-low (i.e., immunohistochemistry (IHC) score 1 + or IHC score 2+, without gene amplification) tumors is challenged by methodological and analytical variables that might influence the sensitivity and reproducibility of HER2 testing. To open all possible therapeutic opportunities for HER2-low breast cancer patients the implementation of more accurate and reproducible testing strategies is mandatory. Here, we provide an overview of the existing barriers that may trouble HER2-low identification in breast cancer and discuss practical solutions that could enhance HER-low assessment.

Biobank for Translational Medicine: Standard Operating Procedures for Optimal Sample Management.

Biobanks are key research infrastructures aimed at the collection, storage, processing, and sharing of high-quality human biological samples and associated data for research, diagnosis, and personalized medicine. The Biobank for Translational and Digital Medicine Unit at the European Institute of Oncology (IEO) is a landmark in this field. Biobanks collaborate with clinical divisions, internal and external research groups, and industry, supporting patients' treatment and scientific progress, including innovative diagnostics, biomarker discovery, and clinical trial design. Given the central role of biobanks in modern research, biobanking standard operating procedures (SOPs) should be extremely precise. SOPs and controls by certified specialists ensure the highest quality of samples for the implementation of science-based, diagnostic, prognostic, and therapeutic personalized strategies. However, despite numerous efforts to standardize and harmonize biobanks, these protocols, which follow a strict set of rules, quality controls, and guidelines based on ethical and legal principles, are not easily accessible. This paper presents the biobank standard operating procedures of a large cancer center.

Atypical Ductal Hyperplasia after Vacuum-Assisted Breast Biopsy: Can We Reduce the Upgrade to Breast Cancer to an Acceptable Rate?

(1) Background: to evaluate which factors can reduce the upgrade rate of atypical ductal hyperplasia (ADH) to in situ or invasive carcinoma in patients who underwent vacuum-assisted breast biopsy (VABB) and subsequent surgical excision. (2) Methods: 2955 VABBs were reviewed; 141 patients with a diagnosis of ADH were selected for subsequent surgical excision. The association between patients' characteristics and the upgrade rate to breast cancer was evaluated in both univariate and multivariate analyses. (3) Results: the upgrade rates to ductal carcinoma in situ (DCIS) and invasive carcinoma (IC) were, respectively, 29.1% and 7.8%. The pooled upgrade rate to DCIS or IC was statistically lower at univariate analysis, considering the following parameters: complete removal of the lesion (p-value < 0.001); BIRADS ≤ 4a (p-value < 0.001); size of the lesion ≤15 mm (p-value: 0.002); age of the patients <50 years (p-value: 0.035). (4) Conclusions: the overall upgrade rate of ADH to DCIS or IC is high and, as already known, surgery should be recommended. However, ADH cases should always be discussed in multidisciplinary meetings: some parameters appear to be related to a lower upgrade rate. Patients presenting these parameters could be strictly followed up to avoid overtreatment.

Wireless ultrasound-guided vacuum-assisted breast biopsy: Experience in clinical practice at European Institute of Oncology.

In the last few years, ultrasound-guided vacuum-assisted breast biopsy (US-VABB) has replaced surgical biopsy due to higher diagnostic accuracy and lower patient discomfort, and, at present, an even greater possibility is represented by the new wireless ultrasound-guided VAB device (Wi-UVAB). The purpose of our study is to determine the diagnostic accuracy of this new device in a sizeable representative number of patients. From January 2014 to June 2018, 168 biopsies were performed in our institution using the new Wi-UVAB device. We analyzed sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of biopsies obtained with the new device using surgical results as reference point, following patients for at least one year. In our cohort, we obtained a complete sensitivity of 97.5%, an absolute sensitivity of 94.3%, a complete specificity of 98%, and an absolute specificity of 98%. The positive predictive value of the procedure was 97.5% while the negative predictive value was 98%. The diagnostic accuracy was 98%. The Wi-UVAB is a safe procedure with high diagnostic accuracy, comparable to that of the traditional vacuum-assisted breast biopsy and even higher than that of core needle biopsy (CNB). Moreover, the Wi-UVAB is easy to use and shows low costs as core needle biopsy (CNB).

Analysis of Efficacy and Accuracy of 2 Vacuum-Assisted Breast Biopsy Devices: Mammotome and Elite.

BACKGROUND: Ultrasound-guided vacuum-assisted breast biopsy (US-VABB) has recently replaced surgical biopsy as a result of its high diagnostic accuracy and low patient discomfort, and at present it relies mainly on 2 devices, Mammotome and, more recently, Mammotome Elite (Elite). Our purpose was to compare the efficacy of these 2 bioptical devices. PATIENTS AND METHODS: We performed US-VABB on 195 patients with Mammotome 8G or 11G in 130 patients and Elite 13G in 65 patients. Of these 195 patients, 95 were submitted to surgery for lumpectomy or mastectomy in case of malignant lesions or of lesions of uncertain malignant potential (B5 and B3), while the remaining 100 were strictly monitored clinically and radiologically for 12 to 24 months. RESULTS: Both the devices showed high absolute sensitivity (96.2% for Mammotome and 83.3% for Elite), complete sensitivity (98.1% for Mammotome and 90.0% for Elite), specificity (92.3% for Mammotome and 94.3% for Elite), and diagnostic accuracy (99.1% for Mammotome and 95% for Elite), thus fulfilling criteria suggested by the European guidelines. Total underestimation rate seemed to be higher in the Elite cohort (14.2%) than in the Mammotome cohort (3.4%) (P = .02). However, none of the patients with a benign diagnosis (B2) presented any event during the follow-up period. CONCLUSION: US-VABB is an accurate method for sampling breast lesions. Our study did not show large, statistically significant differences in diagnostic accuracy between the Elite and Mammotome systems, except for a slight increase in diagnostic underestimation of benign pathologies when using the Elite.

Lapatinib activity in premalignant lesions and HER-2-positive cancer of the breast in a randomized, placebo-controlled presurgical trial.

Dual epidermal growth factor receptor (EGFR) and HER2 targeting with the tyrosine kinase inhibitor lapatinib is approved for treating advanced HER2-positive breast cancer and can prevent estrogen receptor (ER)-negative mammary tumors in HER2 transgenic mouse models. Ki-67 labeling index (LI) has prognostic and predictive value and can be used to screen drugs' therapeutic and preventive potential in a clinical model of short-term presurgical therapy of breast cancer. We conducted a randomized, placebo-controlled trial of lapatinib (1500 mg/d) administered orally for three weeks between biopsy and surgery in 60 women with HER-2-positive breast cancer to assess lapatinib biomarker (including the primary endpoint, Ki-67 LI) and clinical activity in invasive breast cancer, adjacent ductal intraepithelial neoplasia (DIN, which comprises ductal carcinoma in situ and atypical ductal hyperplasia), and distant ductal hyperplasia without atypia (DH). Ki-67 LI increased progressively in association with disease stage, increasing in the placebo arm, for example, by medians of 3% in DH to 20% in DIN to 30% in invasive cancer. Ki-67 LI in cancer tissue decreased by a mean (±SD) of 9.3% (±34.2) in the lapatinib arm and increased by 15.1% (±30.9) in the placebo arm (P = 0.008). Compared with placebo, lapatinib reduced Ki-67 significantly more in ER-negative tumors (by 34.8%; P = 0.01) but not significantly more in ER-positive tumors (by 12.3%; P = 0.2) and reduced Ki-67 more (nonsignificantly) in cytosol PTEN-overexpressing tumors (P = 0.057). The prevalence of DIN in post-treatment surgical specimens of both arms was similar (70%-76%), with a median Ki-67 of 15% (range, 5%-35%) on lapatinib versus 20% (5%-60%) on placebo (P = 0.067). The prevalence of DH also was similar in both arms (>90%), with a median Ki-67 of 1% (1%-7%) on lapatinib versus 3% (1%-5%) on placebo (P = 0.006). Other results of lapatinib versus placebo, respectively, were as follows: Median tumor diameter at surgery of 18 mm (11 mm-57 mm) versus 24 mm (10 mm-37 mm; P = 0.009); partial response of 13.6% versus 3.7%, stable disease of 59.1% versus 40.7%, and progression of 27.3% versus 55.6% (P-trend = 0.035). In conclusion, short-term lapatinib decreased cell proliferation in DIN, DH, and invasive HER-2-positive (especially ER-negative) breast cancer, thus providing the rationale for further clinical development of lapatinib for breast cancer prevention in high-risk patients, including those with HER-2-positive DIN.