Two-phase deep convolutional neural network for reducing class skewness in histopathological images based breast cancer detection

Mixed invasive ductal and lobular carcinoma (Mixed IDC/L) is a rare subtype (3-5%) of invasive breast cancer with elusive pathophysiology. This entity is characterized by a mixed population of both ductal and lobular components within an individual tumor. Few studies have been published to date which compare Mixed IDC/L to invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) from a histopathologic perspective. Available literature on this topic is sparse and has been conflicting with regards to outcomes, and no studies to date describe the response of Mixed IDC/L to neoadjuvant chemotherapy. Patients with ILC have been shown to have lower response rates to neoadjuvant chemotherapy as compared to patients with IDC, which in turn leads to lower rates of successful breast conserving surgery and higher rates of re-excision due to positive margins. We aimed to compare Mixed IDC/L to pure ILC with regards to response to neoadjuvant chemotherapy and the need for repeat surgical intervention. We identified 26 patients with Mixed IDC/L and 113 patients with ILC who received neoadjuvant chemotherapy at our institution between 1990 – 2017. At baseline, the groups had a similar median age, as well as ER H-score, PR H-score, and Ki-67 index. There was no statistical difference in rates of pathologic complete response (pCR) or percent tumor volume reduction post therapy between the two groups. Similarly, the percent of patients that required re-excision was not statistically different. Interestingly, the metastatic pattern was similar between the groups and included sites of dissemination such as the peritoneal cavity and omentum, which are not common sites of metastasis for IDC. These findings suggest that Mixed IDC/L tumors behave similarly to ILC with regard to their response to neoadjuvant chemotherapy and patterns of metastatic spread. These findings support a prominent role for the lobular component in this mixed subtype in driving biology, including response to neoadjuvant therapy and metastatic dissemination. Ongoing efforts are directed towards incorporating data from the IDC cohort, as well as evaluation of changes in histology, ER/PR H-scores, and Ki-67 levels as a result of therapy. These data may imply that Mixed IDC/L tumors may behave clinically more like ILC than IDC, but larger studies are needed to study this rare breast cancer subtype. Citation Format: Azadeh Nasrazadani, Jennifer M Atkinson, Yujia Li, Priscilla F McAuliffe, Rachel C Jankowitz, Leisha A Emens, George C Tseng, Adrian V Lee, Norman Wolmark, Steffi Oesterreich, Peter C Lucas. Mixed invasive ductal and lobular carcinoma (IDC/L) behaves similarly to invasive lobular carcinoma (ILC) with regard to neoadjuvant chemotherapy response and metastatic dissemination [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-16-26.

Background: Breast conserving surgery (BCS) and its following radiotherapy is an accepted therapeutic method for patients with invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC). Objectives: The aim of this study was to investigate the effect of intraoperative electron radiotherapy on women with breast cancer (invasive lobular and ductal carcinoma). Methods: Between August 2013 and September 2017, 968 patients, who were referred to Cancer Research Center, Shahid Beheshti University of Medical Sciences with invasive breast cancer, were treated with breast-conserving surgery and radiotherapy. Of those, 426 patients received a tumor bed boost with intraoperative electron radiotherapy (IOERT) during lumpectomy (58 patients with pure invasive lobular carcinoma, 239 patients with pure invasive ductal carcinoma, and 129 patients with other diagnoses). 542 patients received a tumor bed boost with conventional external beam radiotherapy post lumpectomy (24 patients with pure invasive lobular carcinoma, 418 patients with pure invasive ductal carcinoma, and 100 patients with other diagnoses). The patients were followed up to 49 months. A comprehensive list of clinical and pathologic features was evaluated for all patients. We retrospectively analyzed outcomes of breast cancer treated with boost intraoperative electron radiotherapy (pure ILC and IDC groups) and in other group treated with boost conventional external beam radiotherapy (pure ILC group). Results: None of the ILC patients had recurrence in the two groups. The four-year survival rate for ILC patients was 100%, but in the IDC group the survival rate was 97%. Survival analyses showed patients with IDC had a higher risk of ipsilateral breast tumor recurrence (IBTR) and metastasis. Conclusions: Overall, the rates of IBTR and metastasis in the ILC boost IOERT group were significantly low. This finding suggests that IOERT technique deployment in ILC had no inferiority compared with the control group.

Breast cancer (BC) is a commonest disease that causes death among women worldwide, Current study was designed to identify the different types of BC and find out the most common type. Data were obtained from the medical profiles of the National Center for Teaching Laboratories and Oncology Teaching Hospital/ Medical City, and teaching hospital in Kut, where pathological and medical data were collected from the medical profile of 1497 patients diagnosed with B C from January 2011 to December 2022. The results showed a significant increase in the number of BC cases from 46 in 2011 up to 149 in 2022. The mean ± standard deviation of BC cases significantly increased from (77.1 ± 22.8 ) case/year in (2011- 2017) up to (191.4 ± 34.1) case/year in the later five years (2018 – 2022). Out of 1497 cases of BC, 1343 case (89.7%) of them with ductal carcinoma (DC), 86 case (5.7%) lobular carcinoma (LC), 17 case (1.1%) metaplastic carcinoma, 17 case (1.1%) paget’s disease, 15 case (1%) phylloids tumor, 14 case (0.9%) mucinous carcinoma, and 5 cases (0.4%) sarcoma. According to the age of BC patients, the average age of all patients is (51.2 ± 12.1) years, and without significant difference between those with different types of BC and in the age intervals of BC patients, the majority of them (84.6%) at age interval ≥ 40 year in comparison with 15.4% at young age interval (20 – 39). Moreover, statistical analysis of BC patients based on their menopause status reveals that (50.2%) are premenopausal and (49.8%) are postmenopausal, and there is no significant difference between patients with different types of BC.

In 1973, the European Institute of Oncology performed the first prospective neoadjuvant chemotherapy study in locally advanced, inoperable breast cancer. The original purpose was to downstage the primary tumor in order to achieve surgical resection. This approach has subsequently increased in popularity, and in the last 10 years, randomized controlled trials of neoadjuvant chemotherapy have been performed with a view to further downstage the primary tumor and lymph nodes in order to achieve greater rates of breast-conserving surgery and to test whether systemic therapy given earlier would confer a survival benefit. Although the net result of these trials did demonstrate a higher rate of breast conservation, no overall survival benefit was seen. However, in subgroup analysis, there was a significant survival benefit in patients in whom a complete pathologic response (pCR) was achieved. In the National Surgical Adjuvant Breast and Bowel Project B-18 trial of neoadjuvant chemotherapy, at 9 years median follow-up, the overall survival rate for patients achieving a pCR was 85% compared with 73% in those in whom residual cancer was detected on histopathologic examination. For disease-free survival, the respective rates were 75% and 58%. After adjustment for other prognostic factors, achievement of a pCR was associated with a 50% reduction in deaths compared with the group as a whole. Mauri et al evaluated nine randomized studies, with a total of 3,946 patients with breast cancer in whom neoadjuvant therapy was compared with adjuvant systemic therapy. They found no statistically or clinically significant difference between neoadjuvant therapy and adjuvant therapy arms with regard to overall survival, disease progression, or distant disease recurrence. However, they observed that neoadjuvant therapy was associated with an increased risk of locoregional disease recurrence compared with adjuvant therapy, especially in trials where more patients in the neoadjuvant arm received radiation therapy without surgery. In several retrospective studies, the pCR rates in invasive ductal breast carcinoma (no special type) have been shown to be approximately 15% or less, whereas the pCR rates in invasive lobular carcinoma have been shown to be 2% or less. Katz et al reviewed randomized trials of neoadjuvant chemotherapy and noted that the pCR rate was 1.7% in invasive lobular carcinoma and 11.6% in invasive ductal breast carcinoma (no special type). Regarding invasive lobular carcinoma, they concluded: “the benefit from systemic chemotherapy for individuals with this form of breast disease is unclear.” Similarly, two retrospective studies have demonstrated low rates of successful breast conservation for patients with lobular carcinoma who underwent neoadjuvant chemotherapy. In patients who received breast-conserving surgery after neoadjuvant therapy, Soucy et al found surgical margin involvement in 43% of patients with lobular carcinoma compared with 16% of patients with invasive ductal carcinoma (no special type). Another study, from the M. D. Anderson Cancer Center, of 284 consecutive patients diagnosed with pure invasive lobular carcinoma between 1998 and 2006 compared patients who received neoadjuvant chemotherapy with those who received primary surgery as first-line treatment and concluded that neoadjuvant chemotherapy did not increase the rates of breast conservation in this morphologic subtype. It should be noted that the above studies are retrospective, not randomized, trials. In the three randomized trials of neoadjuvant endocrine therapy (P024 conducted by the Letrozole Neoadjuvant Breast Cancer Study Group, IMPACT [Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen], and PROACT [Pre-Operative “Arimidex” Compared to Tamoxifen]) for women with estrogen receptor (ER) –positive disease, none of which carried out analysis of histological tumor type (ie, lobular v ductal [no special type]), a higher rate of breast conservation was observed in women who received preoperative endocrine treatment. The lack of subgroup analysis in these three studies does not allow one to draw conclusions regarding histologic type-specific effectiveness of neoadjuvant endocrine treatment, although classical lobular carcinoma is well recognized as more often being ER positive than ductal tumors (no special type). JOURNAL OF CLINICAL ONCOLOGY COMMENTS AND CONTROVERSIES VOLUME 28 NUMBER 22 AUGUST 1 2010

Invasive lobular carcinoma (ILC) is a distinct histological subtype of breast cancer that can make early detection with mammography challenging. We compared imaging performance of digital breast tomosynthesis (DBT) to digital mammography (DM) for diagnoses of ILC, invasive ductal carcinoma (IDC), and invasive mixed carcinoma (IMC) in a screening population. We included screening exams (DM; n = 1,715,249 or DBT; n = 414,793) from 2011 to 2018 among 839,801 women in the Breast Cancer Surveillance Consortium. Examinations were followed for one year to ascertain incident ILC, IDC, or IMC. We measured cancer detection rate (CDR) and interval invasive cancer rate/1000 screening examinations for each histological subtype and stratified by breast density and modality. We calculated relative risk (RR) for DM vs. DBT using log-binomial models to adjust for the propensity of receiving DBT vs. DM. Unadjusted CDR per 1000 mammograms of ILC overall was 0.33 (95%CI: 0.30-0.36) for DM; 0.45 (95%CI: 0.39-0.52) for DBT, and for women with dense breasts- 0.33 (95%CI: 0.29-0.37) for DM and 0.54 (95%CI: 0.43-0.66) for DBT. Similar results were noted for IDC and IMC. Adjusted models showed a significantly increased RR for cancer detection with DBT compared to DM among women with dense breasts for all three histologies (RR; 95%CI: ILC 1.53; 1.09-2.14, IDC 1.21; 1.02-1.44, IMC 1.76; 1.30-2.38), but no significant increase among women with non-dense breasts. DBT was associated with higher CDR for ILC, IDC, and IMC for women with dense breasts. Early detection of ILC with DBT may improve outcomes for this distinct clinical entity.

Utility of Breast Magnetic Resonance Imaging in Determining Candidacy for Partial Breast Irradiation

To evaluate the relative effectiveness of letrozole compared with tamoxifen for patients with invasive ductal or lobular carcinoma. Patients diagnosed with early-stage invasive ductal carcinoma (IDC) or classic invasive lobular carcinoma (ILC) who were randomly assigned onto the Breast International Group (BIG) 1-98 trial and who had centrally reviewed pathology data were included (N = 2,923). HER2-negative IDC and ILC were additionally classified as hormone receptor-positive with high (luminal B [LB] -like) or low (luminal A [LA] -like) proliferative activity by Ki-67 labeling index. Survival analyses were performed with weighted Cox models that used inverse probability of censoring weighted modeling. The median follow-up time was 8.1 years. In multivariable models for disease-free survival (DFS), significant interactions between treatment and histology (ILC or IDC; P = .006) and treatment and subgroup (LB like or LA like; P = .01) were observed. In the ILC subset, there was a 66% reduction in the hazard of a DFS event with letrozole for LB (hazard ratio [HR], 0.34; 95% CI, 0.21 to 0.55) and a 50% reduction for LA subtypes (HR, 0.50; 95% CI, 0.32 to 0.78). In the IDC subset, there was a significant 35% reduction in the hazard of a DFS event with letrozole for the LB subtype (HR, 0.65; 95% CI, 0.53 to 0.79), but no difference between treatments was noted for IDC and the LA subtype (HR, 0.95; 95% CI, 0.76 to 1.20). The magnitude of benefit of adjuvant letrozole is greater for patients diagnosed with lobular carcinoma versus ductal carcinoma.

e19291 Background: Invasive lobular carcinoma (ILC), the second most common histological breast cancer type, comprises 10-15% of breast tumors. Although ILC is thought to have a low risk of relapse, patient survival data vary. ILC treatment guidelines mirror those for invasive ductal carcinoma (IDC); however, these were extrapolated from trials that included predominantly IDC. The FLEX Registry captures data from real-world breast cancer patients; the current sub-study evaluated molecular profiles and treatment recommendations in ILC. Methods: The FLEX Registry (NCT03053193) includes stage I-III primary invasive breast cancer patients who receive 70-gene signature (70-GS)/80-gene signature (80-GS) testing and consent to full transcriptome and clinical data collection. This sub-analysis includes 335 ILC patients and 2,179 IDC patients enrolled from 2017 to present. 70-GS stratified tumors by risk of distant metastasis [High (HR), Low (LR), Ultralow (UL) Risk], and 80-GS classified tumors by molecular subtype (Luminal, HER2, or Basal type). Genomic and clinical data were compared for ILC and IDC using chi-square or Fisher’s exact test. Results: ILC represented 13% of FLEX cases (n = 335/2752); 81% were lymph node-negative, 99% ER-positive, and 94% HER2-negative. Clinical risk assessment (MINDACT criteria) classified 61% of ILC and 53% of IDC as low risk (p = 0.03). 70-GS risk distribution in ILC (18% UL, 51% LR, 31% HR) differed from IDC (13% UL, 34% LR, 53% HR; p < 0.01). Discordance between 70-GS and clinical risk was greater in ILC (43%) than IDC (30%, p < 0.01). 80-GS results also differed between ILC (98% Luminal, 1.6% HER2, 0.3% Basal) and IDC (85% Luminal, 3% HER2, 11% Basal; p < 0.01). Inclusion of chemotherapy (CT) in treatment plans was associated with 70-GS risk (p < 0.01); treatment plans that disagreed with 70-GS results were associated with discordant clinical risk (p < 0.05). Treatment plans disagreed with 70-GS in 15% of ILC and 12% of IDC total cases (p = 0.08), and more frequently in HR cases (25% in ILC, 14% in IDC; p < 0.01). Conclusions: The FLEX Registry includes patients with ILC consistent with real-world breast cancer frequencies. ILC demonstrated genomic risk and subtype profiles distinct from IDC. Treatment plans largely agreed with 70-GS results; however, discordance was more frequent in HR ILC than IDC. Future studies will evaluate clinical outcomes; however, these results demonstrate the added value of molecular profiling in ILC and the utility of real-world registry data in evaluating uncommon breast tumor types. Clinical trial information: NCT03053193 .

Background: Invasive lobular carcinoma (ILC) is the second most common histological subtype of breast cancer after invasive ductal carcinoma (IDC). While specific clinical and pathological features differ between ILC and IDC, both histologies are treated the same, due to a lack of knowledge of targetable pathways underlying the observed differences. To identify potential genetic drivers of ILC progression, we set out to identify genes with copy number (CN) alterations, comparing tumors with good outcome to those with poor outcome. Method: We designed probes for a total of 67 genes known to be frequently altered in breast cancer and used sensitive nanoString technology to comprehensively investigate CN alterations of these genes in 70 well-curated primary ILCs. ILC cell lines MDA-MB-134-VI, SUM44PE, and BCK4 were used for functional studies including proliferation, apoptosis, colony formation, and analysis of gene expression. Results: Our studies reveal that ESR1 is frequently amplified in primary ILC (14% gains and 10% amplification), and that tumors with amplified ESR1 are more likely to recur compared to those with normal CN. Our analysis also identified a subset of ILCs with HER2 amplification (19%) despite a negative clinical IHC score, and these tumors expressed high HER2 mRNA, protein, and demonstrated enrichment of a molecular HER2 signature. The other most frequently amplified genes included CCND1 (33%), MDM4 (17%), and MYC (17%), and most frequently lost genes were NCOR2 (7%), FGFR4 (6%) and TP53 (6%). MDM4, a negative regulator of p53, has previously been reported to play a role in breast cancer, though little is known about its role in ILC. We demonstrate that decreasing MDM4 levels in p53 wild type ILC cell lines results in increased apoptosis, decreased proliferation associated with cell cycle arrest, and activation of p53 target genes. Intriguingly, a similar induction of G0/G1 cell cycle arrest and increase in apoptosis was observed in p53 mutant ILC cells after MDM4 downregulation, suggesting a p53-independent function of MDM4. Conclusion: Sensitive detection of CN changes identified amplifications of ESR1 and MDM4 as potential drivers of ILC. Functional studies demonstrate that MDM4 has both p53 dependent and independent functions that warrant further study. Citation Format: Atkinson JM, Cao L, Basudan A, Sikora MJ, Bahreini A, Tasdemir N, Jankowitz RC, McAuliffe PF, Dabbs D, Haupt S, Haupt Y, Peter Lucas PC, Lee AV, Oesterreich S. Copy number analysis identifies ESR1 and MDM4 as drivers of progression in invasive lobular breast carcinoma [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-06-03.

555 Background: Women with early-stage breast cancer (BCa) are living longer, and survivorship issues including second primary cancers (SPCs) are therefore increasingly important. This study seeks to determine the risk of SPCs, including contralateral breast cancer (CBCa), in women with early-stage invasive lobular carcinoma (ILC). Methods: The study population consisted of women with BCa diagnosis between 2000-2018 within the NCI Surveillance, Epidemiology, and End Results (SEER v 3.2.9) registry and between 2000-2021 in the Mayo Clinic Cancer Registry. In the SEER registry, the standardized incidence ratios (SIR) for SPCs were estimated for adult women with histologically confirmed early stage (I-III) ILC compared to the development of any primary cancer in the general population. For reference, SIRs for SPCs for a similar patient population with invasive ductal carcinoma (IDC) of the breast were also estimated. For comparison of CBCa between ILC and IDC, follow up records from the Mayo Clinic Cancer Registry were evaluated among adult women who underwent lumpectomy or unilateral mastectomy for early stage ILC or IDC. A multivariable Cox proportional hazards regression was performed to compare the risk of CBCa between ILC and IDC while adjusting for the age at diagnosis, race/ethnicity and estrogen receptor status of the primary tumor. Results: An increased incidence (p<0.05) of any SPCs and second BCa was noted for both ILC and IDC compared to the expected rate of primary cancer in the general population (Table). Interestingly, women with ILC were observed to have a significantly increased incidence of subsequent gastric cancer which was not seen for women with IDC. An SIR >1.5 was noted for subsequent risk of sarcoma, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) for both ILC and IDC (Table). In the Mayo Clinic Cancer Registry of 2,218 women with ILC and 14,629 women with IDC meeting the inclusion criteria, the 5-year risk of CBCa was 2.6% and 1.5% (log rank statistic p-value =0.001) for ILC and IDC respectively. A significantly increased risk of CBCa was noted in women with ILC (Hazard Ratio 1.82, 95% CI 1.34-2.47, p<0.001) compared to women with IDC in the multivariable analysis. Conclusions: Women with ILC may have an increased risk of SPC and second BCa compared to the risk of any primary cancer in the general population. The increased incidence of gastric cancer and the higher risk of CBCa in ILC survivors compared to women with IDC is intriguing and needs to be investigated further including evaluation of the role of germline genetic factors. [Table: see text]

Introduction: Pleomorphic lobular carcinoma (PLC) is an understudied, rare and aggressive form of invasive lobular carcinoma (ILC), distinct from both invasive ductal carcinoma (IDC) and classical ILC. Though histologically related to ILC, PLC clinically resembles high-grade IDC. We evaluated overall survival (OS) and disease-specific survival (DSS) in PLC relative to IDC and ILC, using robust causal inference methods to adjust for clinicopathologic and treatment differences. Methods: The SEER (Surveillance, Epidemiology, and End Results) 17 database was used to identify all adult female patients with primary invasive breast cancer between 2000 and 2022. Inverse probability of treatment weighting (IPTW) based on a multinomial propensity score was used to adjust for baseline differences in demographics (age, race, income, rurality), tumor characteristics (grade, AJCC stage, receptor subtype) and treatment variables (surgery, radiation, chemotherapy). Covariate balance was assessed using standardized mean differences (SMDs) via Love plots. Residual imbalances (SMDs >0.15) were addressed using multivariable Cox models for doubly robust estimation. Proportional hazards (PH) assumption was assessed via Schoenfeld residuals. If satisfied, IPTW-weighted Cox models were used; if violated, time-varying Cox models with log(time) interactions estimated dynamic hazard ratios. Analyses were conducted at all-time, 5- and 10-year follow-ups. Kaplan-Meier curves were used to visualize survival by subtype. LASSO-regularized logistic regression identified 5- and 10-year OS and DSS predictors among PLC patients. Statistical analysis was conducted in R using p < 0.05. Results: Of the 721,127 patients identified, those with PLC (n = 181) when compared with IDC (n = 631,198) and ILC (n = 75,653) presented with larger (PLC: 3.49 ± 2.57 cm, IDC: 2.06 ± 1.53 cm, ILC: 2.73 ± 1.94 cm), higher-grade (grade 3+; PLC: 51.4%, IDC: 35.3%, ILC: 8.1%) and more advanced-stage tumors (stage III; PLC: 23.2%, IDC: 9.8%, ILC: 14.2%). PLC tumors were less likely to be HR+ (ER+ PLC: 70.7%, IDC: 77.6%, ILC: 94.3%; PR+ PLC: 58.6%, IDC: 67.4%, ILC: 80.0%), less likely to be HER2- (PLC: 43.6%, IDC: 50%, ILC: 60%) and more frequently triple negative (PLC: 8.8%, IDC: 6.9%, ILC: 0.8%). PLC patients received more mastectomies (PLC: 55.2%, IDC: 37.9%, ILC: 48.7%) and chemotherapy (PLC: 56.9%, IDC: 43.4%, ILC: 31.9%) yet had comparatively worse unadjusted OS (PLC: 64.1%, IDC 75.9%, ILC: 74.2%) and DSS (PLC: 86.7%,IDC: 91.4%, ILC: 91.1%). PH assumptions were violated in PLC vs ILC comparisons at all-time and 10-year follow-ups. Time-varying models demonstrated a significant early survival advantage in ILC over PLC in both OS (HR = 0.12, 95% CI: 0.05-0.28, p < 0.0001) and DSS (HR = 0.05, 95% CI: 0.02-0.14, p < 0.0001), though this benefit diminished over time (OS HR(tt) = 1.58, 95% CI: 1.29-1.93, p < 0.0001; DSS HR(tt) = 1.88, 95% CI: 1.46-2.43, p < 0.0001). For IDC, a survival advantage was present against PLC in OS at all-time (HR: 0.72, 95% CI: 0.56-0.93, p < 0.05), 5-year (HR = 0.68, 95% CI: 0.49-0.95, p < 0.05) and 10-year follow-up (HR = 0.74, 95% CI: 0.55-0.98, p < 0.05). In the PLC-specific LASSO analysis, poorer outcomes were associated with larger tumors, more advanced stage tumors and identifying as Black, while improved outcomes were associated with lower grade, HR+/HER2+ status and receiving chemotherapy. Conclusion: PLC is associated with significantly worse survival outcomes compared to both IDC and ILC. While ILC confers an early survival benefit that diminishes over time, IDC maintains a consistent OS advantage. Our findings support PLC as an aggressive subtype of ILC warranting dedicated research to improve earlier detection and treatment. Citation Format: D. Walji, V. Giannakeas, D. W. Lim. Clinical characteristics and survival outcomes of Pleomorphic Lobular Carcinoma: a comparative analysis with classical ILC and IDC [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-08-10.

Background: Invasive lobular carcinoma (ILC) represents the second most common BC subtype and is often characterized as hormone receptor positive and HER2−negative. However a small subset of ILC is found to be HER2+. Isolated case reports have demonstrated high responsiveness to trastuzumab in patients with advanced HER2+ ILC. The HERA trial compares 1 or 2 years of trastuzumab treatment with observation and 1 versus 2 years of trastuzumab treatment after standard chemotherapy in women with HER2+ breast cancer. We sought to evaluate the incidence of HER2+ ILC and the magnitude of trastuzumab benefit in HER2+ ILC in the context of the HERA trial. In addition, we sought to describe the pattern of hormone receptor positivity in the subsets of ILC and invasive ductal carcinoma (IDC) Methods: The database used in the analysis had a clinical cut-off date of 9th June 2008 and 4-year median follow-up (Gianni et al., 2011). Patients randomized to the 1-year trastuzumab and observation arms were included in the present analysis. Central assessment of hormone receptor status was considered. Histological BC subtype was assessed locally. Results: Of the 1703 women randomized to one-year of trastuzumab and 1698 to observation, 5.5% (n=187) and 94.5% (n=3213) were diagnosed as HER2+ ILC and IDC, respectively. Central hormone receptor status was available in 88.3% (n = 2838) of IDC and 86.1% (n=161) of ILC. ER and/or PR positivity was more common in ILC than IDC (63.4% [102/161] vs. 46.3% [1314/2838]; p<0.001). Allred scores for ER are shown in the table below. The DFS hazard ratios comparing one year of trastuzumab versus observation were 0.63 (95% CI 0.34−1.14) for ILC and 0.77 (95% CI 0.67−0.89) for IDC. There was no evidence of an interaction between histological subtype and trastuzumab benefit (interaction [subtype lobular and subtype ductal and not lobular] p=0.49). Conclusion: HER2+ ILC accounts for 5.5% of patients included in a large population of over 3,000 HER2+ BC. While only a limited number of patients with ILC was enrolled, this analysis suggests an increased ER positivity in ILC compared to IDC. There was no suggestion that patients with HER2+ ILC derived a different magnitude of benefit from adjuvant trastuzumab when compared to the HER2+ IDC cohort. The lack of central pathology review for BC subtype assessment is a caveat of our study. Future research in the field of ILC and particularly in the HER2+ subset should be encouraged. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-18-01.

Introduction: MammaPrint, a 70-gene assay used to predict breast cancer recurrence, is typically obtained on the surgical specimen to guide the use of adjuvant chemotherapy. However, MammaPrint results obtained at the time of diagnosis on core biopsy specimen could allow consideration of neoadjuvant chemotherapy (NAC), particularly for tumors that may not traditionally be considered for NAC such as invasive lobular carcinoma (ILC). We hypothesized that MammaPrint scores correlate with pathologic complete response (pCR) and can predict NAC response independent of histology type. Methods: The National Cancer Database was used to identify patients with AJCC Stage I-III unilateral HR+/HER2- breast cancer with MammaPrint scores treated 2010-2018. Patients were stratified by histology: invasive ductal carcinoma (IDC) and ILC; and by MammaPrint score for 5-year breast cancer recurrence: Low Risk (1%) and High Risk (12%). Descriptive statistics identified clinical and treatment differences between groups. Logistic regression was used to identify factors associated with chemotherapy receipt and sequence. A subset analysis of patients receiving NAC compared pCR rates by MammaPrint score and histology type. Results: Of 10,999 patients, 9,351 (85%) were diagnosed with IDC and 1,648 (15%) with ILC. ILC were larger at presentation: 40% of ILC were cT2 or greater vs. 29% of IDC (p< 0.001). However, 90% of patients in both groups had cN0 disease. The majority of ILC were grade II (67% ILC vs. 52% IDC, p< 0.001). High Risk MammaPrint scores were significantly more common in IDC tumors: 44% IDC vs 25% ILC (p< 0.001). Mastectomy and axillary lymph node dissection (ALND) were performed more often for ILC than IDC (unilateral mastectomy 32% vs. 21%, bilateral mastectomy 17% vs. 12%, ALND 29% vs. 24%; all p< 0.001). Conversely, chemotherapy (38% vs. 30%, p< 0.001) and radiation (69% vs. 64%, p< 0.001) were more frequently used to treat IDC than ILC. In the subset analysis of patients who received NAC (n = 715), tumors with High Risk MammaPrint scores had more favorable in-breast and axillary responses than those with Low Risk scores for both ILC and IDC (Table 1). Furthermore, only tumors with High Risk Mammaprint scores achieved an overall pCR: 7% IDC and 5% ILC. There were no significant differences in pCR rates by histology type. On multivariable logistic regression, High Risk MammaPrint score was positively associated with the receipt of NAC (OR 4.3, p< 0.001) and adjuvant chemotherapy (OR 24.8, p< 0.001). NAC, adjuvant chemotherapy, and any chemotherapy were also strongly associated with node-positive disease and tumor size >2cm, but not IDC vs. ILC histology. Conclusions: Superior response to NAC was observed in tumors with High Risk MammaPrint score regardless of histology type, indicating a correlation between pCR rates and genomic assay results. Greater use of NAC guided by High Risk Mammaprint score obtained on core needle biopsy may allow patients with invasive breast cancer to undergo less extensive breast and axillary surgery. Further prospective studies using MammaPrint testing on core biopsy specimens could validate these findings in clinical practice. Table 1. Response to neoadjuvant chemotherapy by MammaPrint score for patients with Invasive breast carcinoma, NCDB 2010–2018 Citation Format: Lauren M. Drapalik, Rashi Singh, Ashley Simpson, Lisa Rock, Robert Shenk, Amanda L. Amin, Megan E. Miller. Using MammaPrint on Core Needle Biopsy to Guide Neoadjuvant Chemotherapy for Invasive Breast Carcinoma [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-02.

Previous studies of patients with breast cancer have compared survival of invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) with contradictory results. This study examines the effect of the diagnosis of IDC or ILC in conjunction with age at diagnosis, pathologic tumor size, pathologic stage, histologic grade, and lymph node status of 307 women with IDC or ILC in 1992 in the Greater Western region of Sydney in Australia. Survival analysis was conducted using the Kaplan-Meier method. Relative risks associated with IDC or ILC and other important prognostic factors and adjusted for each other were computed using Cox proportional hazard regression. The proportion of grade I tumors was significantly higher in ILC (41%) than in IDC (16%). Conversely, the proportion of grade III tumors was only 18% in ILC as against 41% in IDC (p = 0.020). The 10-year survival of women with IDC was 69%, compared to 84% for ILC (p = 0.073). However, the 15 percentile point difference between overall survival of IDC and ILC was markedly reduced after adjustment for nodal status. The difference was eight percentile points for node-negative patients (p = 0.361) and five percentile points for node-positive patients (p = 0.464). Age at diagnosis, tumor size, pathologic stage, and lymph node status were independent prognostic indicators for 10-year survival. There was no prognostic difference between IDC and ILC. The result shows the importance of adjusting for other important clinicopathologic characteristics before comparing the overall survival of IDC and ILC.

Background: Invasive lobular carcinoma (ILC), the second most common histologic subtype of breast cancer, is increasingly recognized as a distinct tumor type compared to the more common invasive ductal carcinoma (IDC). While ILC is known to have lower rates of pathologic complete response to neoadjuvant chemotherapy, ILC tumors are biologically heterogenous. As such, genomic signatures might identify patients with ILC who might benefit from tailored treatment options. The gene expression signature MammaPrint (MP) classifies tumors as having a Low Risk or High Risk of distant recurrence. MP combined with BluePrint (BP), a molecular subtyping signature, categorizes tumors as Luminal A (MP Low Risk), Luminal B (MP High Risk), Basal or HER-2 type. ImPrint is a 53-gene signature that identifies HR+HER2- patients predicted to benefit from immune checkpoint inhibitors. RePrint is a 60-gene DNA repair deficiency (DRD) signature that identifies HR+HER2- patients who may benefit from PARP inhibitors with platinum agents. Response Predictive Subtypes (RPS), used in the I-SPY2 trial, combine clinical subtype and these genomic signatures to personalize treatment planning and improve outcomes. In this study, we determined the distribution of 3 RPS in HR+HER2-: (1) ImPrint-/RePrint-, (2) ImPrint-/RePrint+ (3) ImPrint+, in patients ILC compared to IDC enrolled in the FLEX trial. Methods: This study includes 1078 HR+HER2-women with ILC and 6078 with IDC enrolled in FLEX registry. FLEX (NCT03053193) is a prospective, observational trial that includes stage I-III breast cancer patients who undergo MammaPrint testing (with or without BluePrint) as standard of care, and consent to full transcriptome and clinical data collection. MP High Risk tumors were further stratified into High 1 and High 2. ImPrint and Reprint results were used to determine RPS. A two-tailed proportional z-test was used to assess differences between ILC and IDC as well as between RPS. Results: ILC patients had a significantly lower percentage of MP High Risk tumors in comparison to IDC. Among MP High Risk tumors, those with ILC had significantly more MP High 1 than patients with IDC. BP subtyping in ILC tumors showed significantly lower percentage of Basal, and Luminal B, and higher percentage of Luminal A compared to IDC tumors. For RPS, a higher percentage of ILC tumors were ImPrint-/RePrint- compared to IDC, whereas lower frequencies of ImPrint-/RePrint+ and ImPrint+ were found. Within the ILC ImPrint+ subgroup (n=14), 1 (7.1%) was classified as High 2 and 10 (71.4%) as High 1 and 3 (21.4%) as Low Risk. All 14 (100%) ImPrint+ patients were BP Luminal. In contrast, within the IDC MP High Risk ImPrint+ subgroup (n=328), 233 (71.0%) were High 2, 88 (26.8%) High 1 and 7 Low Risk (2.1%). Furthermore 193 (60.7%) were classified as BP Basal, 2 HER2 (0.6%) and 123 (38.7%) Luminal within this IDC RPS. Conclusions: This is the first study to investigate the distribution of Response Predictive Subtypes in ILC, which will be beneficial to optimize the treatment selection for patients with early-stage HR+/HER2- ILC. Though the percentage of ImPrint+ is lower in ILC, this study revealed a small subset of patients in ILC with potential response to Immunotherapy. Furthermore, these results underscore the heterogeneity of ILC tumors and generate further hypotheses to investigate the immune cell abundance in ILC compared to IDC and correlate immune cell abundance to ImPrint status. Table: Genomic and Tumor Characteristics of HR+HER2- ILC and IDC tumors Citation Format: Rita Mukhtar, Christina Yau, Denise Wolf, Adam Brufsky, Hannah Linden, Natasha Hunter, Reshma Mahtani, Abirami Sivapiragasam, Trevor Feinstein, Fengting Yan, Ian Grady, Priscilla McAuliffe, Michaela Tsai, Joyce O'Shaughnessy, Blanche Mavromatis, Sasha Davis, Josien Haan, William Audeh, Lavanya Samraj, FLEX Investigators' Group. Distribution of MammaPrint, BluePrint, and Response Predictive Subtypes based on ImPrint and Reprint in ER+/HER2- Invasive Lobular Carcinoma – A FLEX sub study [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 PO4-02-03.