Lobular Histology Research Articles

Multiparametric Magnetic Resonance Imaging Assessment of Primary Tumors for Predicting Axillary Tumor Burden in Women with Invasive Breast Cancer.

To assess the association between multiparametric MRI features of primary tumors and axillary lymph node tumor burden in women with invasive breast cancer. In this retrospective study, women diagnosed with invasive breast cancer who underwent 3T multiparametric MRI, including diffusion-weighted imaging (DWI) from 2019-2020, were evaluated. Two radiologists reviewed T2-weighted images (T2WI) for peritumoral edema and intratumoral necrosis, and measured apparent diffusion coefficient (ADC) values by manually placing regions of interest within breast tumors. We also analyzed quantitative kinetic features of breast cancer using computer-aided diagnosis (CAD) and clinical-pathologic characteristics. Uni- and multivariable logistic regression analyses were conducted to identify predictors of a high axillary nodal burden (≥3 positive nodes). In total, 301 women (mean age, 54.13 years) were evaluated. Forty-three (14.3%) had a high axillary nodal burden by surgical pathology. Multivariate analysis revealed that factors significantly associated with high axillary nodal burden included peritumoral edema (OR:7.970; p<0.001), lower tumor ADCmax (≤ 1.098 × 10-3 mm2/s) (OR:6.978; p<0.001), larger tumor size (>2cm) (OR:2.986; p=0.046), lobular histology (OR:12.620; p<0.001), and the presence of lymphovascular invasion (OR:3.622; p=0.003). CAD-derived kinetic features did not show an association with axillary nodal burden. In subgroup analysis of 238 patients with early clinically node-negative breast cancer, both peritumoral edema (OR:7.831; p=0.002) and lower tumor ADCmax (≤ 1.098 × 10-3 mm2/s) (OR:8.002; p=0.002) remained significant predictors. Our results suggest that peritumoral edema as viewed in T2WI and the ADCmax value of breast cancer in DWI are valuable for predicting axillary nodal burden in women with invasive breast cancer. Multiparametric MRI features of a primary tumor are useful for predicting axillary nodal burden in patients with invasive breast cancer.

Significance of Residual Nodal Disease in Clinically Node-Negative Breast Cancer After Neoadjuvant Chemotherapy.

Trials evaluating omission of axillary dissection (ALND) in patients with cN0 breast cancer with positive sentinel lymph nodes (SLNs) haveexcluded neoadjuvant chemotherapy (NACT). It remains unclear whether the data can be extrapolated to cN0 patients undergoing NACT. This study sought to identify factors associated with positive SLNs and additional disease on ALND in cT1-2N0 disease after NACT. The authors queried their database for cT1-2N0 patients treated with NACT followed by SLN biopsy from 1996 to 2022. Physical examination and ultrasound determined clinical nodal status. Multivariable logistic regression identified factors associated with positive SLNs and disease on ALND. Of 1930 patients, 234 (12.1%) had positive SLNs. Positive SLNs were predicted by hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) status (odds ratio [OR] 2.5; p < 0.0001), lobular histology (OR 1.8; p = 0.007), multifocality (OR 2; p = 0.001), grade 1 tumors (OR 2.5; p = 0.002), and cT2 category (OR 1.9; p = 0.004). Of the 234 patients with positive SLNs and known SLN metastasis size, 148 (63.2%) underwent ALND, and 39 (26.4%) had additional positive nodes. Increasing patient age predicted disease on ALND (OR 1.03; p = 0.02). No additional positive nodes on ALND were identified in patients with only isolated tumor cells compared with 12.3% who had micrometastases and 37.6% who had macrometastases (p = 0.01). During a 5-year median follow-up period of the SLN-positive patients, three (1.3%) experienced axillary recurrence and twoof the three underwent ALND at the initial surgerywith no additional positive nodes. In cT1-2N0 breast cancer, HR+/HER2- status, lobular histology, multifocality and cT2 category predicted positive SLNs after NACT. Older age predicted positive nodes on ALND. Patients with positive SLNs had low axillary recurrence rates. These findings support investigation into omission of ALND in cN0 breast cancer and a low volume of SLN disease after NACT.

Survival outcomes of Black/African American (B/AA) patients with HER2-negative (IHC 0, 1+, 2+ and ISH-), advanced breast cancer (HER2-neg aBC) across three academic cancer centers in the United States.

129 Background: As B/AA patients are underrepresented in clinical research, data is limited on survival outcomes of B/AA patients with HER2-neg aBC. This study compared survival outcomes of these patients against those of non-B/AA patients. Methods: This was a retrospective cohort study at Huntsman Cancer Institute, H. Lee Moffitt Cancer Centre and Research Institute, and Winthrop P. Rockefeller Cancer Institute. Adult patients diagnosed with HER2-neg aBC from 2010 to 2021 were eligible. Patient data were extracted via chart review, including self-reported race from clinical records. HER2-low status was defined as immunohistochemistry (IHC) scores 1+ or 2+ and negative fluorescence in situ hybridization test; HER2-neg comprised HER2-low and IHC 0. Overall survival (OS), i.e. time until death, and progression-free survival (PFS), i.e. time until death or disease progression, were estimated using Kaplan-Meier methods with treatment start as index date and censoring at date of last follow-up or 12/31/2021, whichever earlier. Association between B/AA race and survival was evaluated using multivariable Cox regression. Results: A total of 869 patients were HER2-neg, 95 were B/AA, and 64 (67%) were HER2-low while 31 (33%) had IHC 0 disease. Compared to non-B/AA patients (85% non-Hispanic White), fewer B/AA patients had stage IV disease (38% vs 57%, p=0.001), lobular histology (3% vs 14%, p=0.001) and positive hormone receptor status (HR) (60% vs 78%, p&lt;0.001). B/AA patients showed shorter median OS and PFS than non-B/AA patients overall and in subgroups defined by stage and HR but 95% confidence intervals (CI) overlapped (Table). Controlling for stage and HR, B/AA patients had shorter OS (Hazards ratio: 1.4, 95% CI: 1.0-1.9) but no difference in PFS (Hazards ratio: 1.2, 95% CI: 0.9-1.6). Conclusions: OS of B/AA patients with HER2-neg aBC was shorter than that of non-B/AA patients controlling for staging and HR. A sizable proportion of B/AA patients have HER2-low disease and more studies are needed to confirm if this patient population has different outcomes compared to non-B/AA. Survival outcomes of B/AA patients vs non-B/AA patients. Overall Survival (months) Progression-free Survival (months) B/AA Non-B/AA B/AA Non-B/AA n Mdn (95% CI) n Mdn (95% CI) n Mdn (95% CI) n Mdn (95% CI) Overall 95 41.4 (28.3 to 69.4) 774 56.7 (50.0 to 66.2) 95 9.9 (8.0 to 20.3) 773 16.1 (13.9 to 18.3) Staging IIIB/IIIC 60 69.4 (39.1 to NR) 339 NR (110.1 to NR) 60 10.2 (8.0 to 23.8) 339 22.5 (15.0 to 37.8) IV 35 28.1 (18.2 to 40.9) 435 39.4 (35.5 to 44.0) 35 9.6 (7.3 to 25.7) 434 13.9 (11.6 to 17.0) Hormone receptor Positive 57 41.4 (27.8 to 69.4) 609 62.0 (55.1 to 69.7) 57 8.6 (7.8 to 20.3) 609 17.1 (14.1 to 19.7) Negative 38 40.9 (23.1 to NR) 162 41.6 (24.2 to 68.3) 38 10.2 (7.7 to NR) 161 11.8 (9.3 to 17.2) B/AA – Black/African American, Mdn – median, NR – not reached.

Accelerated Partial Breast Irradiation for Early-Stage Invasive Lobular Carcinoma

Purpose: Invasive lobular carcinoma (ILC) represents 10-15% of invasive breast cancers with limited representation among trials of accelerated partial breast irradiation (APBI). Contemporary guidelines advise against treating ILC with APBI given a paucity of supportive evidence. Here, we evaluated oncologic outcomes among patients with ILC treated with APBI. Methods: Patients treated from 2010 –2022 with APBI following breast conserving surgery for ILC (or mixed ILC with other histologies) were ascertained from a prospectively-maintained institutional database. All patients received external beam APBI to 40Gy in 10 daily fractions. Outcomes of interest included local recurrence (LR) and overall survival (OS). Results: Of 1248 patients who underwent APBI at our center, the study cohort comprised 132 (11%) who had ILC, either exclusively or mixed with another histology (median age 63). Median tumor size was 1.1cm (IQR: 0.8, 1.5), nearly all had estrogen receptor positive disease (99%) and received endocrine therapy (91%), and most underwent sentinel node biopsy (89%) with the remainder having no axillary surgery. At 530 person-years and a median follow-up of 39 months, two LRs were observed yielding a 48-month cumulative incidence of LR of 3.0% (95% CI 0.56 –9.5%). Both events arose in patients with mixed lobular histology (none arose in patients with pure ILC). Two unrelated deaths were also observed yielding a 48-month overall survival of 98% (95% CI: 95% - 100%) Conclusion: Among patients with ILC who received APBI following BCS, we observed a 4-year LR rate of 3%. No regional or distant recurrences were observed, and overall survival was excellent. The safety of APBI for ILC will require confirmation among larger trials with longer follow-up, although the excellent outcomes observed here are consistent with those seen for invasive ductal carcinomas among contemporary trials of APBI.

290P Subtype-specific prognostic value of lobular histology in patients with early-stage breast cancer: A nationwide population-based study

290P Subtype-specific prognostic value of lobular histology in patients with early-stage breast cancer: A nationwide population-based study

Long-term outcomes by lobular versus ductal histology in four NSABP adjuvant breast cancer trials.

We evaluated differences in long-term outcomes of invasive lobular carcinoma (ILC) vs breast cancers of no special type (NST) treated with anthracycline-based adjuvant chemotherapy using 4 National Surgical Adjuvant Breast and Bowel Project (NSABP) randomized phase III trials (B-22, B-25, B-28, B-30). Our cohort included 11,251 patients with NST and 1,231 with ILC. Patients with ILC were older, had larger and more often estrogen receptor-positive tumors, and more positive lymph nodes. During early follow-up (0-5 years), patients with ILC had fewer recurrences (HR: 0.797; 95% confidence interval [CI] 0.685-0.929) and deaths (HR: 0.756; 95% CI 0.623-0.917). After 5 years patients with ILC had more recurrences (HR: 1.30; 95% CI 1.085-1.558) and deaths (HR: 1.044; 95% CI 0.898-1.214). Conditional probability analysis showed significant interactions between time-period and histologic type for recurrences (p < .001) and deaths (p < .001). Patients with ILC have elevated risk of late recurrence and death compared to patients with NST.

ER-Targeted PET for Initial Staging and Suspected Recurrence in ER-Positive Breast Cancer

There are insufficient data comparing 16α-18F-fluoro-17β-estradiol (FES) positron emission tomography (PET) computed tomography (CT) with standard-of-care imaging (SOC) for staging locally advanced breast cancer (LABC) or evaluating suspected recurrence. To determine the detection rate of FES PET/CT and SOC for distant metastases in patients with estrogen receptor (ER)-positive LABC and recurrences in patients with ER-positive BC and suspected recurrence. This diagnostic study was conducted as a single-center phase 2 trial, from January 2021 to September 2023. The study design provided 80% power to find a 20% detection rate difference. Participants included patients with ER-positive LABC (cohort 1) or suspected recurrence (cohort 2). Data were analyzed from September 2023 to February 2024. Participants underwent both SOC imaging and experimental FES PET/CT. When there were suspicious lesions on imaging, 1 was biopsied for histopathological reference standard to confirm presence (true positive) or absence (false positive) of malignant neoplasm. The outcome of interest was the detection rate of FES PET CT vs SOC for distant metastases and recurrences. A total of 124 patients were accrued, with 62 in cohort 1 (median [IQR] age, 52 [32-84] years) and 62 in cohort 2 (median [IQR] age, 66 [30-93] years). In cohort 1, of 14 true-positive findings, SOC imaging detected 12 and FES detected 11 (P > .99). In cohort 2, of 23 true-positive findings, SOC detected 16 and FES detected 18 (P = .77). In 30 patients with lobular histology, of 11 true-positive findings, SOC detected 5 and FES detected 9 (P = .29). There were 6 false-positive findings on SOC and 1 false-positive finding on FES PET/CT (P = .13). In this diagnostic study with pathological findings as the reference standard, no difference was found between FES PET/CT and current SOC imaging for detecting distant metastases in patients with ER-positive LABC or recurrences in patients with ER-positive tumors and suspected recurrence. FES PET/CT could be considered for both clinical indications, which are not part of current Appropriate Use Criteria for FES PET. The findings regarding FES PET/CT in patients with lobular tumors, and for lower false positives than current SOC imaging, warrant further investigation.

Disparities in the Use of Preoperative Breast Magnetic Resonance Imaging After Breast Cancer Diagnosis.

Preoperative magnetic resonance imaging (MRI) after breast cancer diagnosis is increasingly used to improve locoregional staging, particularly among women with dense breasts, extensive ductal carcinoma in situ, and lobular histology. The goals of this study were to (1) assess whether use of preoperative MRI varies by race and insurance type; and (2) determine whether preoperative MRI is associated with downstream surgical management. We performed a retrospective cohort study of women with stage 0-III breast cancer who were treated with surgical resection within our academic health system (2016-2019). Patients were categorized by race and insurance type. The primary outcome was receipt of preoperative MRI. Secondary outcomes included surgery extent (lumpectomy v mastectomy) and receipt of a second operation. A total of 1,410 women (27% Black, 73% White; 67% private insurance, 26% Medicare, 6% Medicaid) were included. Black patients were significantly less likely to undergo preoperative MRI than White patients (odds ratio [OR], 0.54 [95% CI, 0.38 to 0.76]; P < .001). There was no association between insurance type and preoperative MRI (Medicare v private: OR, 0.77 [95% CI, 0.52 to 1.15]; P = .208; Medicaid v private: OR, 0.67 [95% CI, 0.36 to 1.25]; P = .210). White patients who underwent preoperative MRI were less likely to undergo lumpectomy versus those who did not (OR, 0.53 [95% CI, 0.37 to 0.76]; P < .001). Likelihood of re-excision was lower for Black women who had undergone MRI versus those who had not (OR, 0.43 [95% CI, 0.20 to 0.93]; P = .031). Black patients were less likely than White patients to undergo preoperative MRI, yet Black women who underwent MRI were less likely to require re-excision. Standardizing preoperative MRI use may mitigate provider- and system-level biases and promote more equitable care.

Evaluating Surgical Outcomes Between Estrogen Receptor Positive Invasive Lobular and Invasive Ductal Carcinoma of the Breast—A Propensity Matched Analysis

IntroductionInvasive lobular carcinoma (ILC) contributes significantly to the global cancer burden and is the most common of the histological “special types” of breast cancer. ILC has unique features setting it apart from the more common invasive ductal carcinoma (IDC). Despite differences, treatment algorithms do not consider histological differences. AimTo determine the differences in treatment and outcomes of ILC relative to IDC in a strict case-matched cohort study at a tertiary referral, specialist, breast cancer center. MethodsAll Estrogen receptor positive (ER+) ILCs from 1999 to 2015 were matched for; age, tumor size, grade, PR/HER2 status, nodal stage and metastases with ER+ IDCs from the same period. Surgical and systemic treatments were assessed along with overall (OS) and disease-free survival (DFS). Results762 cases in total were analyzed (1:1 matching; ILC:IDC). ILC cases were more often treated with mastectomy (37.5% vs. 28.6%, P .009) and those who received breast conserving surgery (BCS) more often had an incomplete resection (30.2% vs. 19.6%, P .01). IDC were more often treated with NACT (5.5% vs. 14.4%, P < .001). Mean DFS were similar between ILC and IDC; 148.3 vs. 141.4 months (P .112) but OS was significantly longer in the ILC group; 165.7 vs. 134 months (P .002). This trend was consistent among the subset of patients undergoing BCS. For ILC undergoing BCS, mean DFS was 129.8 vs. 128.3 months for IDC (P .418) and OS was 155.4 and 110.7 months respectively (P < .001). Incomplete resection at the time of index surgery did not alter the disease free or overall survival in either the ILC or IDC patients to a level that reached statistical significance. ConclusionIn this cohort study, the strict matching of ILC and IDCs for a number of prognostic indicators, demonstrates the impact of lobular histology with a clarity not previously observed. ILCs have comparable survival outcomes to patients with IDC but at the expense of more extensive index and revisional surgery. There is a need for awareness of these facts among surgeons and patients for optimal treatment prioritization and provision.

Tucatinib and trastuzumab for previously treated HER2−mutated metastatic breast cancer (SGNTUC−019): A phase 2 basket study.

1105 Background: Approximately 2-5% of breast cancers harbor HER2 mutations, often occurring in hormone receptor-positive (HR+) disease. There are currently no approved treatment options for patients (pts) with HER2-mutated metastatic breast cancer (HER2-mut MBC). Tucatinib (TUC) is a tyrosine kinase inhibitor highly selective for HER2 and is approved for previously treated HER2+ MBC with or without brain metastases in combination with trastuzumab (Tras) and capecitabine. Here, we report the efficacy and safety results of TUC combined with Tras in pts with previously treated HER2-mut MBC. Methods: SGNTUC-019 (NCT04579380) is an open-label phase 2 basket study evaluating efficacy, safety, and tolerability of TUC and Tras in pts with metastatic HER2-altered solid tumors. Pts in the HER2-mut MBC cohort must have HER2 mutations determined locally by tissue- or blood-based next-generation sequencing, not be HER2+ per local testing, been previously treated with ≥1 systemic therapy in the locally advanced, unresectable, or metastatic setting, and if HR+, have received a CDK4/6 inhibitor. Pts were treated in 21-day cycles with TUC (300 mg orally twice a day) and Tras (8 mg/kg IV followed by 6 mg/kg every 3 wks). Pts with HR+ disease also received fulvestrant (F; 500 mg IM once every 4 wks starting from cycle 1 day 1, and cycle 1 day 15). Disease status was determined based on RECIST v1.1 with assessments performed every 6 wks for 24 wks and every 12 wks thereafter. The primary endpoint is cORR per investigator assessment. Secondary endpoints include OS, DCR, DOR, PFS, and safety. Results: As of Nov 1, 2023, 31 pts were enrolled in the HER2-mut MBC cohort. The median duration of follow-up for OS was 15.0 months. Twenty-seven (87%) pts had HR+ disease and 18 (58%) had lobular histology. The pts received a median of 4 prior lines of systemic therapy in any setting. cORR was 41.9% (90% CI, 26.9-58.2) with 13 responses including 2 complete responses. Median DOR was 12.6 months (90% CI, 4.7, not estimable), DCR was 80.6% (n=25; 90% CI, 65.3-91.2), median PFS was 9.5 months (90% CI, 5.4-13.8), and median OS was 20.1 months (90% CI, 15.9 to not estimable). The most common treatment-emergent adverse events (TEAEs) reported were diarrhea (64.5%) and nausea (35.5%). The most common grade ≥3 TEAEs reported were diarrhea (13%), alanine aminotransferase increase (10%), and hypertension (10%). Two (6.5%) pts discontinued TUC due to TEAEs, but these pts continued Tras. No deaths were due to TEAEs. Additional biomarker analyses will be included in the presentation. Conclusions: The investigational combination of TUC and Tras, plus F in pts with HR+ disease, was well tolerated and had clinical activity in pts with previously treated HER2-mut MBC. The results support further evaluation of the combination of TUC and Tras as a potential treatment option for this pt population. Clinical trial information: NCT04579380 .

Clinical behavior of breast cancer in young BRCA carriers and prognostic impact of the timing of genetic testing: Results from an international cohort study.

10503 Background: Germline BRCA testing is recommended in all patients (pts) diagnosed with breast cancer (BC) at a young age (40 years or younger). Limited evidence exists regarding clinical behavior of BC in young BRCA1and BRCA2 carriers or the impact of the timing of genetic testing (before or at diagnosis) on tumor characteristics and pts outcomes. Methods: This was an international, multicenter, hospital-based, retrospective cohort study including pts harboring germline pathogenic variants (PVs) in BRCA1or BRCA2 and diagnosed with stage I-III invasive BC at 40 years or younger between January 2000 and December 2020 (NCT03673306). Baseline pt, tumor, and treatment characteristics, as well as survival outcomes (disease-free survival [DFS] and overall survival [OS]) were compared between BRCA1and BRCA2carriers. A further comparison was performed between pts who underwent genetic testing before (i.e. any time up to 2 months prior to BC diagnosis) or at (i.e. between 2 months prior and up to 6 months after diagnosis) BC diagnosis. Results: From 78 centers worldwide, 4,752 pts were included, of whom 3069 harbored BRCA1and 1683 BRCA2 PVs. Compared to BRCA2carriers, BRCA1 carriers were significantly younger, had more grade 3 tumors, less nodal involvement, lobular histology, hormone receptor and HER2 positivity, and received chemotherapy more frequently and endocrine therapy less frequently. Median follow-up was 7.8 years (range 4.4-12.6 years). Second primary BCs (13.7% vs. 9.3%) and non-breast new primary malignancies (4.5% vs. 3.0%) were significantly more frequent among BRCA1 carriers, while distant recurrences were less frequent (9.7% vs. 13.6%). No differences in DFS or OS were observed between BRCA1 and BRCA2 carriers. However, BRCA1 carriers had worse DFS and OS in the first 5 years due to a peak in DFS events in the first 2 years while BRCA2 carriers had a constant risk of recurrence over time and worse OS after year 9. Compared to pts tested for BRCA at BC diagnosis (n = 1671), those tested before BC diagnosis (n = 411) had significantly smaller tumors (T1: 61.3% vs 32.4%) and less nodal involvement (N0: 65.9% vs 50.8%). 8-year DFS and OS in patients tested before and at BC diagnosis were 73% vs 70% (HR 1.25; 95% CI 0.99-1.58) and 91% vs 87% (HR 1.65; 95% CI 1.08-2.52), respectively. Conclusions: In this global study of young BRCA carriers, different pts, tumor, and treatment characteristics, as well as pattern and risk of DFS/OS events over time were observed between BRCA1and BRCA2. Identification of carrying a BRCA PV in healthy individuals led to earlier BC diagnosis and improved OS. These findings highlight the importance of conducting efforts to identify women at risk for carrying a BRCA1or BRCA2PV to offer them genetic counseling and testing to inform not only prevention, but tailored earlier detection, treatment and follow-up strategies once diagnosed.

A single center retrospective cohort study of patients with metastatic breast cancer and leptomeningeal disease: Updated survival data and subgroup analyses by breast cancer subtype.

1108 Background: Patients (pts) with metastatic breast cancer (MBC) and leptomeningeal disease (LMD) have a poor prognosis with limited therapies. We previously reported data from our retrospective LMD registry; here we provide an update with additional pts and subgroup analyses highlighting differences in treatment and survival by breast cancer subtype. Methods: In this single center retrospective cohort study, we identified pts with MBC and LMD who received care from 2000-2024 and abstracted key clinical, treatment, and overall survival (OS) data. Results: We identified 111 pts with MBC and LMD, including pts with the following subtypes: HR+/HER2- (n=53, 47.7%), HER2+ (n=30, 27.0%), and triple negative breast cancer (TNBC; n=28, 25.2%). The majority of pts had concurrent brain metastasis (n=82, 73.9%). Median time from diagnosis of MBC to LMD was 16.4 months (mo) (range 0-101.3 mo). Pts received a median of 3 lines of therapy prior to the diagnosis of LMD (range 0-10) and 1 line after the diagnosis of LMD (range 0-4). Most pts received central nervous system-directed (CNS)-directed therapy (n=94, 84.7%), including intrathecal (IT) therapy (n=42, 37.8%) and/or CNS radiation (n=70, 63.1%). Median OS from the diagnosis of LMD to death was 4.1 mo (range 0.1-78.1 mo) and varied by subtype, with pts with HR+/HER2- or HER2+ MBC and LMD living longer than those with TNBC and LMD (4.2 and 6.8 mo respectively vs. 2.0 mo, p&lt;0.01, HR 2.15, 95% CI 1.36-3.39). There was no difference in OS by histology ductal vs. lobular or by presence or absence of concurrent parenchymal brain metastases. Pts who received IT therapy survived longer than those who did not (7.1 vs. 2.7 mo, p=0.01, HR 0.60, 95% CI 0.40-0.90). There was difference in OS by receipt of CNS-directed radiation therapy. Pts diagnosed with LMD from 2015-2024 lived longer than those diagnosed from 2000-2014 (6.4 vs. 2.9 mo, p=0.04, HR 0.67, 95% CI 0.46-0.99). On multivariable analysis, having TNBC was associated with shorter OS from time of LMD to death (p=0.004, HR 2.03, 95% CI 1.25-3.30). Conclusions: This study represents one of the largest case series of pts with MBC and LMD, including the most pts diagnosed after 2015 to our knowledge. Pts with lobular histology, HER2+ BC, TNBC, and those with de novo MBC were over-represented compared to the general MBC population. Pts with HR+/HER2- or HER2+ disease, LMD diagnosed after 2015, and those who received IT therapy survived longer than their respective cohorts. Novel diagnostic and therapeutic strategies for pts with MBC and LMD remains an area of unmet clinical need.

Comparison of antitumor efficacy of first-line palbociclib, ribociclib, or abemaciclib in patients with HR+/HER2- aBC: Results of the multicenter, real-world, Italian study PALMARES-2.

1014 Background: The Cyclin Dependent Kinase 4/6 inhibitors (CDK4/6i) Palbociclib, Ribociclib and Abemaciclib in combination with Endocrine Therapy (ET) represent the standard-of-care, 1st line treatment for patients with Hormone Receptor-positive, Human Epidermal growth factor Receptor 2-negative, advanced Breast Cancer (HR+/HER2- aBC). So far, no large real-world studies have compared the efficacy of the three CDK4/6i in this clinical setting. Methods: The multicenter, population-based study PALMARES-2 evaluated the antitumor efficacy of 1st line Palbociclib, Ribociclib or Abemaciclib in combination with ET in consecutive HR+/HER2- aBC patients treated in 18 Italian cancer centers between 1st January 2016 and 1st September 2023. The primary study endpoint was real-world Progression-Free Survival (rwPFS), as defined as the time interval between ET plus CDK4/6i initiation and disease progression. Multivariate Cox regression model was used to adjust the association between individual CDK4/6i and rwPFS for clinically relevant variables. Results: With a data cut-off date of January 1st, 2024, we enrolled 1850 patients, 750 (40.6%), 676 (36.5%) and 424 (22.9%) of whom received Palbociclib, Ribociclib and Abemaciclib, respectively. Among 1226 (66.3%) patients with endocrine-sensitive disease, 1087 (89%) received concomitant Aromatase Inhibitors, whereas 441 (70.7%) out of 624 (33.7%) patients with endocrine-resistant disease received concomitant Fulvestrant. Patients treated with Abemaciclib were more likely to have endocrine-resistant disease, liver metastases, lobular tumor histology and lower PgR tumor expression, and less likely to have de novometastatic disease (p&lt;0.001). Median rwPFS in the whole study cohort was 34.9 months (95% CI 32.0-37.4). Abemaciclib and Ribociclib were independently associated with better rwPFS when compared to Palbociclib (Table), whereas Abemaciclib and Ribociclib showed no significantly different efficacy (aHR 0.91, 95% CI 0.70-1.19; p=0.505). Other covariates independently associated with rwPFS are shown (Table). Conclusions: The real-world study PALMARES-2 revealed different antitumor efficacy of individual CDK4/6i in HR+/HER2- aBC patients. Longer follow-up is required to study if Palbociclib, Ribociclib and Abemaciclib are associated with different overall survival. [Table: see text]

Abstract PO3-06-05: Association of tumor-derived extracellular vesicles with circulating tumor DNA alterations in metastatic breast cancer patients: exploring differences in inflammatory breast cancer

Abstract Background: Liquid biopsy provides a real-time assessment of metastatic breast cancer (MBC). Recently, the complementary prognostic value of tumor-derived extracellular vesicles (tdEVs) and circulating tumor cells (CTCs) has been reported. We have previously confirmed the strong prognostic significance of CTCs and tdEVs in inflammatory breast cancer (IBC). While previous studies have reported the association of CTCs with circulating tumor DNA (ctDNA) alterations in MBC, no evidence is available for tdEVs. This study aimed to analyze the association of tdEVs with ctDNA alterations, to investigate the molecular pathways underlying their presence. Moreover, we explored potential differences of this association in patients (pts) with IBC to provide a comprehensive liquid biopsy-based portrait of this aggressive subtype of BC. Methods: Blood samples were collected from 355 pts with MBC before starting a new line of therapy at Northwestern University (Chicago, IL) between 2016 and 2021 (NU16B06 trial). For CTCs and tdEVs analysis, 7.5 mL of blood was processed with the CellSearch® system. The ACCEPT software was applied to CellSearch® images to automatically enumerate CTCs and tdEVs. Positivity cutoff was ≥5 for CTCs, while tdEV cutoff points were &amp;lt; 20 (low), 20-79 (intermediate), and ≥80 (high). For ctDNA analysis, matched plasma samples (± 1 month) were analyzed with the Guardant360™ NGS platform for the detection of somatic single nucleotide variants (SNVs) and copy number variations (CNVs), which were classified into oncogenic pathways based on defined profiles generated on the Cancer Genome Atlas database (p53, PI3K, ER, RTK, RAS, RAF, WNT, MYC, cell cycle, notch). Associations between ctDNA pathways alterations and tdEVs were tested in the overall population by multinomial logistic regression and corrected for significant clinical characteristics. Differences in liquid biopsy features between IBC and non-IBC subgroups were analyzed through Fisher's exact test. Results: Of the 355 MBC pts, 210 (62%) had HR+ BC, 61 (17%) had HER2+ BC, and 68 (20%) had triple-negative BC. Eighty-three (23%) had a diagnosis of IBC and had a numerically lower tdEV count. Also, lower tdEVs were detected in HER2+ BC as compared with HR+. Significantly higher tdEVs were observed among pts with lobular histology, liver, and bone metastases. CTC count was significantly associated with tdEV number. A matched plasma sample for ctDNA analysis was available for 175 pts (62 IBC and 113 non-IBC). In the overall population, SNVs in ER pathway were associated with intermediated/high levels of tdEVs (p=0.004 and 0.008). A similar association was observed for CNVs in the cell cycle pathway (p=0.008 and 0.007). Moreover, associations with ≥80 tdEVs were observed for PI3K SNVs and CNVs (p=0.039 and 0.004, respectively), RTK CNVs (p=0.023), and MYC CNVs (p=0.001). In multivariable analysis, clinical characteristics associated with higher tdEVs were lobular histology (p=0.014 for 20-79 and &amp;lt; 0.001 for ≥80) and bone metastases (p=0.019 for 20-79 and 0.002 for ≥80). When considering clinical variables of interest, only ER SNVs and MYC CNVs were significantly associated with intermediate (p=0.031) and high (p=0.022) tdEV counts, respectively. While the association with ER SNVs and cell cycle CNVs was significant both in the IBC and non-IBC subgroups, others were specific for a certain subgroup: higher tdEVs were significantly associated with PI3K SNVs only in non-IBC pts whereas the significant association with CNVs in PI3K and MYC pathways was observed only in pts with IBC. Conclusion: Detection of tdEVs was associated with particular genomic profiles. These alterations seem to be different in IBC further underlying a different biology of this BC subtype. Additional studies are needed to explore how to integrate different liquid-biopsy based biomarkers in the management of pts with MBC. Citation Format: Eleonora Nicolò, Lorenzo Gerratana, Lorenzo Foffano, Laura Munoz Arcos, Mara Serena Serafini, Maroua Manai, Letizia Pontolillo, Nadia Bayou, Elisabetta Molteni, Amanda Kaylan Strickland, Youbin Zhang, Paolo D’Amico, Andrew Davis, Jeannine Donahue, Huiping liu, William Gradishar, Ami Shah, Giuseppe Curigliano, Carolina Reduzzi, Massimo Cristofanilli. Association of tumor-derived extracellular vesicles with circulating tumor DNA alterations in metastatic breast cancer patients: exploring differences in inflammatory breast cancer [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 PO3-06-05.

Abstract PO1-17-10: Impact of COVID19 on neoadjuvant endocrine therapy use in breast cancer: A National Cancer Database analysis

Abstract Background: Neoadjuvant endocrine therapy (NET) is associated with similar response rates as neoadjuvant chemotherapy in hormone receptor positive (HR+) breast cancer (BC), with less toxicity. While gene expression assays such as the 21-gene recurrence score (RS) have led to decreased chemotherapy use in early HR+/HER2- BC, NET is often underutilized. In 2020, the COVID19 pandemic led to disruption in oncologic care, including cancellation of surgeries. Guidelines for BC management during the pandemic recommended NET for HR+/HER2- BC patients unable to obtain surgery due to pandemic restrictions. We evaluated NET use in 2020, compared to NET use in prior years. Methods: Female pts with nonmetastatic HR+/HER2- BC diagnosed between 2016 and 2020 were identified from the 2004-2020 National Cancer Database (NCDB). Annual number of pts receiving NET, and duration of use, were compared between years, and characteristics of pts treated with and without NET were evaluated within and across years, using Chi-squared test for categorical variables and Wilcoxon rank-sum test or Kruskal-Wallis test for continuous variables. Results: 554,733 pts met inclusion criteria; 84.50% white, 9.19% Black, 4.06% Asian; 5.88% Hispanic. 25,553 (4.61%) pts received NET. Annual NET use increased slightly between 2016 and 2018 [3.25% vs 3.49% (p=0.021) vs 3.89% (p &amp;lt; 0.0001)], remained stable in 2019 (3.98%), and then increased to 8.67% in 2020 (p &amp;lt; 0.0001). Median duration of NET remained relatively stable between 2016 and 2019 [74 days (d), 68d, 73d and 61d, 2016-2019] but declined in 2020 (56d, p&amp;lt; 0.0001 for 2020 vs 2016, 2017, 2018, and 2019). Older age and greater comorbidities were associated with NET use in all years (p &amp;lt; 0.0001). No racial association with NET use was seen in 2016-2018, but Black race was associated with greater NET use in 2019 (p=0.0122) and 2020 (p &amp;lt; 0.0001). Lobular histology, moderate grade, larger tumor size, and node involvement were associated with increased NET use in all years (p &amp;lt; 0.0001). Progesterone receptor positivity (PR+) and lower Ki67 were associated with NET use in 2020 (p=0.0007 and p&amp;lt; 0.0001), but not prior. Median tumor size for pts receiving NET was smaller in 2020 (16mm) compared with prior years (22, 23, 22, and 21mm for 2016-2019, p&amp;lt; 0.0001). Annual RS use increased for all pts between 2016 (34.59%) and 2020 (43.47%). RS use in NET pts was stable in 2016 (27.79%) and 2017 (27.54%), with modest increase in 2018 (29.56%; p 0.094, 2016 vs 2018, p=0.045, 2017 vs 2018), and then increased annually in 2019 (33.28%, p=0.0001) and 2020 (40.64%, p&amp;lt; 0.0001). Median RS was higher in pts receiving NET than in pts who did not in 2016-2019 (p=0.0078, 0.0003, 0.0271, and &amp;lt; 0.0001), but was similar in 2020 (RS=16; IQR 11, 22). Conclusions: Frequency of NET administration more than doubled in 2020, but duration was shorter than in prior years, possibly due to use of NET as “bridging therapy” due to COVID19 restrictions. Black race was associated with receipt of NET in 2020, possibly reflecting disparate impact of COVID19 on Black communities. NET use in 2020 was also associated with smaller tumor size, lower Ki67, and greater likelihood of PR+ disease than in prior years. Use of RS to guide NET increased annually, beginning in 2018. Association of NET with older age, greater comorbidities, higher stage, moderate grade, and lobular histology were seen in all years. Citation Format: Della Makower, Jaeun Choi, Susan Fineberg. Impact of COVID19 on neoadjuvant endocrine therapy use in breast cancer: A National Cancer Database analysis [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 PO1-17-10.

Abstract PO5-25-12: CDH1 mutations predict resistance to neoadjuvant taxane therapy

Abstract Background: Despite recent advances in personalized medicine, conventional chemotherapy remains a backbone in breast cancer therapy. Thus, identifying markers predicting sensitivity or resistance to individual chemotherapeutics is of great importance. Methods: In the EpiTax neoadjuvant trial, enrolling patients between 1997-2003, patients with primary breast cancers (T2 &amp;gt;4cm, T3/T4 and/or N2/N3) were randomized to epirubicin 90mg/m2/3W or paclitaxel 200mg/m²/3W monotherapy, with cross-over in case of inferior response. Pre-treatment snap-frozen tumor biopsies from 223 patients were analyzed by targeted NGS of a 360 gene panel. Endpoint for comparison was clinical response to the first regimen, since pCR was rare due to the large tumor sizes at inclusion. For validation purposes we performed targeted sequencing of tumor samples from a total of 478 patients included in the Gepar Trio (n=132), Quattro (n=171) and Quinto (n=175) trials, in which patients with &amp;gt;2cm tumors received neoadjuvant anthracycline/taxane combination regimens. Here, the primary endpoint was clinical response to combined treatment, but since these tumors were smaller than in the EpiTax-trial, pCR was included as a secondary endpoint. In addition, experimental validations were performed -by CDH1 knock-down and CRISPR/Cas9 knock-out in cell line models. Results: In samples from the EpiTax-trial, CDH1 mutations predicted an inferior response (trend across response groups; cPD, cSD, cPR and cCR) in the paclitaxel arm (p=0.01) as well as the epirubicin arm (p=0.04). The predictive value was observed within the subgroup of ER-positive cases (both for paclitaxel (p=0.005) and epirubicin (p=0.003)) but not among ER-negative tumors. The majority of CDH1 mutations (24/34=71%) were observed in lobular cancers. While lobular histology predicted resistance to paclitaxel (but not epirubicin), CDH1 mutations predicted resistance also within the subgroup of lobular cases (p=0.002), demonstrating CDH1 mutations to be an independent predictor and not only a co-variate to lobular histology. As assessing functionally linked genes, mutations in GATA3, a transcriptional regulator of CDH1, were predominantly observed in ductal cancers, and were not predictive of resistance to any compound. Yet, combining GATA3 and CDH1 mutations into a composite biomarker predicted resistance to both paclitaxel (p=0.007) and epirubicin (p=0.01), especially in ER-positive cases (p=0.002 and p=0.0004, respectively). While EMT-signatures had predictive value, this effect was largely dominated by CDH1, while other EMT-related genes had limited impact on response. In the independent validation cohort from the Gepar trials, selected with enrichment for lobular cancers (34%), CDH1 mutations were not significantly associated with resistance to therapy (p=0.19) although predicted lack of pCR (p=0.01). Combining GATA3 and CDH1 mutations predicted lack of clinical response (p=0.05) and lack of pCR (p=0.0007) respectively in this cohort. In the in vitro analyses, resistance to paclitaxel was observed in three different breast cancer cell lines upon siRNA mediated knock-down of CDH1, as well as in a CRISPR/Cas9 mediated CDH1 knock-out model, as measured by growth rate, induction of apoptosis, G2 arrest, mitochondrial respiration and tubulin stability. For anthracyclines, similar effects were observed for mitochondrial respiration. Conclusions: In conclusion, mutations in CDH1 predicted resistance to paclitaxel and epirubicin. Our data suggest that CDH1 mutations should be explored further as a predictive biomarker for potential application. Citation Format: Stian Knappskog, Reham Helwa, Sivaramakrishna Rachakonda, Liv B. Gansmo, Carsten Denkert, Lucy R. Yates, Christine Solbach, Michael Untch, Bruno V. Sinn, Anne-Sophie Litmeyer, Beyhan Ataseven, Jens Huober, David C. Wedge, Thomas Karn, Oleksii Nikolaienko, Frederik Marmé, Peter A. Fasching, Hans Petter Eikesdal, Elmar Stickeler, Christian Schem, Paul Jank, Marion van Mackelenbergh, Volkmar Müller, Baerbel Felder, Johannes Holtschmidt, Peter J. Campbell, Sibylle Loibl, Per Lonning. CDH1 mutations predict resistance to neoadjuvant taxane therapy [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 PO5-25-12.

Abstract PO1-22-09: Current margin assessment practice for breast-conserving surgery in China: a single institution audit

Abstract Background The appropriate negative margin width following breast-conserving surgery (BCS) for both ductal carcinoma in situ (DCIS) and invasive carcinoma (IC) has witnessed a shift towards de-escalation in international guidelines. However, there are limited nationwide data regarding margin assessment practice for BCS in China. This study aims to clarify the current real-world status of margin assessment from a single institution audit and secondarily to update the evidence on the association between margin width and local recurrence. Methods Eligible cases were derived from an extensive series of consecutive unselected patients with early invasive breast cancer who were treated with BCS at the Department of Breast Surgery in Shanghai Cancer Center Fudan University (FUSCC) between January 2015 and December 2017. Patient demographic and clinicopathological information as well as follow-up data were extracted from the hospital's electronic medical records. Pathological evaluation of negative margins was defined as no ink on tumor for IC in accordance with the SSO/ASTRO consensus guidelines released in 2014. Where applicable, margins were categorized as tumor on ink (involved), close margins (no tumor on ink but ≤1 mm), clear margins (1-2 mm), wide margins (2-5 mm), and wider margins (&amp;gt;5 mm). The positive margin rate (PMR), reoperation rate, and ipsilateral breast recurrence (IBR) rate were calculated according to different margin widths. Multivariable analyses of factors associated with re-excision were performed using binary logistic regression. Kaplan‒Meier survival curve analysis was performed for local recurrence-free survival (LRFS). Results A total of 2707 patients were enrolled in the current study, with a total PMR of 2.7%. The distribution of margin width revealed that wider margins (&amp;gt;5 mm) were optimized by most surgical oncologists (2092/2707, 77.3%) for BCS in our center. Additionally, the reoperation rates were 1.9% in the whole population, accounting for 48.3%, 7.5%, 4.2%, 0.8%, and 0.4% in each margin group. Specifically, among 247 patients with margins ≤2 mm, 41 (16.6%) received reoperation either by margin re-excision or mastectomy. Multivariable analyses identified that lobular histology, no selective additional resection and in situ pathology of involved/close margins are independent factors of re-excision recommendation. With a median follow-up of 54.3 months, the incidence of IBR was 1.7% in the whole cohort, representing for 5.2%, 4.2%, 2.8%, 1.9%, and 1.3% in each margin group, respectively. Kaplan‒Meier survival curve analysis showed a marginally significant difference in 5-year LRFS between groups with margins &amp;gt;2 mm and margins ≤2 mm (95.9% vs 97.8%, Table 1). Conclusions A wider margin width was preferably adopted in the routine practice of BCS. Our audit was aligned with previous evidence that a minimum clear margin of 2 mm is associated with a lower reoperation rate but favorable local control. Patients with margins no more than 2 mm were more likely to have re-excision in cases of lobular histology, no selective additional resection, and in situ pathology of involved/close margins. Ipsilateral breast recurrence models by margin status Citation Format: Feilin Qu, Cheng-Jia Shen, Wen-Tao Yang, Jun-Jie Li, Guangyu Liu, Zhi-Ming Shao. Current margin assessment practice for breast-conserving surgery in China: a single institution audit [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 PO1-22-09.

Abstract PO5-15-05: Clinical and genomic landscape of ERBB2 and ERBB3 mutated breast cancer

Abstract Background: Our understanding of tumorigenesis in ERBB2 (HER2) non-amplified breast cancer has recently evolved through genome sequencing efforts identifying somatic mutations in ERBB2 and its ERBB3 coreceptor (ERBB2/3). These alterations result in upregulation of HER2 activity and have been implicated in resistance to certain targeted therapies. To develop efficacious therapeutic strategies in this context, further delineation of the clinical and genomic landscape of ERBB2/3-mutated (ERBB2/3-mut) breast cancers is paramount. Methods: Patients (pts) with breast cancer who underwent tumor and normal tissue sequencing using the MSK-IMPACT assay between April 2015 to August 2019 were surveyed in this analysis. We performed gene enrichment analyses to assess the frequency, type and pattern of ERBB2/3-mut, and compared demographics and clinicopathologic characteristics of this cohort with those of pts with ERBB2/3-wild-type (wt) tumors. The landscape of co-occurring and mutually exclusive genomic alterations in oncogenic (as per OncoKB) ERBB2/3-mut vs. ERBB2/3-wt was studied in the context of receptor status. Finally, we investigated the association between ERBB2/3-mut status and clinical outcomes in HR+/HER2- pts. Progression free survival (PFS) on first line CDK4/6 inhibitors and endocrine therapy (CDK4/6i-ET) was assessed utilizing Cox proportional hazard models adjusted for endocrine therapy partner. Results: Of 4,458 evaluable pts with breast cancer, 260 were ERBB2/3-mut (ERBB2 n=182, 4.1%; ERBB3 n=90, 2.0%, with both ERBB2/3 n=12, 0.27%). A total of 368 ERBB2/3 alterations were identified in 321 samples, of which 324 were SNVs (88.0%) and 44 indels (12.0%). Of the 256 ERBB2-mut, 185 (72.3%) were pathogenic variants (PVs), with the most frequent alterations being L755S (28.6%), V777L (13.5%), G778_P780dup (10.3%) and S310F (12.4%). Of the 112 ERBB3-mut, 53 (47.3%) were PVs; E928G (47.3%) and G284R (11.3%) were the most common. ERBB2/3-mut tumors were enriched in lobular (n=72, 13.3%) over ductal histology (n=164, 4.6%; Odds ratio [OR]: 3.15, 95% confidence interval [CI]: 2.31–4.25; p=8.2 e-13). When duplicates from each category were excluded, ERBB2/3 variants were more prevalent in metastatic tumors (n=165, 7.3%) compared to primaries (n=119, 4.7%; OR: 1.61, 95% CI: 1.25–2.06, p=0.0001). A similar trend was observed in the HR+/HER2- subgroup (metastatic: 6.7% vs. primary: 4.3%; OR: 1.61, 95% CI: 1.12–2.2, p=0.0024). In the HR+/HER2- subgroup (n=3,039), ERBB2-mut (4.0%, PVs: 3.1%) were significantly co-altered (q&amp;lt; 0.1) with CDH1, TBX3, ERBB3, RUNX1, CBFB, MAP3K1, FOXA1 and NF1 and mutually exclusive with GATA3. In the HER2+ subgroup (n=640), ERBB2-mut (7.2%, PVs: 4.7%) were significantly co-altered with CDH1, TBX3, and CDKN2A/B. In the TNBC cohort (n=779), ERBB2-mut (2.3%, PVs: 1.7%) were mutually exclusive with TP53, and co-altered with PIK3CA, ARID1A, MAP3K1, CBFB, and CDH1. Overall, the ERBB3-mut were co-altered with ERBB2, CDH1, and CBFB. In HR+/HER2- pts with tumor sequencing performed prior to receiving first-line CDK4/6i-ET (n=468), PFS for ERBB2/3-mut (n=23) was not significantly different than ERBB2/3-wt (hazard ratio: 1.19, 95% CI: 0.75–1.90, p=0.46). Conclusion: Here we describe the clinical and genomic characteristics of a large cohort of ERBB2/3-mut breast cancers. We identify a notable enrichment of ERBB2/3-mut in lobular histology and metastatic tumors and tendency for co-alteration with CDH1 and multiple transcription factors reflecting the unique biology of ERBB2/3-mut breast cancers. Further analyses on an expanded cohort (n &amp;gt;6000 pts), including outcomes on HER2-directed antibody-drug conjugates (T-DXd) and targeted therapies such as PI3K inhibitors, will be presented at the 2023 SABCS Annual Meeting. Citation Format: Nadeem Bilani, Jacqueline Tao, Anton Safonov, Dana Casey, Joshua Drago, Mehnaj Ahmed, Barbara Acevedo, Komal Jhaveri, Jorge Reis-Filho, Mark Robson, Eneda Toska, Ariella Hanker, Carlos Arteaga, Sarat Chandarlapaty, Hanna Y Wen, Pedram Razavi. Clinical and genomic landscape of ERBB2 and ERBB3 mutated breast cancer [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 PO5-15-05.

Abstract PO1-16-01: Clinicopathological and global transcriptional complexity of estrogen receptor low positive breast cancers in a contemporary Swedish prospective population-based cohort

Abstract Background: Estrogen receptor (ER) expression is currently the most consequential biomarker for prognostic and therapeutic decision making in clinical management of early breast cancer. Endocrine therapy (ET) is an important part of standard of care in most cases with ER-positive disease, and an effective therapy for patients with endocrine-responsive tumors, decreasing the risk of recurrence and improving the rate of survival. Unfortunately, ET comes with frequently bothersome side-effects and tend to decrease quality of life. The threshold to define ER positivity as a marker of endocrine responsiveness is non-uniform between international and local guidelines. Among ER low positive tumors (ERlow ,1-10% expression) endocrine responsiveness is uncertain. Swedish national guidelines recommend a cut-off of ≥10% for ER positivity and ET prescriptions, thus patients with ERlow tumors are often exempted from adjuvant ET. This study explores the clinicopathological characteristics, global transcriptional complexity and clinical outcome of ERlow tumors to better understand their biology and response to therapy. Methods: 9138 patients diagnosed with early breast cancer between 2010 – 2021 in Sweden with available clinicopathological data and RNA sequencing data were included. Patients were classified according to ER expression: ERneg (&amp;lt; 1%; n=897), ERlow (1-10%, n=158) and ERhigh ( &amp;gt;10%, n=8083). Adjuvant ET was provided to 3.6%, 16.8% and 91.5% of patients with ERneg, ERlow, and ERhigh tumors, respectively. Clinicopathological characteristics, overall survival (OS) and global transcriptional profiles of ERlow tumors were compared with ERneg and ERhigh tumors, respectively. Results: Generally, ERlow and ERneg tumor pathological characteristics were more similar to each other but were significantly distinct compared to ERhigh tumors. However, among patients with HER2-negative disease only, significant differences related to tumor biology persisted between ERlow compared with ERneg tumors; ERlow was enriched with tumors displaying a lobular histology, NHG grades 1&amp;2, PgRlow/high expression, low proliferation and Luminal &amp; HER2-enriched molecular subtypes (p&amp;lt; 0.05 for all comparisons). Moreover, multivariable survival analyses revealed that the risk of dying was significantly lower for patients with ERlow tumors compared to patients with ERneg (p=0.005) or ERhigh tumors (p=0.011) in this cohort. The distribution of clinicopathological characteristics and overall survival between ERlow compared with ERneg or ERhigh tumors were similar among patients with HER2-positive tumors only. Global transcriptional comparisons identified only 42 genes to be differentially expressed between ERlow vs ERneg tumors (FDR&amp;lt; 0.05); but gene set enrichment analyses failed to identify any significantly enriched cancer-related processes/pathways within the queried databases. Conclusions: Identification of optimal therapies for all subsets of breast cancer is necessary in the pursuit of personalized medicine. These results confirm that ERneg and ERlow tumors are pathologically and transcriptionally distinct from ERhigh tumors. Although subtle differences exists in the underlying biology of ERlow compared to ERneg tumors, similar therapeutic management excluding ET for patients with ERlow and ERneg disease is recommended in the Swedish context. Omission of adjuvant ET did not seem to compromise overall survival for ERlow relative to ERneg or ERhigh tumors, urging the need for prospective studies investigating the true benefit of ET for ERlow tumors. Our results also raise reasonable clinical thoughts on the benefits of new treatment strategies such as cyclin-dependent kinase 4/6 inhibitors, immunotherapy and antibody-drug conjugates for patients with ERlow expressing tumors. Citation Format: Siker Kimbung, Srinivas Veerla, Anna Ehinger, Johan Vallon-Christersson, Martin Malmberg, Niklas Loman. Clinicopathological and global transcriptional complexity of estrogen receptor low positive breast cancers in a contemporary Swedish prospective population-based cohort [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 PO1-16-01.

Abstract PO4-16-08: Prognostic factors for tumor recurrence after breast-conserving and radiotherapy treatment for early invasive breast cancer: ten years of results in a referral center in Mexico City

Abstract Background: Breast cancer is the most common malignancy in the world, reporting more than 2 million new cases in 2020. In early stages, patients undergo primary surgery. Breast-conserving surgery (BCS) has generally been accepted as a treatment for invasive breast cancer, findings at 20 years still show that lumpectomy and breast irradiation, as compared with mastectomy, have no significant difference in overall survival among the treatment groups. Approximately 10-15% of patients will develop local or systemic recurrence in 5 to 10 years. Factors such as young age (&amp;lt; 45 years), close/positive margins, no breast radiation, are associated with ipsilateral breast tumor recurrence. High grade has been related to distant metastasis. The mortality trend is upward due to a higher incidence of the disease and earlier detection. Methods: This is an observational and retrospective cohort study, which included patients with early breast cancer, who were treated with conserving surgery and received radiotherapy, at the Breast Oncology Service at the UMAE Gineco 4 "Luis Castelazo Ayala" during the period from January 2012 to December 2022. The aim of our study was to describe the prognostic factors associated with disease-free survival (DFS) and overall survival (OS) in patients with localized breast cancer treated with BCS. DFS was defined as time from surgery to recurrence event (local recurrence, distant recurrence, contralateral breast cancer, second primary cancer, or death from any cause) whichever occurred first. For statistical analysis, Kaplan Meier and Log-rank methods were used for survival analysis. Cox proportional hazard model was used for multivariate analysis. Results: We included 399 patients, the median follow-up was 88 months (95%CI 86-91). Median age was 59 years. The most common pathological stage was IA in 44.9%, the predominant immunophenotype was luminal A in 56.1% of patients, follow by luminal B in 19.3% and 13% were triple negative. Management of axilla with sentinel node biopsy occurred in 50.1% and 49.9% underwent to lymph node dissection. Regarding surgery outcomes 40.4% of the patients required widening of the margins, 5% of the patients remained with close surgical margins ≤2 mm, 7.5% had complications associated with the surgery, and none related death ocurred. All patients received adjuvant radiotherapy, the median time to initiation was 32 weeks (range 3-70) and 65.4% received adjuvant chemotherapy. Recurrence events occurred in 15.5% of patients, local 2.8%, systemic 8.8%, contralateral breast cancer 1.7%, and second primary 2.2%. Estimated disease-free survival at 5 and 10 years were 86.6% and 74.2%, respectively. In the multivariate analysis independent prognostic factors for DFS were: lobular histology HR 2.95 (95%IC 1.5-5.7), tumor size ≥ 2cm HR 1.95 (95%IC 1.1-3.6), close surgical margins HR 2.62 (95%IC 1-6.6), and ER low expression (1-10%) HR 4.39 (95%CI: 1.6-12.4). Estimated OS at 5 and 10 years for patients who experienced recurrence were 78.4% and 47.4% and for patients without recurrence were 96.8% and 93.5%, respectively (adjusted HR: 10.4, 95%CI: 5.2-20.6). Conclusion: These results suggest that patients with early breast cancer treated with conserving surgery and radiotherapy with risk factors such as lobular carcinoma, tumor size ≥2cm, close margins, and low expression of estrogen receptors have a high risk of recurrence and significantly decreased overall survival at 5 and 10 years. Citation Format: Nayeli Ortega-Avila, Yuly A. Remolina-Bonilla, Janett Caballero-Jasso. Prognostic factors for tumor recurrence after breast-conserving and radiotherapy treatment for early invasive breast cancer: ten years of results in a referral center in Mexico City [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 PO4-16-08.