High Nuclear Grade Research Articles

PATH-67. THE ROLE OF STATUS OF HER-2, ESTROGEN-RECEPTOR, BRCA 1, AND BRCA 2, IN THE INCIDENCE OF BRAIN METASTASIS IN BREAST CANCER

Abstract Breast cancer (BC) is the most diagnosed tumor in women and the second-leading cause of brain metastasis (BM), with a prevalence ranging from 10-36%. According to the Epidemiological Strategy and Medical Economics research program, advanced BC patients face an estimated 25% risk of developing BM within 2-3 years after the initial diagnosis. The frequency of BM is significantly increased by the primary tumor profile, including larger tumors, higher nuclear grade, HER-2 positivity, estrogen-receptor negativity, and triple-negative status. A gap remains in the classification of the BM site relative to primary tumor biomarkers, and the absence of multimodality treatment methodologies poses challenges to survival rates and quality of life in BC patients. This retrospective cross-sectional study at Aga Khan University Hospital identified 52 cases of brain metastasis secondary to breast cancer over a 10-year period. The median age of patients was 55 years, ranging from 32 to 78 years. Primary breast tumors were predominantly high-grade ductal carcinomas (65%), followed by lobular carcinomas (25%) and other rare histological types (10%). Secondary brain metastases were primarily located in the cerebrum (60%), cerebellum (25%), and brainstem (15%). Tumor profiles indicated a significant correlation between HER-2 positivity and the development of brain metastasis, with 70% of HER-2 positive patients presenting with extensive brain metastasis. Tumor progression varied, with a median time to brain metastasis of 2.5 years from the initial breast cancer diagnosis. Despite aggressive multimodality treatments, including surgery, radiation, and chemotherapy, the overall prognosis remained poor. The study found that early detection of HER-2 positive and triple-negative tumors could potentially delay the progression of brain metastasis through targeted therapies. Mortality rates in this cohort were high, with a median survival of 8 months following the diagnosis of brain metastasis. These findings underscore the need for improved diagnostic, preventive, and therapeutic strategies to manage brain metastasis in breast cancer patients.

Role of Ultrasonographic and Clinicopathological Characteristics in Assessing Stromal Tumor-Infiltrating Lymphocyte Density in Triple-Negative Breast Cancer

A high density of stromal tumor-infiltrating lymphocytes (sTILs) is positively correlated with the pathological complete response rate and favorable survival in patients with triple-negative breast cancer (TNBC). Heterogeneity in stromal lymphocyte distribution and limited tumor sampling may affect the accuracy of sTIL quantification in biopsy samples from patients receiving neoadjuvant therapy. Thus, identifying additional biomarkers to complement sTIL evaluation is essential. To identify biomarkers that could be used to complement sTILs evaluation. Retrospective cohort study. A total of 162 patients with invasive TNBC were enrolled in the study. The following data were gathered: sTIL density, Ki67, nuclear grades of cancer cells, lymphovascular invasion status, the American Joint Committee on Cancer stage, axillary lymph node metastasis status, and ultrasonographic parameters of the tumor (size, shape, orientation, margin, internal echo pattern, posterior feature, and vascularity). The relationship between sTIL density and ultrasonographic or clinicopathological characteristics was investigated using both continuous and categorical analyses. Posterior features of the primary tumors was associated with sTIL density (p = 0.038). Additionally, the Ki67 levels and nuclear grades were also associated with sTIL density (p < 0.001 and p = 0.024, respectively). When stratified according to a 20% cut-off of sTIL density, the posterior features of primary tumors, Ki67 levels, and nuclear grades significantly differed between the high and low sTIL density tumors. Tumors with high Ki67 levels were more likely to exhibit high sTIL density than low sTIL density [odds ratio (OR): 2.75, p = 0.021]. Furthermore, nuclear grade III tumors demonstrated significantly higher sTIL density than nuclear grade I-II tumors (OR: 2.49, p = 0.014). Additionally, tumors with posterior enhancement or no posterior features were more likely to exhibit high sTIL density than tumors with acoustic shadows (OR: 2.91, p = 0.028; OR: 2.74, p = 0.022, respectively). Low sTIL density is frequently observed in tumors exhibiting acoustic shadows on ultrasound. However, high sTIL density is more common in tumors with posterior enhancement or no posterior features. Furthermore, high Ki67 levels (> 40%) and high nuclear grades are positively correlated with high sTIL density. This study findings highlight the need for closer surveillance of these biomarkers to complement sTIL evaluation in TNBC.

Examination of Vitreolenticular Interface in Relation to Different Phacoemulsification Parameters in Early and Late Postoperative Period.

Background: The surgical parameters of phacoemulsification can significantly impact the behavior of the anterior hyaloid membrane (AHM). Methods: In this prospective study, anterior segment optical coherence tomography was used to examine the attachment or detachment of the AHM of 82 eyes after uneventful phacoemulsification preoperatively and postoperatively over 1 year. The impacts of the capsulorhexis' size, number of hydrodissections, nuclear sclerosis grade, cumulative dissipated energy (CDE), ultrasonic time, total surgical time, weakness of zonular fibers, presence of lens materials in Berger's space (LM-BS), and fluid usage were investigated in relation to the behavior of the AHM. Results: A significant linear trend regarding anterior vitreous detachment (AVD) was observed in the presence of zonular weakness and high CDE at all postoperative times (p ≤ 0.024 and p ≤ 0.005, respectively). Similarly, AVD was observed at 1-month, 3-month, and 1-year follow-ups in cases of high nuclear sclerosis grades (p ≤ 0.044) and high fluid usage (p ≤ 0.021). A significant correlation was observed in the group of LM-BS as the zonular weakness value increased (OR: 0.085; 95% CI: 0.017 to 0.420; p = 0.002), and the fluid usage was also significantly higher (OR: 1.049; 95% CI: 1.003-1.096; p = 0.037). Conclusions: Zonular weakness, high CDE, a hard nucleus, and high fluid usage are risk factors for postoperative AVD.

Early-Stage Colon Cancer Surveillance: Pattern and Timing of Recurrence and the Role of 5-Year Surveillance

Introduction: Colorectal cancer is the third most prevalent cancer among both men and women with 80% of patients having localized disease enabling curative treatments. Given the low recurrence rate in early-stage disease, there is a growing interest in reviewing follow-up protocols. The aim of this study was to assess the frequency and timing of recurrence in early-stage colon cancer, as well as recurrence patterns. Methods: The data from all patients with colon adenocarcinoma consecutively treated with surgery at the Instituto Português de Oncologia do Porto, EPE, between January 2013 and December 2016, were retrospectively reviewed. Results: A total of 1,372 patients with colon cancer were submitted to surgery during the study period. From this group, 51.4% (n = 705) were early-stage colon cancers. Regarding the pathological stage, 3.5% were stage 0, 37.4% were stage I and 59.1% were stage II. The overall recurrence rate was 6.7%. When considering the group of patients without risk factors, the recurrence rate was 5.6%. The majority of recurrences occurred in the first 3 years of follow-up. The recurrence was diagnosed in the majority of patients through carcinoembryonic antigen elevation, followed by imaging exams. The presence of one or more risk factors (high nuclear grade, vascular invasion, extramural venous invasion, and perineural invasion) showed a statistically significant association with recurrence rate. Conclusion: The recurrence rate was low in early-stage colon cancer, with the majority of recurrences occurring in the first 3 years. Our study results show that surveillance should be tailored according to individual risk factors.

Is it time to de-escalate axillary surgery in patients with ductal carcinoma in-situ undergoing mastectomy?

IntroductionAxillary surgery has been de-escalated in invasive breast carcinoma and may be omitted in certain age groups. Up to 10–20 % of patients with ductal carcinoma in-situ (DCIS) will have an element of invasion. Therefore, SLNB is indicated to rule out nodal metastasis. Our purpose was to identify the rate and possible risk factors for lymph node metastasis in DCIS, and to measure oncological outcome of positive SLNB in this group. MethodsA retrospective analysis was performed on 113 female patients with DCIS, who underwent mastectomy and SLNB. Their clinical and radiological features, as well as pre and post-operative histopathological characteristics were evaluated and data was reported over an average follow up period of 48 months. ResultDCIS was upgraded to invasive cancer in 11 patients out of 113 (9.7 %). Five patients had positive SLNB (4.4 %), one micro-metastasis (0.8 %) and four macro-metastasis (3.5 %) All the five underwent axillary lymph node dissection (ALND) and all additional nodes retrieved were negative. High nuclear grade, Her2 neu overexpression, and palpable mass showed higher odds of association with metastasis to sentinel nodes. However, due to the low event rate, the association did not reach statistical significance. Seven patients (6.2 %) developed lymphedema, 4 of which after SLNB only. No regional recurrence was reported among our study sample. ConclusionThis study confirms the very low rate of positive SLNB in patients with DCIS. It is time to de-escalate axillary surgery for patients with DCIS undergoing mastectomy and consider delayed SLNB for high risk group of patients.

The Comparison of Newly Diagnosed Invasive Breast Patient Cohorts in Genomics Evidence Neoplasia Information Exchange Biopharma Collaborative (GENIE-BPC) and Other Real-World Databases.

Oncology databases that integrate genomic and clinical data have become valuable resources for precision medicine. However, the generalizability of these databases has not been comprehensively assessed. To describe the demographics, clinical characteristics, treatments, and overall survival of breast cancer cohorts in GENIE-BPC and three other databases. This study utilized GENIE-BPC, SEER, SEER-Medicare, and Merative MarketScan Research Databases. Women with invasive breast cancer were identified through EHR, cancer registries or ICD-9/10-CM codes. The ages were 18+ years or per database requirement. Treatments were based on EHR or HCPCS/NDC codes in claims. Overall survival was estimated as time from diagnosis to death. Of female breast cancer patients in GENIE-BPC (n = 775), SEER (n = 548 336), SEER-Medicare (n = 68 914), and Marketscan (n = 109 499) databases, the median ages at initial diagnosis were 44, 62, 74, and 57 years, respectively. A greater proportion of patients in GENIE-BPC, compared to SEER/SEER-Medicare, had higher nuclear grades (%III-%IV: 57% vs. 26%/24%), advanced disease stage (%IV: 25.3% vs. 5%/3.6%), percent of triple negative breast cancer (19.7% vs. 10.2%/8.5%), and receipt of chemotherapy (85.0% vs. NA/22.3%). The 1-, 3-, and 5-year overall survival rates were lower in GENIE-BPC (78.5%, 60.5%, 55.5%) than in SEER (95.8%, 89.5%, 85.5%) and SEER-Medicare (91.6%, 81.4%, 75.0%). Breast cancer patients in GENIE-BPC were younger, had more advanced disease, had a higher proportion of triple negative breast cancer and recipients of chemotherapy, and had poorer overall survival. Researchers must use statistical adjustment when extrapolating results (e.g., biomarker prevalence) from GENIE-BPC to the larger breast cancer population.

Volumetric imaging of the tumor microvasculature reflects outcomes and genomic states of clear cell renal cell carcinoma.

Tumor structure is heterogeneous and complex, and it is difficult to obtain complete characteristics by two-dimensional analysis. The aim of this study was to visualize and characterize volumetric vascular information of clear cell renal cell carcinoma (ccRCC) tumors using whole tissue phenotyping and three-dimensional light-sheet microscopy. Here, we used the diagnosing immunolabeled paraffin-embedded cleared organs pipeline for tissue clearing, immunolabeling, and three-dimensional imaging. The spatial distributions of CD34, which targets blood vessels, and LYVE-1, which targets lymphatic vessels, were examined by calculating three-dimensional density, vessel length, vessel radius, and density curves, such as skewness, kurtosis, and variance of the expression. We then examined those associations with ccRCC outcomes and genetic alteration state. Formalin-fixed paraffin-embedded tumor samples from 46 ccRCC patients were included in the study. Receiver operating characteristic curve analyses revealed the associations between blood vessel and lymphatic vessel distributions and pathological factors such as a high nuclear grade, large tumor size, and the presence of venous invasion. Furthermore, three-dimensional imaging parameters stratified ccRCC patients regarding survival outcomes. An analysis of genomic alterations based on volumetric vascular information parameters revealed that PI3K-mTOR pathway mutations related to the blood vessel radius were significantly different. Collectively, we have shown that the spatial elucidation of volumetric vasculature information could be prognostic and may serve as a new biomarker for genomic alterations. High-end tissue clearing techniques and volumetric immunohistochemistry enable three-dimensional analysis of tumors, leading to a better understanding of the microvascular structure in the tumor space.

Evaluation of biomarkers of response in patients with breast cancer with BRCA 1/2 pathogenic variants treated with PARP inhibitors.

e15188 Background: Several prospective studies highlight the pivotal role of PARP inhibitors (PARPi) in treating BRCA-associated breast cancers (BC), demonstrating a significant overall response rate (ORR) of up to 60% in advanced BC patients with BRCA 1/2 germline pathogenic variants (PV). Despite their clinical efficacy, the factors predicting PARPi response, the mechanisms of resistance to PARPi, and the clinical strategies to overcome these challenges are still unknown. The aim of this study is to establish tissue microarrays (TMA) from primary breast tumor tissue from BC patients with BRCA1/2 PVs who were treated with PARPi and identify biomarkers of PARPi resistance. Methods: Stage 4 BC patients with BRCA 1/2 PVs who presented to the University of Texas MD Anderson Cancer Center Breast Medical Oncology clinics and were treated with PARPi between 2008-2023 were identified using our database. Available patient tissue samples were obtained from institutional tumor banks. TMA from breast tumor tissue created and evaluated by our collabrating pathologists for expression of biomarkers:Wee-1, MRE, BP1,and c-Myc. Clinical and tumor characteristics analyzed included:Age at diagnosis, treatment details, tumor characteristics including histological type, hormonal receptor status, Her-2/Neu status, grade, Ki-67 and clinical outcome. Descriptive statistics, the Fisher exact test, and the log rank test were used to report patient characteristics and outcomes. Here we report on initial TMA construct and biomarker analysis. Results: So far TMA from 12 patients treated with PARPi were succesfully constructed. Patient characteristics include: Median age of 36.5 years (29-57). Nine (75%) and 3 (25%) patients had BRCA1 and BRCA2 mutations, respectively. All patients had invasive ductal carcinoma and 9 (75%) had triple negative BC. Most patient (75%) had high nuclear grade BC and median Ki-67 was 75 (15-90). In 11 evaluable patients, the ORR was 72.7%. The median OS was 383.6 months (95% CI 62.5-383.6) and median PFS was 31.5 months (95% CI 10.8-NE). No significant difference in biomarker expression was observed between PARPi-responders and non-responders (Table1). Conclusions: This report presents unique data on novel predictive biomarkers of response and evaluates the evidence for potential biomarkers. Further analysis on a larger TMA cohort is ongoing. [Table: see text]

Multiphase comparative study for WHO/ISUP nuclear grading diagnostic model based on enhanced CT images of clear cell renal cell carcinoma

To compare and analyze the diagnostic value of different enhancement stages in distinguishing low and high nuclear grade clear cell renal cell carcinoma (ccRCC) based on enhanced computed tomography (CT) images by building machine learning classifiers. A total of 51 patients (Dateset1, including 41 low-grade and 10 high-grade) and 27 patients (Independent Dateset2, including 16 low-grade and 11 high-grade) with pathologically proven ccRCC were enrolled in this retrospective study. Radiomic features were extracted from the corticomedullary phase (CMP), nephrographic phase (NP), and excretory phase (EP) CT images, and selected using the recursive feature elimination cross-validation (RFECV) algorithm, the group differences were assessed using T-test and Mann–Whitney U test for continuous variables. The support vector machine (SVM), random forest (RF), XGBoost (XGB), VGG11, ResNet18, and GoogLeNet classifiers are established to distinguish low-grade and high-grade ccRCC. The classifiers based on CT images of NP (Dateset1, RF: AUC = 0.82 ± 0.05, ResNet18: AUC = 0.81 ± 0.02; Dateset2, XGB: AUC = 0.95 ± 0.02, ResNet18: AUC = 0.87 ± 0.07) obtained the best performance and robustness in distinguishing low-grade and high-grade ccRCC, while the EP-based classifier performance in poorer results. The CT images of enhanced phase NP had the best performance in diagnosing low and high nuclear grade ccRCC. Firstorder_Kurtosis and firstorder_90Percentile feature play a vital role in the classification task.

Abstract PO3-20-08: Case Studies on Detecting Ductal Carcinoma in Situ Using Contrast-Enhanced Spectral Mammography and Predictive Indicators for Underestimation

Abstract Purpose: To introduce clinical cases of ductal carcinoma in situ (DCIS) underestimation focusing on additional benefits of contrast-enhanced spectral mammography (CESM). Background: DCIS, a noninvasive breast cancer, is often underestimated during diagnosis. Predicting which cases will upgrade to invasive cancer is crucial. CESM offers superior diagnostic performance compared to mammography and mammography with targeted ultrasound (US). Its low-energy images improve microcalcification conspicuity, enable accurate tumor extent measurement, and provide information on enhancements associated with nonmass microcalcifications. Enhanced areas on CESM can be easily compared with mammographic microcalcifications, for they are obtained during the same session. Indicators heralding DCIS underestimation 1. Detectability: underestimated DCIS is more likely to be detected on CESM and mammogram than pure DICS, whereas detection rates do not statistically differ on US and MRI. 2. Lesion type: underestimated DCIS mostly presents as enhancing mass or nonmass lesions on CESM and calcifications on low-energy conventional mammography. 3. Disease extent: on CESM, pure DCIS show smaller tumor extent than the underestimated ones. 4. CESM gray value (CGV) of the lesion on recombined image: the pure DCIS types show lower mean, standard deviation, maximum, and difference values, whereas the underestimated types demonstrate lower minimum values, and vice versa. Case 1: Screen detected pure DCIS without postsurgical upgrade in an asymptomatic 44-year-old woman. US-guided core biopsy yielded DCIS, intermediate nuclear grade with necrosis. Postsurgical pathology confirmed a 1.5 cm pure ductal carcinoma in situ, intermediate nuclear grade with necrosis. (A) US shows a 1.3 cm irregular hypoechoic mass in the right breast. (B) Routine mammography demonstrates no definite abnormality in the right breast. (C) CESM shows a 1.2 cm irregular enhancing mass in the upper central portion of right breast and CGV was 2034 AU. (D) Contrast-enhanced MR images show a 2.1 cm irregular enhancing mass in 12 o’clock direction of the right breast. Case 2: Screen detected DCIS with postsurgical upgrade to microinvasive ductal carcinoma in a 64-year-old woman with nonspecific discomfort in her right breast. US-guided core biopsy yielded DCIS, high nuclear grade with necrosis. Postsurgical pathology confirmed a 2.8 cm sized microinvasive ductal carcinoma, high nuclear grade, histologic grade 3 with necrosis. (A) US demonstrates a 1.9 cm irregular hypoechoic mass with calcifications in 9 o’clock direction 2.1 cm from the nipple in the right breast. (B) Right magnification view shows a 2.5 cm-extent segmentally distributed fine pleomorphic calcifications in the right breast. (C) CESM shows a 3 cm irregular enhancing mass with calcifications in the right breast, and CGV was 2045 AU. (D) Contrast-enhanced MR images shows a 2.3 cm irregular enhancing mass in the right breast. Case 3: Screen detected DCIS with postsurgical upgrade to invasive ductal carcinoma with DCIS in a 47-year-old woman who had a family history of breast cancer. US-guided core biopsy yielded DCIS, intermediate nuclear grade with necrosis. Postsurgical pathology confirmed a 0.2 cm invasive ductal carcinoma with 2.4 cm DCIS. (A) US demonstrates a 2.3 cm irregular hypoechoic mass in the left breast. (B) Routine mammography shows asymmetry in the upper portion of the left breast. (C) CESM shows a 3 cm enhancing mass in the left breast, and CGV of the lesion on MLO-recombined image was 2072 AU. (D) Contrast-enhanced MR image shows a 6 cm irregular enhancing mass in the upper portion of the left breast. Conclusion: CESM provides added advantages over mammography and breast US in detecting underestimated DCIS, and it is comparable to breast MRI. Key indicators to consider include detectability, enhancing lesion, larger tumor extent, higher mean CGV on CESM. Citation Format: Minji Song, Hee Jung Shin. Case Studies on Detecting Ductal Carcinoma in Situ Using Contrast-Enhanced Spectral Mammography and Predictive Indicators for Underestimation [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-20-08.

Abstract PO4-26-02: Evaluation of Tumor Infiltrating Lymphocytes as a predictive biomarker of recurrence in patients with Ductal Carcinoma In Situ of the breast

Abstract Introduction: Ductal carcinoma in situ (DCIS) represents around 20% of early breast cancer diagnoses globally. Some studies evaluated risk factors associated with DCIS recurrence. Among these, age, surgical margins, comedonecrosis (CN), high nuclear grade, negative hormone receptors and HER2 expression stand out. Recent approaches have been evaluating the role of the immune microenvironment and its association with recurrence and progression of DCIS. Objective: To evaluate the association between Tumor Infiltrating Lymphocytes (TILs) in DCIS samples and disease recurrence. To characterize the immunological microenvironment of DCIS, analyzing the presence of TILs, “touching TILs” and desmoplastic reaction and their association with recurrence. Epidemiological, clinical, histological and immunohistochemical (IHC) characteristics were also evaluated. Methods: This is a retrospective cohort study with patients diagnosed with DCIS and treated at Sao Paulo State Cancer Institute and Hospital das Clinicas of University of Sao Paulo. We included women over 18 years old with a diagnosis of DCIS who underwent treatment from Jan/2007 to Dec/2020. Male patients, patients with a diagnosis of invasive or microinvasive disease in the anatomopathological examination of the surgical specimen or patients with history of any neoplasm were excluded. The main outcome was survival analysis according to the quantification of TILs, adjusted for potential confounders. For that, we collected data on age, presence of palpable mass, imaging findings, histological and IHC characteristics, such as expression of estrogen receptor (ER), progesterone receptor (PR) and hyperexpression of HER2, type of surgical approach, type of radiation therapy, use of endocrine therapy, length of follow-up, recurrence, and its type. Two pathologists evaluated TILS in the sample with the highest tumor representation and numerically quantified it as percentage. They also evaluated the presence of “touching tils” (lymphocytes in contact with the basement membrane) and desmoplastic reaction in the tumor stroma. Kaplan-Meier curves, log-rank tests and Cox regression models were used to evaluate survival. Chi-square tests were used to evaluate the association between categorical variables. Results: 283 patients met the eligibility criteria. Mean age of patients was 55 years. 15% had a palpable nodule at physical examination. Clustered amorphous microcalcifications were the most prevalent mammographic presentation, found in 41% of the patients. The most frequent histological and IHC features were cribriform presentation (73%) and ER positivity (86%), respectively. Desmoplastic reaction was absent in 10.5%, discreet in 51.9%, moderate in 24% and intense in 13.6% of the patients. Breast conserving surgery was performed in 189 patients, and 100 of them received adjuvant radiation therapy. Mean follow-up was 77.2 months, with a recurrence rate of 9.2%. We observed that tumors with focal necrosis (HR 6.4 [1.39-34.71] p 0.018) or CN (HR 4.53 [1.34 – 15.28] p 0.015) had higher risks of recurrence. Patients with a percentage value of TILs greater than or equal to 17% also had a higher risks of recurrence (HR 2.97 (1.17-7.51) p 0.02). These patients were mostly under 65 years of age (OR 0.45 [0.21 - 0.97] p 0.049). In a multivariate model, CN and TILs&amp;gt;17% remained significantly associated with recurrence (p=0.034 and p=0.035 respectively). There was a trend for invasive recurrence in 76.9% of the patients that relapsed when TILS were greater than or equal to 17% (p 0.062). “Touching TILs” were present in 12.9% of the patients but were not associated with recurrence (p=0.575). Conclusion: In our cohort, high value of TILs (&amp;gt;= 17%) and presence of CN were independently associated with DCIS recurrence. Our findings suggest that TILS are a prognostic immunological biomarker in DCIS and warrant further investigation in prospective trials to determine the most adequate cut-point. Citation Format: Camila Pasetto, Fernando Aguiar, Marcella Peixoto, Maira Doria, Bruna Mota, Jonathan Maesaka, Jose Roberto Filassi, Edmund Baracat, Rodrigo Gonçalves. Evaluation of Tumor Infiltrating Lymphocytes as a predictive biomarker of recurrence in patients with Ductal Carcinoma In Situ of the breast [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-26-02.

Abstract PO5-06-14: Genomic Landscape and Clinical Outcomes of Triple-Negative Invasive Lobular Carcinoma

Abstract Background: Triple-negative (TN) invasive lobular carcinoma (ILC) of the breast is a rare entity, comprising roughly 2% of primary ILC. Clinicopathologic studies have shown that TN ILC is associated with more pleomorphism, higher nuclear grade, older patient age, and worse disease-related outcomes compared to estrogen receptor-positive (ER+) ILC. Intrinsic subtyping indicates that TN ILC less frequently expresses basal markers than TN invasive ductal carcinoma (IDC). This prompted investigation of the genomic landscape and clinical management of TN ILC to provide insight into potential therapeutic approaches. Methods: Twenty patients with TN ILC were included in this study. Three patients were treated at a single academic center and underwent comprehensive genomic profiling (CGP) of breast or metastatic tissue; clinicopathologic details were obtained from their electronic health records. Seventeen patients with TN ILC who underwent CGP of breast or metastatic biopsies were included from the Foundation Medicine, Inc. database. PD-L1 testing for all patients was determined by immunohistochemistry (IHC) using the VENTANA SP142 or Dako 22C3 commercial assays. HER2 expression was determined by IHC. Negative HER2 expression was defined as an IHC score of 0, or IHC 1+ or 2+ with non-amplified fluorescence in situ hybridization (FISH). Results: In the Foundation Medicine database of patients with TN ILC, the most frequent genomic alterations were in CDH1 (15/17 patients [88.2%]), TP53 (10/17 patients [58.8%]), and PIK3CA (10/17 patients [58.8%]). Short variant mutations in ERBB2 were found in 3/17 patients (17.6%). Fourteen patients were HER2-low (HER2 IHC 1+ or 2+ with non-amplified FISH). No cases were MSI high or expressed PD-L1 (8 of 17 cases underwent PD-L1 assessment by SP142). Median tumor mutational burden (TMB) was 5 muts/Mb. Among the three patients with TN ILC treated at a single center, the most common somatic mutations were in CDH1 and TP53, and no cases were MSI high or expressed PD-L1 (by SP142 or 22C3). All three patients had pleomorphic ILC, histologic grade 2 or 3, and HER2 IHC 0. One patient with mpT1cN1a(sn) ER+/HER2- ILC of the right breast in 2011 received adjuvant TAC (docetaxel, doxorubicin, cyclophosphamide), breast/axillary radiation, and ten years of adjuvant endocrine therapy. She was diagnosed with TN ILC of the left supraclavicular nodes in 2022; she did not exhibit a response to docetaxel and carboplatin with pembrolizumab, and she subsequently received palliative radiation followed by capecitabine. Another patient with locally advanced TN ILC progressed on the KEYNOTE-522 regimen, immediately developed metastases, and is currently receiving palliative sacituzumab govitecan. The third patient with cT3N1 TN ILC progressed on neoadjuvant therapy (through the I-SPY 2 trial) with oral paclitaxel, encequidar, and dostarlimab, followed by dostarlimab with dose-dense doxorubicin and cyclophosphamide. Her surgical pathology demonstrated ypT3N3a disease with 10 × 7 cm of tumor, and she developed skin metastases on the chest wall within weeks post-operatively. She received comprehensive chest wall and nodal radiation and is currently receiving palliative capecitabine with neratinib given a high variant allele frequency driver somatic ERBB2 mutation. Conclusions: The most common somatic mutations among TN ILC patients included in this study were in CDH1, TP53, and PIK3CA. Currently the management of TN ILC is extrapolated from that of TN IDC, however our patients did not respond to chemoimmunotherapy. The presence of HER2-low status or somatic ERBB2 mutations may provide opportunities for treatment with an anti-HER2 antibody-drug conjugate or tyrosine kinase inhibitor. Studies with larger sample sizes of TN ILC are needed for molecular profiling and assessment of outcomes with specific therapeutic approaches. Citation Format: Hemali Batra-Sharma, Smruthy Sivakumar, Prashanth Ashok Kumar, Ethan Sokol, Rebecca Shatsky, Jeffrey Ross. Genomic Landscape and Clinical Outcomes of Triple-Negative Invasive Lobular Carcinoma [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-06-14.

Abstract PO4-17-05: Patterns of care: radiotherapy after breast conserving surgery and the use of endocrine therapy for screen-detected ductal carcinoma in situ (DCIS) in the UK

Abstract Background The use of adjuvant radiotherapy (RT) and endocrine therapy (ET) in the management of pure ductal carcinoma in situ (DCIS) remains controversial. We investigate how the use of adjuvant RT after breast conserving surgery (BCS) and use of adjuvant ET (in BCS and mastectomy patients) has changed over time. Methods A prospective cohort SQL database of 11,284 patients (the Sloane Project) diagnosed 2003-2012 with screen-detected DCIS in the UK was interrogated for use of adjuvant RT and ET over time and association with factors reported to be predictive of recurrence (patient age, DCIS nuclear grade, size, comedo necrosis, resection margins), as well as institution of surgery, travel time to radiotherapy facility, Index of Multiple Deprivation and outcome (provided by the National Disease Registration Service, NDRS). RT data by site were confirmed with more recent data from the National Audit of Breast Cancer in Older Patients (NABCOP), which looked at patterns of care and outcomes for women aged 70 years and over, compared with those aged 50-64 in England and Wales. Results Among the 7,949 women (70.6%) treated by BCS, post-operative adjuvant RT was given to 4,939 (62.1%); RT use after BCS increased over time (R2 =0.92; p&amp;lt; 0.01). RT use was associated with year of diagnosis (p &amp;lt; 0.01), younger age at diagnosis (p &amp;lt; 0.01), larger DCIS size (p &amp;lt; 0.01), presence of comedo necrosis (p &amp;lt; 0.01), higher nuclear grade (p &amp;lt; 0.01) and presence of microinvasion (p &amp;lt; 0.01). Adjusted analyses showed the most significant factor for RT after BCS was the surgery institution. Travel time to RT facility, Index of Multiple Deprivation and final radial margin were not associated with RT use. When compared with the more recent data from the NABCOP, a marked variation in radiotherapy use across hospitals remains. Ipsilateral recurrence rate varied significantly by hospital, with some of the difference associated with RT utilisation. ET was prescribed in 1313 women (12%), more often following BCS than mastectomy (p &amp;lt; 0.001), with significant variation by institution and a decline in the use of ET over time. Conclusion Marked geographic variation in the use of RT and ET after surgery for DCIS persists in the UK and is likely due to physician choice rather than other factors such as travel times to RT facilities. This is contributing to geographic variation in ipsilateral recurrence rates, suggesting the need for adoption of more authoritative guidelines to support clinical decision-making. Consistent national practice could provide auditable performance standards for adjuvant therapy of screen detected DCIS and contribute to more uniform patient care. Citation Format: Karen Clements, David Dodwell, Elinor Sawyer, Ramsey Cutress, Nisha Sharma, Abeer Shaaban, Alastair Thompson. Patterns of care: radiotherapy after breast conserving surgery and the use of endocrine therapy for screen-detected ductal carcinoma in situ (DCIS) in the UK [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-17-05.

Abstract PO5-13-11: Quantitative Assessment of HER2 Expression in Intraductal Neoplasms of the Breast

Abstract HER2 (ERBB2) is an established prognostic and predictive marker for patients with invasive breast cancer and used in HER2-targeted therapy. The clinical and biological significance of expression of HER2 protein in patients with intraductal neoplasms of the breast is not well characterized. In this study, we used our HS-HER2 (High Sensitivity-HER2) which is a CAP/CLIA certified laboratory derived test (LDT) using quantitative immunofluorescence (QIF). We evaluated HER2 expression in DCIS (ductal carcinoma in situ), LCIS (lobular carcinoma in situ) and benign lesions to correlate with their clinicopathologic characteristics. Thirty- eight cases of DCIS, and fourteen cases of LCIS and thirty benign cases were selected from the Yale Pathology department archives and 252 ROIs (regions of interest) were annotated by a board-certified pathologist. DCIS is classified according to the three-tier nuclear grading system: low, intermediate, and high-nuclear grade. LCIS is classified as PLCIS (pleomorphic variant) and CLCIS (classic LCIS) according to the WHO classification of breast tumors. Serial sections of FFPE tumor specimens were used to accurately quantify the HER2 expression by the HS-HER2 assay and the acquisition by QuPath v.04 with Qymia extension. According to the LOD (limit of detection,3 amol/mm2), LOQ (limit of quantification, 9 amol/mm2) and LOL (limit of linearity, 23 amol/mm2) of the optimized HS-HER2 assay as performed in our CLIA lab shows a broad range of HER2 expression in both DCIS and LCIS lesions, ranging from 0.7 amol/mm2 to 111.4 amol/mm2 in DCIS and 3.6 amol/mm2 to 49.9 amol/mm2 in LCIS. High grade DCIS lesions express higher average HER2 levels (111.4 + 0.7 amol/mm2) than combined low and intermediate grade DCIS (77.9 +1.9 amol/mm2) with no significant difference between low/intermediate and high-grade DCIS. CLCIS lesions express higher average HER2 level (49.9 + 3.6 amol/mm2) than PLCIS (35.1 + 5.4amol/mm2) but again this is not statistically significant. HER protein expression is relatively low in benign lesions ranging from 0.8 to 8.4 amol/mm2. Using the HS-HER2 assay, our results show quantitative level HER2 levels in DCIS and LCIS breast lesions. These findings may be important as HER2 targeted therapies that work in gene-unamplified cancer (HER2 conjugated ADCs) gain broader usage in the clinic. Citation Format: Nay Nwe Nyein Chan, Haiying Zhan, Revekka Khaimova, Thazin Aung, Charles Robbins, Patricia Gaule, David Rimm. Quantitative Assessment of HER2 Expression in Intraductal Neoplasms of the Breast [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-13-11.

Clinical and Imaging Characteristics of Contrast-enhanced Mammography and MRI to Distinguish Microinvasive Carcinoma from Ductal Carcinoma In situ

Rationale and ObjectivesThe prognosis of ductal carcinoma in situ with microinvasion (DCISM) is more similar to that of small invasive ductal carcinoma (IDC) than to pure ductal carcinoma in situ (DCIS). It is particularly important to accurately distinguish between DCISM and DCIS. The present study aims to compare the clinical and imaging characteristics of contrast-enhanced mammography (CEM) and magnetic resonance imaging (MRI) between DCISM and pure DCIS, and to identify predictive factors of microinvasive carcinoma, which may contribute to a comprehensive understanding of DCISM in clinical diagnosis and support surveillance strategies, such as surgery, radiation, and other treatment decisions. Materials and MethodsForty-seven female patients diagnosed with DCIS were included in the study from May 2019 to August 2023. Patients were further divided into two groups based on pathological diagnosis: DCIS and DCISM. Clinical and imaging characteristics of these two groups were analyzed statistically. The independent clinical risk factors were selected using multivariate logistic regression and used to establish the logistic model [Logit(P)]. The diagnostic performance of independent predictors was assessed and compared using receiver operating characteristic (ROC) analysis and DeLong's test. ResultsIn CEM, the maximum cross-sectional area (CSAmax), the percentage signal difference between the enhancing lesion and background in the craniocaudal and mediolateral oblique projection (%RSCC, and %RSMLO) were found to be significantly higher for DCISM compared to DCIS (p = 0.001; p < 0.001; p = 0.008). Additionally, there were noticeable statistical differences in the patterns of enhancement morphological distribution (EMD) and internal enhancement pattern (IEP) between DCIS and DCISM (p = 0.047; p = 0.008). In MRI, only CSAmax (p = 0.012) and IEP (p = 0.020) showed significant statistical differences. The multivariate regression analysis suggested that CSAmax (in CEM or MR) and %RSCC were independent predictors of DCISM (all p < 0.05). The area under the curve (AUC) of CSAmax (CEM), %RSCC (CEM), Logit(P) (CEM), and CSAmax (MR) were 0.764, 0.795, 0.842, and 0.739, respectively. There were no significant differences in DeLong's test for these values (all p > 0.10). DCISM was significantly associated with high nuclear grade, comedo type, high axillary lymph node (ALN) metastasis, and high Ki-67 positivity compared to DCIS (all p < 0.05). ConclusionThe tumor size (CSAmax), enhancement index (%RS), and internal enhancement pattern (IEP) were highly indicative of DCISM. DCISM tends to express more aggressive pathological features, such as high nuclear grade, comedo-type necrosis, ALN metastasis, and Ki-67 overexpression. As with MRI, CEM has the capability to help predict when DCISM is accompanying DCIS.

Radiomics Analysis of Contrast-Enhanced Breast MRI for Optimized Modelling of Virtual Prognostic Biomarkers in Breast Cancer.

Breast cancer clinical stage and nodal status are the most clinically significant drivers of patient management, in combination with other pathological biomarkers, such as estrogen receptor (ER), progesterone receptor or human epidermal growth factor receptor 2 (HER2) receptor status and tumor grade. Accurate prediction of such parameters can help avoid unnecessary intervention, including unnecessary surgery. The objective was to investigate the role of magnetic resonance imaging (MRI) radiomics for yielding virtual prognostic biomarkers (ER, HER2 expression, tumor grade, molecular subtype, and T-stage). Patients with primary invasive breast cancer who underwent dynamic contrast-enhanced (DCE) breast MRI between July 2013 and July 2016 in a single center were retrospectively reviewed. Age, N-stage, grade, ER and HER2 status, and Ki-67 (%) were recorded. DCE images were segmented and Haralick texture features were extracted. The Bootstrap Lasso feature selection method was used to select a small subset of optimal texture features. Classification of the performance of the final model was assessed with the area under the receiver operating characteristic curve (AUC). Median age of patients (n = 209) was 49 (21-79) years. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy of the model for differentiating N0 vs N1-N3 was: 71%, 79%, 76%, 74%, 75% [AUC = 0.78 (95% confidence interval (CI) 0.72-0.85)], N0-N1 vs N2-N3 was 81%, 59%, 24%, 95%, 62% [AUC = 0.74 (95% CI 0.63-0.85)], distinguishing HER2(+) from HER2(-) was 79%, 48%, 34%, 87%, 56% [AUC = 0.64 (95% CI 0.54-0.73)], high nuclear grade (grade 2-3) vs low grade (grades 1) was 56%, 88%, 96%, 29%, 61% [AUC = 0.71 (95% CI 0.63-0.80)]; and for ER (+) vs ER(-) status the [AUC=0.67 (95% CI 0.59-0.76)]. Radiomics performance in distinguishing triple-negative vs other molecular subtypes was [0.60 (95% CI 0.49-0.71)], and Luminal A [0.66 (95% CI 0.56-0.76)]. Quantitative radiomics using MRI contrast texture shows promise in identifying aggressive high grade, node positive triple negative breast cancer, and correlated well with higher nuclear grades, higher T-stages, and N-positive stages.

Nuclear morphological atypia in biopsy accurately reflects the prognosis of myxoid liposarcoma.

Currently, it is difficult to predict the prognosis of myxoid liposarcoma (MLS) in biopsy specimens. In this study, we determined whether nuclear morphology may be used to predict the prognosis of MLS in primary biopsy specimens. Two pathologists evaluated nuclear morphology using the modified WHO/ISUP and Fuhrman grades. Survival analyses were performed by grouping nuclear high- and low-grades. We examined 53 MLS cases, which included 29 (54.7%) male and 24 (45.3%) female patients with a median age of 46years (interquartile range, 37 - 60). In total, 7 (13.2%) and 16 (30.2%) cases were assigned to the high nuclear grade group based on the modified WHO/ISUP and Fuhrman gradings, respectively. Survival analyses revealed a significantly worse disease-free survival in the high-grade group (hazard ratio (HR), 7.51; 95% confidence interval (CI), 2.67-21.1, p < 0.001 by the modified WHO/ISUP grading; HR, 4.45; 95% CI, 1.63-12.1, p = 0.001 by the modified Fuhrman grading). Moreover, the modified WHO/ISUP grade showed a significantly worse overall survival in the high-grade group (HR, 4.39; 95% CI, 1.04-18.6, p = 0.028), and the modified Fuhrman grade exhibited a similar, but not significant, trend. Our results indicate that nuclear morphology grading is a good predictor of patient prognosis at the time of biopsy in MLS. Even when cell density is sparse, treatment strategies should be carefully considered when individual tumor cells exhibit atypical nuclei.

Patients with high nuclear grade pT1-ccRCC are more suitable for radical nephrectomy than partial nephrectomy: a multicenter retrospective study using propensity score

BackgroundPartial nephrectomy (PN) is usually recommended for T1 stage clear cell renal cell carcinoma (ccRCC) regardless of the nuclear grades. However, the question remains unresolved as to whether PN is non-inferior to RN in patients with T1-ccRCC at higher risk of recurrence. In fact, we found that patients with high nuclear grades treated with PN had poorer prognosis compared with those treated with radical nephrectomy (RN). Therefore, this study was designed to evaluate the associations of PN and RN in the four nuclear grade subsets with oncologic outcomes.MethodsA retrospective study was conducted in three Chinese urological centers that included 1,714 patients who underwent PN or RN for sporadic, unilateral, pT1, N0, and M0 ccRCC without positive surgical margins and neoadjuvant therapy between 2010 and 2019. Associations of nephrectomy type with local ipsilateral recurrence, distant metastases, and all-cause mortality (ACM) were evaluated using the Kaplan–Meier method and multivariable Cox proportional hazards regression models after overlap weighting (OW).ResultsA total of 1675 patients entered the OW cohort. After OW, in comparison to PN, RN associated with a reduced risk of local ipsilateral recurrence in the G2 subset (HR = 0.148, 95% CI 0.046–0.474; p < 0.05), G3 subset (HR = 0.097, 95% CI 0.021–0.455; p < 0.05), and G4 subset (HR = 0.091, 95% CI 0.011–0.736; p < 0.05), and resulting in increased five-year local recurrence-free survival rates of 7.0%, 17.9%, and 36.2%, respectively. An association between RN and a reduced risk of distant metastases in the G4 subset (HR = 0.071, 95% CI 0.016–0.325; p < 0.05), with the five-year distant metastases-free survival rate increasing by 33.1% was also observed. No significant difference in ACM between PN and RN was identified.ConclusionsOur findings substantiate that opting for RN, as opposed to PN, is more advantageous for local recurrence-free survival and distant metastases-free survival in patients with high nuclear grade (especially G4) pT1-ccRCC. We recommend placing a heightened emphasis on enhancing preoperative nuclear grade assessment, as it can significantly influence the choice of surgical plan.Trial registrationThis study was registered at Chinese Clinical Trial Registry (ID: ChiCTR2200063333).

Expression of PD-L1 in breast invasive lobular carcinoma.

The purpose of this study was to investigate the expression of PD-L1 in invasive lobular carcinoma (ILC) and to determine its implications. Tissue microarrays were constructed for 101 cases of ILC, and immunohistochemical staining for PD-L1 (using 22C3, SP142, and SP263 antibodies) was performed to examine the correlation between staining results and clinicopathologic parameters. The positive cut-off values were defined as tumor cell (TC)≥1%, immune cell (IC)>0%, and IC≥1%. The range of PD-L1 TC positivity was 0.0-2.0%, with PD-L1 SP263 TC showing the highest positivity of 2.0%. The range of PD-L1 IC positivity was 0-21.8% for IC ≥ 1%, with PD-L1 22C3 IC showing the highest positivity. When PD-L1 IC was positive (IC≥1%), the highest antibody agreement was observed between SP263 and SP142 (OA = 93.1%), while the lowest agreement was observed between 22C3 and SP263 (OA = 73.3%, κ = 0.040). PD-L1 22C3 IC positivity (≥1%) was associated with high nuclear grade (p = 0.002), HER-2 positivity (p = 0.019), and pleomorphic type (p = 0.002). PD-L1 expression in ILC shows a low TC positivity rate (0-2%) with various antibody clones and a variable IC positivity rate (0-21.8%). Pleomorphic type ILC exhibits higher PD-L1 IC positivity.

Inflammatory breast cancer: An overview about the histo-pathological aspect and diagnosis.

Inflammatory Breast Cancer (IBC) is a rare and aggressive form of locally advanced breast cancer, classified as stage T4d according to the tumor-node-metastasisstaging criteria. This subtype of breast cancer is known for its rapid progression and significantly lower survival rates compared to other forms of breast cancer. Despite its distinctive clinical features outlined by the World Health Organization, the histopathological characteristics of IBC remain not fully elucidated, presenting challenges in its diagnosis and treatment. Histologically, IBC tumors often exhibit a ductal phenotype, characterized by emboli composed of pleomorphic cells with a high nuclear grade. These emboli are predominantly found in the papillary and reticular dermis of the skin overlaying the breast, suggesting a primary involvement of the lymphatic vessels. The tumor microenvironmentin IBC is a complex network involving various cells such as macrophages, monocytes, and predominantly T CD8+lymphocytes, and elements including blood vessels and extracellular matrix molecules, which play a pivotal role in the aggressive nature of IBC. A significant aspect of IBC is the frequent loss of expression of hormone receptors like estrogen and progesterone receptors, a phenomenon that is still under active investigation. Moreover, the overexpression of ERBB2/HER2 and TP53 in IBC cases is a topic of ongoing debate, with studies indicating a higher prevalence in IBC compared to non-inflammatory breast cancer. This overview seeks to provide a comprehensive understanding of the histopathological features and diagnostic approaches to IBC, emphasizing the critical areas that require further research.