Determination of Factors Associated with Upstage in Atypical Ductal Hyperplasia to Identify Low-Risk Patients Where Active Surveillance May be an Alternative.

BACKGROUND: Excision is routinely recommended for atypical ductal hyperplasia (ADH) found on core biopsy given cancer upstage rates of near 20%. Identifying a cohort at low-risk for upstage may avoid low-value surgery. Objectives were to elucidate factors predictive of upstage in ADH, specifically near-complete core sampling, to potentially define a group at low upstage risk. PATIENTS AND METHODS: This retrospective, cross-sectional, multi-institutional study from 2015 to 2019 of 221 ADH lesions in 216 patients who underwent excision or active observation (≥ 12 months imaging surveillance, mean follow-up 32.6 months) evaluated clinical, radiologic, pathologic, and procedural factors for association with upstage. Radiologists prospectively examined imaging for lesional size and sampling proportion. RESULTS: Upstage occurred in 37 (16.7%) lesions, 25 (67.6%) to ductal carcinoma in situ (DCIS) and 12 (32.4%) to invasive cancer. Factors independently predictive of upstage were lesion size ≥ 10 mm (OR 5.47, 95% CI 2.03-14.77, p < 0.001), pathologic suspicion for DCIS (OR 12.29, 95% CI 3.24-46.56, p < 0.001), and calcification distribution pattern (OR 8.08, 95% CI 2.04-32.00, p = 0.003, "regional"; OR 19.28, 95% CI 3.47-106.97, p < 0.001, "linear"). Near-complete sampling was not correlated with upstage (p = 0.64). All three significant predictors were absent in 65 (29.4%) cases, with a 1.5% upstage rate. CONCLUSIONS: The upstage rate among 221 ADH lesions was 16.7%, highest in lesions ≥ 10 mm, with pathologic suspicion of DCIS, and linear/regional calcifications on mammography. Conversely, 30% of the cohort exhibited all low-risk factors, with an upstage rate < 2%, suggesting that active surveillance may be permissible in lieu of surgery.

Expression-Based Diagnosis, Treatment Selection, and Drug Development for Breast Cancer.

There is currently no gene expression assay that can assess if premalignant lesions will develop into invasive breast cancer. This study sought to identify biomarkers for selecting patients with a high potential for developing invasive carcinoma in the breast with normal histology, benign lesions, or premalignant lesions. A set of 26-gene mRNA expression profiles were used to identify invasive ductal carcinomas from histologically normal tissue and benign lesions and to select those with a higher potential for future cancer development (ADHC) in the breast associated with atypical ductal hyperplasia (ADH). The expression-defined model achieved an overall accuracy of 94.05% (AUC = 0.96) in classifying invasive ductal carcinomas from histologically normal tissue and benign lesions (n = 185). This gene signature classified cancer development in ADH tissues with an overall accuracy of 100% (n = 8). The mRNA expression patterns of these 26 genes were validated using RT-PCR analyses of independent tissue samples (n = 77) and blood samples (n = 48). The protein expression of PBX2 and RAD52 assessed with immunohistochemistry were prognostic of breast cancer survival outcomes. This signature provided significant prognostic stratification in The Cancer Genome Atlas breast cancer patients (n = 1100), as well as basal-like and luminal A subtypes, and was associated with distinct immune infiltration and activities. The mRNA and protein expression of the 26 genes was associated with sensitivity or resistance to 18 NCCN-recommended drugs for treating breast cancer. Eleven genes had significant proliferative potential in CRISPR-Cas9/RNAi screening. Based on this gene expression signature, the VEGFR inhibitor ZM-306416 was discovered as a new drug for treating breast cancer.

Initiation and tolerance of chemoprevention among women with high-risk breast lesions: the potential of low-dose tamoxifen.

PURPOSE: High-risk lesions (HRLs) of the breast are an indication for chemoprevention, yet uptake is low, largely due to concerns about side effects. In 2019, low-dose (5 mg) tamoxifen was demonstrated to reduce breast cancer risk with improved tolerance. We describe chemoprevention uptake in an academic clinic before and after the introduction of low-dose tamoxifen. METHODS: Females age ≥ 35 with HRLs who established care from April 2017 through January 2020 and eligible for chemoprevention were included. Rates of chemoprevention initiation before and after the introduction of low-dose tamoxifen (pre-2019 vs. post-2019) were compared with chi-squared tests. Logistic regression identified demographic and clinical factors associated with chemoprevention initiation. Kaplan-Meier methods determined the rates of discontinuation. RESULTS: Among 660 eligible females with HRLs, 22.7% initiated chemoprevention. Median time from first visit to chemoprevention initiation was 54 days (interquartile range (IQR): 0-209); 31.0% (46/150) started chemoprevention > 6 months after their initial visit. Chemoprevention uptake was not significantly different pre-2019 vs. post-2019 (21.2% vs. 26.3%, p = 0.16); however, post-2019, low-dose tamoxifen became the most popular option (41.5%, 34/82). On multivariable analyses, age and breast cancer family history were significantly associated with chemoprevention initiation. Discontinuation rates at 1 year were lowest for low-dose tamoxifen (6.7%) vs. tamoxifen 20 mg (15.0%), raloxifene (20.4%), or an aromatase inhibitor (20.0%). CONCLUSION: In this modern cohort, 22.7% of females with HRLs initiated chemoprevention with 31.0% initiating chemoprevention > 6 months after their first visit. Low-dose tamoxifen is now the most popular choice for chemoprevention, with low discontinuation rates at 1 year.

Positive predictive value for malignancy of uncertain malignant potential (B3) breast lesions diagnosed on vacuum-assisted biopsy (VAB): is surgical excision still recommended?

PURPOSE: Breast lesions classified as of "uncertain malignant potential" represent a heterogeneous group of abnormalities with an increased risk of associated malignancy. Clinical management of B3 lesions diagnosed on vacuum-assisted breast biopsy (VABB) is still challenging: surgical excision is no longer the only available treatment and VABB may be sufficient for therapeutic excision. The aim of the present study is to evaluate the positive predictive value (PPV) for malignancy in B3 lesions that underwent surgical excision, identifying possible upgrading predictive factors and characterizing the malignant lesions eventually diagnosed. These results are compared with a subset of patients with B3 lesions who underwent follow-up. METHODS: A total of 1250 VABBs were performed between January 2006 and December 2017 at our center. In total, 150 B3 cases were diagnosed and 68 of them underwent surgical excision. VABB findings were correlated with excision histology. A PPV for malignancy for each B3 subtype was derived. RESULTS: The overall PPV rate was 28%, with the highest upgrade rate for atypical ductal hyperplasia (41%), followed by classical lobular neoplasia (29%) and flat epithelial atypia (11%). Only two cases of carcinoma were detected in the follow-up cohort, both associated with atypical ductal hyperplasia at VABB. CONCLUSION: Open surgery is recommended in case of atypical ductal hyperplasia while, for other B3 lesions, excision with VABB only may be an acceptable alternative if radio-pathological correlation is assessed, if all microcalcifications have been removed by VABB, and if the lesion lacks high-risk cytological features. KEY POINTS: • Surgical treatment is strongly recommended in case of ADH, while the upgrade rate in case of pure FEA, especially following complete microcalcification removal by VABB, may be sufficiently low to advice surveillance as a management strategy. • The use of 11-G- or 8-G-needle VABB, resulting in possible complete diagnostic excision of the lesion, can be an acceptable alternative in case of RS, considering open surgery only for selected high-risk patients. • LN management is more controversial: surgical excision may be recommended following classical LN diagnosis on breast biopsy if an additional B3 lesion is concurrently detected while in the presence of isolated LN with adequate radiological-pathological correlation follow-up alone could be an acceptable option.

How Do We Approach Benign Proliferative Lesions?

PURPOSE OF REVIEW: The aim of this review is to summarize recently published literature addressing atypical ductal hyperplasia (ADH), lobular neoplasia (atypical lobular hyperplasia [ALH] and classic lobular carcinoma in situ [C-LCIS]), non-classic lobular carcinoma in situ (NC-LCIS), papillary lesions, and flat epithelial atypia (FEA). RECENT FINDINGS: While ADH, ALN, and C-LCIS are well-established markers of an increased risk of future breast cancers, the risk implications are less clear for papillary lesions and FEA. NC-LCIS is the least well-characterized lesion, with scant published literature on its natural history and surgical management when encountered on needle biopsy. Recent data suggest that lobular neoplasia on core biopsy of a BI-RADS ≤ 4 concordant lesion does not require an excision, while ADH, atypical papillomas, and NC-LCIS should be excised. Evidence on FEA and papillomas without atypia suggests a low risk of upgrade on excision, and prospective studies on the upgrade of these lesions are ongoing.

Spectrum of Papillary Breast Lesions According to World Health Organization Classification of Papillary Neoplasms of Breast.

Introduction Papillary breast lesions are segregated into benign and malignant based on the presence or absence of myoepithelial cells in the papillary cores. Papillary breast lesions are further classified into: intraductal papilloma, papilloma with atypical ductal hyperplasia (ADH)/ductal carcinoma in situ (DCIS), papillary DCIS, solid papillary carcinoma in situ, solid papillary carcinoma with invasion, invasive solid papillary carcinoma, encapsulated papillary carcinoma and encapsulated papillary carcinoma with invasion. In this study, we evaluated the spectrum of papillary breast lesions in resection specimens of the breast according to the latest World Health Organization (WHO) classification of breast tumors. Methods This was a retrospective cross-sectional study, and was conducted at Liaquat National Hospital for a period of six years, from January 2012 till December 2017. Data of patients that underwent surgeries for breast tumors were included in the study. All specimens were grossed, according to defined protocols, and representative sections were taken after inking resection margins. Hematoxylin and eosin-stained sections were examined by experienced histopathologists, and myoepithelial stains (p63 and myosin) were done in selected sections of all tumors. Histopathological classification of papillary tumors was performed according to WHO classification of breast tumors. Results The study involved 190 excision specimens of papillary breast lesions. Mean age of the patients was 45.6±17.1 years. Most of the lesions were between two and five centimetres (69.1%). For invasive carcinomas (n = 76), the most frequent grade was II (52.6%). For in situ and invasive carcinomas (n = 129), lymphovascular invasion and axillary metastasis were noted in 5.4% and 9.3% cases, respectively. Among papillary breast lesions, 36.8% were benign (intraductal papilloma, solitary or multiple) while 63.2% harbored ADH, DCIS, or invasive carcinoma. Invasive papillary carcinoma was the most frequent malignant papillary lesion (20%), followed by solid papillary carcinoma with invasion (12.6%). We found significant associations between patient's age and tumor size with histological type of papillary lesion as benign papillary lesions had smaller size and younger age compared to malignant papillary lesions. Conclusion We noted a high frequency of malignancy in papillary breast lesions. Moreover, malignant papillary lesions were significantly associated with higher age and larger tumor size.