High-grade Ductal Carcinoma Research Articles

Solid-basaloid Variant of Mammary Adenoid Cystic Carcinoma – Report of an Unusual Case with Literature Review

Abstract Introduction/Objective Adenoid cystic carcinoma (AdCC) of breast is a rare subtype of malignancy, constituting approximately 0.1% of all breast carcinomas. The solid-basaloid variant (SB-AdCC) is exceedingly uncommon. Here, we present such an unusual case of SB-AdCC. Methods/Case Report A 64-year-old woman who underwent screening mammography presented with abnormal findings, revealing a hypoechoic ovoid, lobulated nodule at 7:00 of the left breast, which prompted an ultrasound- guided biopsy. Histologically, the biopsy cores demonstrated a 9 mm infiltrative round, solid nests with focal “cribriforming” areas. It was composed of monomorphic basaloid epithelial cells with marked nuclear atypia and high mitotic count. High-grade ductal carcinoma in situ, solid papillary carcinoma, and nonspecific invasive carcinoma were in differentials. Immunohistochemical (IHC) staining expressed positivity for CD117 and CK 5/6, while p63, SMMHC, and synaptophysin were negative. MYB gene rearrangement confirmed by fluorescence in situ hybridization. As expected, the tumor lacked ER, PR, and HER2 expression by IHC. Left breast mastectomy and axillary lymph node dissection have been scheduled. Results (if a Case Study enter NA) NA Conclusion Per literature review, the mean age of SB-AdCC at diagnosis was 68 years (33-84 years) with an average tumor size of 25 mm (12-70 mm). It had more aggressive behavior, with a higher propensity for lymph node metastasis, locally recurrence, and distant metastasis. The median disease-free survival was 46.5 months versus 151.8 months in those with class AdCC. Notably, neovascularization has emerged as a strong independent predictor of outcome in SB-AdCC. Most patients were treated with surgical excision, axillary lymph node dissection, and/or adjuvant chemotherapy. Limited studies demonstrated that neoadjuvant chemotherapy may induce an excellent response. Furthermore, a distinct molecular mutation enriched in NOTCH and CREBBP genes has been identified, which could be novel potential therapeutic target. Thus, awareness of this extremely rare breast cancer subtype and accurate differentiation from other entities are paramount for appropriate management strategies.

Clinical and Pathological Predictors of Recurrent Breast Cancer

Objectives: Recurrence of breast cancer is common. There are reported risk factors for recurrence which are patient age, tumor size, tumor grade, (lymph vascular invasion (LVI), extensive intraductal component (EIC), and margin status. Nodal involvement also contributes to the recurrence rate as well as hormonal status, and if the patient receives neoadjuvant/adjuvant therapy or not. The aim of this study is to look for the clinical and pathological predictors of patients who have recurrent breast cancer after surgical treatment. Methods: We conducted a retrospective cohort study at one center (Royal hospital) between 2010 to 2020 for patients who were treated surgically for nonmetastatic breast cancer. We collected the clinical which was mainly the age at the diagnosis and pathological predictors (final histopathology report of the surgical specimen) from the medical records system of the hospital after obtaining the ethical approval. Total sample size was 270 Omani patients. The primary endpoint was the time to locoregional recurrence or systemic recurrence as the first event. A multivariate analysis of the predictors was carried and a P-value of < 0.05 was considered statistically significant with 95% CI. Results: Out of 270 patients with breast cancer who were surgically treated, 113 had recurrence and 157 had no recurrence. There were 104 patients with recurrence have invasive ductal carcinoma (IDC) and 9 patients with high-grade ductal carcinoma in situ (DCIS). The Mean age of patients with recurrence was 44.0 while in patients without recurrence was 48.3. The difference in age between the two groups is not statistically significant in predicting the recurrence (p = 0.816). ER, LVI, EIC, nodal involvement, grade, margin, and type of tumor were the significant predictors of recurrence by bivariate analysis. However, High grade (Hazard ratio (HR) = 3.823, 95% CI: 1.104-13.240; p = 0.034), EIC (HR = 17.407, 95% CI: 1.538-196.999; p = 0.021), and nodal involvement (HR = 2.314, 95% CI: 1.123-4.767; p = 0.023) remain the significant predictors for recurrent breast cancer in the multivariate Cox regression analysis. By using Kaplan-Meier, the median survival time was 132 months and the recurrence-free survival at two years was 88.0% (The recurrence rate = 12.0%). Conclusions: High grade, extensive intraductal component, and nodal involvement are significant predictors for breast cancer recurrence. The recurrencefree survival at 2 years is 88.0%. Our recommendation is a close follow-up for patients with these predictors.

Low progesterone receptor levels in high-grade DCIS correlate with HER2 upregulation and the presence of invasive components.

In this study, we investigated pivotal molecular markers in human high-grade breast ductal carcinoma in situ (DCIS). Expression status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth receptor 2 (HER2) was measured among various subtypes (Luminal (Lum) A, LumB HER2-, LumB HER2+, HER2-enriched and triple-negative). In total, 357 DCIS cases were classified into respective subtypes, according to the 2013 St. Gallen guidelines. Each subtype was categorized into three subcategories: "Pure" (those without an invasive component), "W/invasive" (those with an invasive component), and "All" (the entire group of the given subtype). ER and PR expression were registered as intervals. Equivocal HER2 immunohistochemistry (IHC) cases (2+) were further investigated using dual-color in situ hybridization. The majority of patients (71%) were over the age of 50. We discovered no significant differences in the proportion of age between the "Pure" and "W/invasive" groups. There was no significant difference in ER/PR expression between "Pure" luminal subtypes of DCIS and "W/invasive" cases. We compared the HER2 IHC scores of "0", "1+", and "2+" among LumA and LumB HER2 subtypes and identified no statistically significant differences between "Pure" and "W/invasive" (p = 0.603). ER and PR expression ≥ 50% cutoff value was present in > 90% of all LumA cases. The incidences of cases with ER expression at cutoff values of < 10% and ≥ 50% in LumA were significantly different compared to other luminal subtypes (p < 0.0001). The proportion of cases with PR expression < 20% showed significant differences in the various luminal subtypes. In luminal B subtypes, low PR expression (< 20%) was significantly associated with both strong HER2 expression (3+) and the presence of an invasive component (p = 0.0001 and p = 0.0365, respectively). ER and PR expression at ≥ 50% cutoff values were found in more than 90% of LumA cases. Samples with ER < 10% and ≥ 50% in LumA were significantly different compared to other luminal subtypes (p < 0.0001). Low PR expression in high-grade DCIS was strongly associated with HER2 overexpression (3+) and an invasive component (p = 0.0001 and p = 0.0365, respectively).

Abstract 2998: Regulation of epidermal growth factor receptor signaling by BRCA1-microRNA 146a network

Abstract Inherited defects in the breast cancer susceptibility gene, BRCA1 are associated with an increased risk for hereditary breast, ovarian, and other cancers. BRCA1-associated basal like breast cancers (BLBCs) are high-grade ductal carcinomas that do not express ER, PR or HER2, but frequently overexpress epidermal growth factor receptor (EGFR/ErbB1/HER1). The EGFR-driven signaling network plays a pivotal role in BLBC pathogenesis. EGFR overexpression is associated with tumor progression and metastasis, resistance to radiation and chemotherapy, and poor prognosis. Growth factor receptors are regulated by multiple miRNAs, each having many targets, coordinately controlling the complex pathways of downstream signaling. We have previously reported a post-transcriptional mechanism by which BRCA1 regulates EGFR expression through the induction of miR-146a and provided a rationale for the development of miR-146a based therapeutic strategies. In addition, we have shown that BRCA1 also exerts regulatory control over dozens of important miRNAs that appear to play a critical role in breast neoplasia. From TCGA analysis, we show that low expression of these miRNAs is associated with distinctively poor overall survival of TNBC patients. Using miR-146a loss or gain of function experiments in vitro, we show that BRCA1 and miR-146a regulate EGFR signaling, stemness, epithelial-to-mesenchymal transition (EMT), extracellular matrix (ECM) remodeling and chemoresistance. Using in vivo mouse models, we demonstrate that miR-146a overexpression delays tumor formation leading to better overall survival. BLBC unlike the other subtypes, lacks targeted therapy approaches making cytotoxic chemotherapy essentially the only option for treatment. Though EGFR inhibitors have been used to treat other cancers, clinical trials for breast cancer have so far been unsuccessful due to poor response rates. Since one miRNA can target multiple genes and regulate multiple signaling pathways, our study provides evidence to suggest that restoring miR-146a could suppress EGFR-RAS-MEK signaling and the other compensatory pathways, providing a targeted therapeutic option for BRCA1 associated BLBC. Citation Format: Easwari Kumaraswamy, Raeann M. Koren Shimak, Sumedha Gunewardena, Karen L. Wendt, Dani Alexander, Stacey L. Hembruff, Roy A. Jensen. Regulation of epidermal growth factor receptor signaling by BRCA1-microRNA 146a network [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2998.

Rare breast cancers with seemingly benign features on conventional imaging: Radio-pathological correlation and review of literature

Oval or rounded breast masses with circumscribed margins, absence of microcalcifications, and architectural distortions are usually benign. However, 10-20% of breast cancers may have circumscribed margins, which may be misdiagnosed as benign breast mass or lead to delayed diagnosis in advanced stages of cancer. Most frequently, circumscribed breast cancers are high-grade invasive ductal carcinoma of triple-negative molecular subtype. However, there are many other rare histological subtypes of cancers in the breast with circumscribed margins or less aggressive features on imaging and mimic benign breast lesions. A radiologist needs to be familiar with the imaging features of various atypical malignant breast tumors to avoid delay in diagnosis. These rare malignant breast tumors are mucinous carcinoma, papillary carcinoma, lymphoma, leukemia, myeloma, metastasis from extramammary primaries, adenoid cystic carcinoma, signet-ring carcinoma, malignant phyllodes tumor, mesenchymal sarcoma, Ewing’s sarcoma, and medullary carcinoma. This pictorial review illustrates the clinical, multimodality imaging features of rare malignant breast tumors with less aggressive features on conventional breast imaging with pathological correlation.

Brain Metastases from Breast Cancer Histologically Exhibit Solid Growth Pattern with at Least Focal Comedonecrosis: A Histopathologic Study on a Monocentric Series of 30 Cases.

Since there are no morphological clues capable of making a pathologist suspect a possible mammary origin of a metastatic lesion without adequate clinical information, the histologic diagnosis of brain metastasis from BC is still based on the immunohistochemical expression of mammary gland markers such as GATA-3, ERs, PgRs and HER-2. The present retrospective study aimed to select purely morphological features capable of suggesting the mammary origin of a metastatic carcinoma in the brain. The following histological features were collected from a series of 30 cases of brain metastases from breast cancer: (i) a solid growth pattern; (ii) the presence of comedonecrosis; and (iii) glandular differentiation. Our results showed that most cases histologically exhibited a solid growth pattern with at least focal comedonecrosis, producing an overall morphology closely reminiscent of mammary high-grade ductal carcinoma in situ. Although the above-mentioned morphological parameters are not strictly specific to a mammary origin, they may have an important diagnostic utility for leading pathologists to suspect a possible breast primary tumor and to include GATA-3, ERs, PgRs and HER-2 in the immunohistochemical panel.

Is it Time to Retire the Term of Low-Grade Ductal Carcinoma in Situ and Replace it with Ductal Neoplasia?

As the leading cause of cancer morbidity and the second leading cause of cancer mortality among women, breast cancer continues to remain a major global public health problem. Consequently, significant attention has been directed toward early breast cancer detection and prevention. As a result, the number of image-detected biopsies has increased, and minimally invasive diagnostic procedures have almost replaced open surgical biopsies. Therefore, pathologists are expected to provide more information with less tissue and diagnose increasing numbers of atypical proliferative breast lesions, in situ lesions, and small breast carcinomas. This is a difficult task, as reflected by continuous reports highlighting the challenges associated with morphologic distinction between atypical ductal hyperplasia and low-grade ductal carcinoma in situ. The current interobserver variability among pathologists to accurately define these 2 entities often leads to silent overdiagnosis and overtreatment. Up to now, there are no reproducible morphologic features and/or any reliable biomarkers that can accurately separate the above-mentioned entities. Despite these reports, patients diagnosed with low-grade ductal carcinoma in situ are subject to cancer therapy regardless of the fact that low-grade ductal carcinoma in situ is known to be an indolent lesion. Studies have shown that low and high-grade ductal carcinoma in situ are genetically different forms of breast cancer precursors; however, the term ductal carcinoma in situ is followed by cancer therapy regardless of the grade and biology of the tumor. In contrast, patients with the diagnoses of atypical ductal hyperplasia do not undergo cancer therapy. In the current article, attempts are made to highlight the continuous dilemma in distinction between atypical ductal hyperplasia and low-grade ductal carcinoma in situ. Going forward, we suggest that low-grade ductal carcinoma in situ be referred to as ductal neoplasia. This alternative terminology allows for different management and follow-up strategies by eliminating the word carcinoma.

Subtypes of high-grade breast ductal carcinoma in situ (DCIS): incidence and potential clinical impact

ObjectiveThe purpose of this study was to investigate and classify the molecular subtypes of high-grade ductal carcinoma in situ (DCIS) and identify possible high-risk subtypes. The heterogenicity of DCIS with variable clinical and histopathological presentations has been recognized. Nevertheless, only histopathological grading and diameter are currently implemented in clinical decision-making following the diagnosis of DCIS. The molecular subtypes of DCIS and their IHC surrogate markers have not been defined in conventional treatment guidelines and recommendations. We applied the definitions of molecular subtypes according to the IHC surrogate markers defined for IBC and subclassified high-grade DCIS, accordingly.MethodsHistopathological specimens were collected, revised, and regraded from 494 patients diagnosed with DCIS between 1996 and 2018. Other in situ and papillary lesions observed in breast biopsies were excluded from this study. 357 high-grade DCIS cases were submitted to IHC analysis. The markers investigated were ER, PR, HER2, and Ki67.Results45 cases were classified as grade 1, 19 as grade 2, and 430 as grade 3. Sixty patients with high-grade DCIS had an additional invasive component in the surgical specimen. Thirty-three patients were diagnosed with recurrent DCIS or invasive cancer (minimum one year after their primary DCIS diagnosis). The proportions of luminal A and luminal B HER2-negative subtypes varied depending on whether 2011 or 2013 St. Gallen Consensus Conference guidelines were adopted. Luminal A was the most prevalent subtype, according to both classifications. The luminal B HER2-positive subtype was found in 22.1% of cases, HER2-enriched subtype in 21.8%, and TPN subtype in 5.6%. There were strong indications that HER2-enriched subtype was significantly more frequent among DCIS with invasive component (p = 0.0169).ConclusionsHigh-grade DCIS exhibits all the molecular subtypes previously identified in IBC, but with a somewhat different distribution in our cohort. HER2-enriched subtype is substantially related to the presence of an invasive component in DCIS; consequently, it is regarded as a high-risk entity.

Novel computational biology modeling system can accurately forecast response to neoadjuvant therapy in early breast cancer

BackgroundGeneralizable population-based studies are unable to account for individual tumor heterogeneity that contributes to variability in a patient’s response to physician-chosen therapy. Although molecular characterization of tumors has advanced precision medicine, in early-stage and locally advanced breast cancer patients, predicting a patient’s response to neoadjuvant therapy (NAT) remains a gap in current clinical practice. Here, we perform a study in an independent cohort of early-stage and locally advanced breast cancer patients to forecast tumor response to NAT and assess the stability of a previously validated biophysical simulation platform.MethodsA single-blinded study was performed using a retrospective database from a single institution (9/2014–12/2020). Patients included: ≥ 18 years with breast cancer who completed NAT, with pre-treatment dynamic contrast enhanced magnetic resonance imaging. Demographics, chemotherapy, baseline (pre-treatment) MRI and pathologic data were input into the TumorScope Predict (TS) biophysical simulation platform to generate predictions. Primary outcomes included predictions of pathological complete response (pCR) versus residual disease (RD) and final volume for each tumor. For validation, post-NAT predicted pCR and tumor volumes were compared to actual pathological assessment and MRI-assessed volumes. Predicted pCR was pre-defined as residual tumor volume ≤ 0.01 cm3 (≥ 99.9% reduction).ResultsThe cohort consisted of eighty patients; 36 Caucasian and 40 African American. Most tumors were high-grade (54.4% grade 3) invasive ductal carcinomas (90.0%). Receptor subtypes included hormone receptor positive (HR+)/human epidermal growth factor receptor 2 positive (HER2+, 30%), HR+/HER2− (35%), HR−/HER2+ (12.5%) and triple negative breast cancer (TNBC, 22.5%). Simulated tumor volume was significantly correlated with post-treatment radiographic MRI calculated volumes (r = 0.53, p = 1.3 × 10–7, mean absolute error of 6.57%). TS prediction of pCR compared favorably to pathological assessment (pCR: TS n = 28; Path n = 27; RD: TS n = 52; Path n = 53), for an overall accuracy of 91.2% (95% CI: 82.8% – 96.4%; Clopper–Pearson interval). Five-year risk of recurrence demonstrated similar prognostic performance between TS predictions (Hazard ratio (HR): − 1.99; 95% CI [− 3.96, − 0.02]; p = 0.043) and clinically assessed pCR (HR: − 1.76; 95% CI [− 3.75, 0.23]; p = 0.054).ConclusionWe demonstrated TS ability to simulate and model tumor in vivo conditions in silico and forecast volume response to NAT across breast tumor subtypes.

An Outstanding Rapid Clinical Response to Olaparib in A Patient with gBRCA2m Fungating Breast Cancer: A Case Report

Background: Breast cancer is a heterogeneous, phenotypically complex disease made up of various biologic subgroups with unique behaviors and therapeutic responses. Noted that despite lack of a cure for metastatic breast cancer (MBC), there have been appreciable advancements in survival that have occurred at the same time as newer systemic treatments. BRCA1 or BRCA2 mutations cause homologous recombination deficient (HRD) cells, which are vulnerable to PARPi agent treatment. Case Report: This case report presents a 40 years old single female, known case of multiple co-morbidities who was diagnosed with Bilateral breast cancer in June 2022. She has a Positive family history of malignancy; mother died from endometrial cancer and aunt from paternal side has breast cancer. She underwent needle core biopsy from her Right breast mass, which revealed Invasive high-grade ductal carcinoma with metaplastic features (foci of keratinizing squamous differentiation, and myxoid stromal change). DCIS, of intermediate and high grades and a solid pattern, was noted, focally suspicious for lymphovascular invasion, Triple negative (ER negative (&lt;1%), PR negative (&lt;1%) and her-2 (+2) FISH negative (Her-2 Low), KI 67= 70%. Left breast mass Biopsy done on 12/9/2022 showed Invasive Lobular carcinoma, grade 3, ER negative, PR negative, Her-2 +1, KI 67=70%, BRCA2 POSITIVE &amp; PDL1 CPS score 10%. Staging positron emission tomography scan done on 10 October 2022. She had a Large hypermetabolic fungating right breast mass infiltrating the chest wall, consistent with biopsy-proven malignancy. Additional smaller FDG-avid lesions noted in the right breast. Moreover, she had FDG-avid right axillary and right internal mammary nodal metastases. Mildly FDG-avid left breast mass, consistent with biopsy-proven malignancy. FDG-avid liver and pleural metastases. She was started on PARP inhibitor (Olaparib) on 20/9/2022 after which she had amazing fast clinical response leading to falling off the large fungating mass. Conclusion: The chance of developing breast and ovarian cancer is extremely elevated if one possesses BRAC 1 or BRCA 2 mutation. In this situation, PARP inhibitors, mutation-targeted therapy, has better outcomes in reducing the morbidity and mortality associated with metastatic breast cancer (Olaparib).

High-Grade Ductal Carcinoma In Situ of the Breast With Regressive Changes: Radiological and Clinicopathological Findings.

Tumour regression is defined as continuity of changes leading to the elimination of a neoplastic population and is reflected as periductal fibrosis and intraductal tumour attenuation. The aim of this study was to describe the radiological and clinicopathological characteristics of high-grade breast ductal carcinoma in situ (DCIS) with regressive changes (RC). Thirty-two cases of high-grade DCIS with RC on biopsy specimens followed by excision were included. The mammographic, ultrasonographic (US), and magnetic resonance imaging (MRI) findings of cases were retrospectively reviewed according to the breast imaging reporting and data system (BI-RADS) lexicon. Clinical and histopathological findings [comedonecrosis, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) status and Ki-67 proliferation index] were recorded. The rate of upgrade to invasive cancer after surgical excision and lymph node involvement were evaluated. The most common mammographic finding was microcalcifications alone (68.8%). The most frequently seen findings on US were microcalcifications only (21.9%), followed by microcalcifications and hypoechoic area (18.7%). On MRI, most lesions presented as clumped non-mass enhancement with segmental distribution. ER/PR negativity (53.1%, 65.6%), HER2 positivity (56.3%) and high Ki-67 (62.5%), which are known to be associated with more aggressive behavior, were found to be proportionally higher. The rate of upgrade to invasive cancer was 21.8%. DCIS with RC lesions present most often as microcalcifications alone on both mammography and US. MRI features are not distinguishable from those of other DCIS lesions. DCIS with RC lesions show biomarker status reflecting more aggressive behavior and high upgrade rate to invasive cancer.

Amorphous breast calcifications: is BI-RADS 4a appropriate?

To evaluate the positive predictive value (PPV) of amorphous calcifications and to analyze the imaging variables that could alter the risk of malignancy associated with this finding. This was a retrospective study of 138 stereotactically guided percutaneous vacuum-assisted biopsies of amorphous calcifications, performed between January 2012 and December 2017. All of the patients included were referred for radiological follow-up for a minimum of one year (if the histopathology showed a benign lesion) or for surgical treatment (if the histopathology showed malignancy or a lesion of uncertain malignant potential). We found that the PPV of amorphous calcifications was 9.42%. However, most of the malignant amorphous calcifications were in cases of invasive carcinoma or high-grade ductal carcinoma in situ, indicating clinically relevant disease. The relative risk of malignancy associated with amorphous calcifications was 6.15 times higher in patients with a family or personal history of breast or ovarian cancer. Neither being postmenopausal nor having dense breasts was found to be predictive of malignancy in patients with amorphous calcifications. Amorphous calcifications in the breast had a PPV for malignancy of 9.42%, indicating the possibility of placing the finding in subcategory 4a, which requires histopathological analysis. Our finding that the risk of malignancy associated with this subtype of calcifications is up to 6.15 times higher in patients with a family or personal history of breast cancer warrants greater concern regarding the clinical, radiologic, and histopathologic correlations after biopsy.

Updates of Prostate Cancer from the 2022 World Health Organization Classification of the Urinary and Male Genital Tumors.

Prostate cancer is a heterogeneous disease with a wide spectrum of pathological, clinical, and molecular features. The diagnosis and classification of prostate cancer have been constantly modified with the incorporation of new data. The 5th edition of the World Health Organization (WHO) Classification of Urinary and Genital Tumors was recently published six years after the 4th edition. In this new edition, the classification of prostate cancer has been refined in the diagnostic criteria, grading, nomenclature, and genomics. This paper reviews significant updates to the new WHO classification of prostate cancer, including high-grade prostatic intraepithelial neoplasia, acinar adenocarcinoma, intraductal carcinoma, ductal carcinoma, and neuroendocrine tumors. Controversial issues in the Gleason grading are discussed, such as intraductal carcinoma and tertiary grade. We also highlight distinct genetic and epigenetic alterations in prostate cancer that may contribute to its diverse clinicopathologic features. Overall, the 5th edition of the WHO classification provides a comprehensive assessment of prostate cancer with morphologic, immunohistochemical, genomic, and clinical data, which may represent an optimal paradigm for diagnosing and treating prostate cancer.

Polarization clustering of biological structures with Mueller matrix parameters.

Mueller matrix imaging polarimetry (MMIP) is a promising technique for the characterization of biological tissues, including the classification of microstructures in pathological diagnosis. To expand the parameter space of Mueller matrix parameters, we propose new vector parameters (VPs) according to the Mueller matrix polar decomposition method. We measure invasive bladder cancer (IBC) with extensive necrosis and high-grade ductal carcinoma in situ (DCIS) with MMIP, and the regions of cancer cells and fibrotic stroma are classified with the VPs. Then the proposed and existing VPs are mapped on the Poincaré sphere with 3D visualization, and an indicator of spatial feature is defined based on the minimum enclosing sphere to evaluate the classification capability of the VPs. For both IBC and DCIS, the results show that the proposed VPs exhibit evident contrast between the regions of cancer cells and fibrotic stroma. This study broadens the fundamental Mueller matrix parameters and helps to improve the characterization ability of the MMIP technique.

ODP527 To Treat or Not to Treat Pembrolizumab-Induced Thyroiditis: Using Common Terminology Criteria for Adverse Events as a Decision-Making Aid

Abstract Introduction Programmed cell death-1 (PD-1) checkpoint inhibitors are immunotherapeutic agents that are used to treat advanced malignancies including breast cancer. The adverse effects of these medications include thyroid and pituitary dysfunction and may be treated with glucocorticoids, which may cause steroid-induced effects such as hyperglycemia, osteoporosis, and adrenal suppression. The Common Terminology Criteria for Adverse Events (CTCAE) widely used by oncologists for management can support treatment decisions by endocrinologists in patients undergoing treatment with PD-1 checkpoint inhibitors. Case Description A 42-year-old female with stage IIIc high-grade triple negative left breast invasive ductal carcinoma was started on pembrolizumab immunotherapy (PD-1 inhibitor). Prior to starting treatment, the patient's thyroid function tests were normal: free T4 0.93 ng/dL (normal range [NR] 0.89-1.76 ng/dL) and thyroid-stimulating hormone (TSH) 1.42 uIU/mL (NR 0.55-4.78 uIU/mL). Two weeks later, she developed heat intolerance, diarrhea, weight loss, and dysphagia. At that time, thyroid tests were consistent with thyrotoxicosis with elevated total T3 644.6 ng/dL (NR 60-180 ng/dL) and totalT4 &amp;gt;12. 00 ng/dL with suppressed TSH 0. 01 uIU/mL. Despite negative TSH receptor antibody and thyroid-stimulating immunoglobulin, CT scan of the neck showed diffuse enlargement of the thyroid gland and thickening of the extraocular muscles. On physical examination she had mild exophthalmos. The etiology of thyrotoxicosis was initially thought to be Graves’ disease, but thyroiditis could not be ruled out. Treatment with methimazole and beta blockers was initiated. Three weeks after methimazole was started, her symptoms improved significantly, with repeat thyroid function tests: TSH 3.64 uIU/mL and free T4 1.29 ng/dL. Methimazole was held. Four weeks later, the second dose of pembrolizumab was administered. Later that day, repeat thyroid function tests showed high TSH 53.12 uIU/ml, and low T4 0.55 ng/dL with negative thyroid-stimulating immunoglobulin and thyroid peroxidase antibodies, consistent with thyroiditis. Endocrinology and Oncology teams discussed the CTCAE determining that the severity of thyroiditis was grade 2 (moderate symptoms, able to perform activities of daily living, TSH persistently above 10 uIU/L). Pembrolizumab was continued and hypothyroidism was treated with levothyroxine. Discussion CTCAE is used by oncologists to aid in treatment decisions in patients treated with PD-1 inhibitors. Endocrinologists should consider using the CTCAE grading (severity) scale for each adverse event. Adoption and utilization of the CTACE severity scale by endocrinologists may lead to a more standardized and systematic approach for treatment of thyroid disorders associated with PD-1 inhibitor immunotherapy Presentation: No date and time listed

Salivary duct carcinoma- Role of accurate diagnosis for an accurate therapy

Salivary duct carcinoma is an aggressive subtype of primary salivary gland carcinoma with advanced stage at presentation, high rates of metastasis and recurrence. It is most commonly seen in parotid gland of older men with microscopic resemblance to high-grade breast ductal carcinoma. Salivary duct carcinoma mainly affects men over 50 years of age and accounts for 5% to 10% of all salivary gland malignancies. Characteristic histomorphology and immunohistochemical expression of Androgen Receptor (AR) aids the diagnosis of salivary duct carcinoma. Fine-needle aspiration typically reveals cytologic features of high-grade carcinoma. Heterologous alterations have been recognized in oncogenes and tumor suppressor genes such as TP53, HRAS, PIK3CA, PTEN, and BRAF as well as AR and HER2. Targeted therapy against these genes may help in broadening treatment options for salivary duct carcinoma. Salivary Duct Carcinoma is one of the most aggressive salivary malignancies with 33% local recurrence and 45% metastasis. We report a case of a 75 years old female patient, who presented with a swelling obliterating the retromandibular groove. FNAC &amp; histopathology confirmed the diagnosis of salivary duct carcinoma.&#x0D;

AB156. SOH22ABS143. High-grade ductal carcinoma in situ (DCIS) arising within fibroadenoma in a teenager: a rare case report and review of the literature

AB156. SOH22ABS143. High-grade ductal carcinoma in situ (DCIS) arising within fibroadenoma in a teenager: a rare case report and review of the literature

Abstract P3-09-02: Mutational assessment of newly diagnosed breast cancer using Germline and tumor genomICs

Abstract Background :For patients with newly diagnosed breast cancer, real-time identification of pathogenic germline mutations in hereditary breast cancer (HBC) genes can provide important information to inform decisions regarding surgery, medical oncology, radiation oncology and to enable activate risk mitigation strategies for unaffected relatives. The potential to dramatically improve outcomes by identifying HBC gene mutation carriers at diagnosis has been demonstrated in the OlympiA. The current strategy of offering germline testing based on NCCN guidelines or validated scores inherently fails to identify all patients with germline HBC gene mutations with adverse consequences for patients and their families. Also, in about 15% of patients without HBC gene mutations, the breast tumors have characteristics suggestive of a more aggressive course. Although universal HBC gene testing has been reported for sub-types of breast cancer or at specialist centers, the MAGIC study is the first prospective trial of unselected invasive breast cancers in general practice combining upfront germline and somatic sequencing with well-validated methods to assess the acceptability of universal testing to patients and clinicians. Methods :This is an Australian multi-center prospective study with 150 consecutive consented patients who are newly diagnosed with nonmetastatic breast cancers. High-grade ductal carcinoma in-situ and pleomorphic lobular cancers were included. Germline testing was performed by whole genome sequencing on DNA from blood or saliva and the data analyzed for actionable HBC gene mutations, including large genomic rearrangements. Whole genome Tumor sequencing was performed on DNA extracted from formalin fixed paraffin-embedded diagnostic tumor and the data analyzed for actionable somatic mutations as well as scoring for homologous recombination deficiency using HRDetect and mutational signatures. The frequency of actionable HBC gene mutations and the number of additional carriers identified compared to standard referral guidelines was the primary objective. For additional analysis, a 3-generation pedigree was done and NCCN, MANCHESTER, and BOADICEA scores were calculated to see whether they would qualify for germline testing according to American and Australian guidelines. Well validated questionnaires were given pre and post-testing for all patients to assess the favorability of universal testing. Health economic analysis will be performed to see the cost vs benefit of offering germline testing. Results :A total of 12 carriers of actionable germline mutations were identified (8.0%) in BRCA1 (n=2), BRCA2 (n=1), PALB2 (n=3), CHEK2 (n=2), ATM (n=2) and PMS2 (n=2). No actionable HBC germline mutations were identified in the 14 cases diagnosed with DCIS only. Only 3 of the 12 mutation positive cases (25%) were referred by the treating clinician for germline testing and including BOADICEA and MANCHESTER scores, would only have identified 6 cases (50%) eligible for germline testing. 9/12 (75%) cases were ER positive including 4 carriers of BRCA1, BRCA2 or PALB2 mutations. Preliminary ascertainment of patient acceptance demonstrates &amp;gt;90% were in favor of universal testing. Among the 12 HBOC gene mutation carriers, the study changed the surgical recommendation for 7 patients (58%) which included the recommendation of B/L salpingo-oophorectomy and radiation management for 3 (25%) patients. Conclusion :Universal germline HBC gene testing is the best method for detecting carriers as over 50% are missed using current. Identifying an actionable mutation in real-time can inform the decision in all specialties involved in the treatment and has a high rate of impacting the clinical decision-making process. This approach was favored by the patients and the clinicians and provided a pathway forward for breast cancer management. Citation Format: Dilanka L De Silva, Anita R Skandarajah, Michelle Sinclair, Maira Kentwell, Lisa Devereux, Magnus Zeethoven, Kirsten Hogg, Luxi Lal, Lesley Stafford, Paul A James, Geoffrey J Lindeman, Gregory B Mann, Ian G Campbell. Mutational assessment of newly diagnosed breast cancer using Germline and tumor genomICs [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-09-02.

Preneoplastic Low-Risk Mammary Ductal Lesions (Atypical Ductal Hyperplasia and Ductal Carcinoma In Situ Spectrum): Current Status and Future Directions.

Simple SummaryOvertreatment which means providing a patient with unnecessary medical intervention has recently become the center of attention in breast diseases. One of these lesions is low-risk ductal carcinoma in situ (DCIS), for which the standard of treatment is wide local excision/mastectomy, with or without radiation therapy, with or without hormonal therapy. There are many worldwide ongoing clinical trials aiming to de-escalate this therapy by examining whether active surveillance (AS) is sufficient. These trials vary in pathology inclusion and exclusion criteria. There is lack of consensus on the definition of low-risk DCIS, in particular the overlap with atypical ductal hyperplasia (ADH), DCIS grading, and lack of definition of comedonecrosis. This review discusses AS trial from pathology standpoint and provides few recommendations.Intraepithelial mammary ductal neoplasia is a spectrum of disease that varies from atypical ductal hyperplasia (ADH), low-grade (LG), intermediate-grade (IG), to high-grade (HG) ductal carcinoma in situ (DCIS). While ADH has the lowest prognostic significance, HG-DCIS carries the highest risk. Due to widely used screening mammography, the number of intraepithelial mammary ductal neoplastic lesions has increased. The consequence of this practice is the increase in the number of patients who are overdiagnosed and, therefore, overtreated. The active surveillance (AS) trials are initiated to separate lesions that require active treatment from those that can be safely monitored and only be treated when they develop a change in the clinical/radiologic characteristics. At the same time, the natural history of these lesions can be evaluated. This review aims to evaluate ADH/DCIS as a spectrum of intraductal neoplastic disease (risk and histomorphology); examine the controversies of distinguishing ADH vs. DCIS and the grading of DCIS; review the upgrading for both ADH and DCIS with emphasis on the variation of methods of detection and the definitions of upgrading; and evaluate the impact of all these variables on the AS trials.

Immunohistochemistry Applied to Breast Cytological Material.

Fine-needle aspiration biopsies (FNABs) of the breast are minimally invasive procedures enabling the diagnosis of suspicious breast lesions. Unfortunately, they are often perceived as inferior to core-needle biopsies, namely because they are supposedly unable to differentiate between high-grade ductal carcinoma in situ and invasive carcinoma or provide material for ancillary testing. Several studies have shown, however, that FNAB samples, when handled properly, are indeed capable of providing sufficient and adequate material for ancillary testing, namely immunocytochemistry (ICC). We reviewed the published literature regarding the use of ICC for both diagnostic and theranostic uses in the different types of cytological samples obtained from FNABs of the breast, including smears, liquid-based cytology samples, and cellblocks. We found that p63 and 34βE12 show promise in aiding in the differential diagnosis between in situ and invasive lesions and that most other diagnostic markers may be used as in tissue. Regarding theranostic ICC markers, results vary between publications, but with care, these can successfully be performed in cytological samples. Air-dried smears should be avoided, and cellblocks are overall more versatile than cytology slides, enabling the evaluation of not only hormonal receptors and HER2 by ICC, but also of Ki-67. Particular attention should be paid to fixation and antigen retrieval procedures in all cases. We recommend that laboratories without experience perform short validation runs before adopting these techniques into clinical practice.