Surveillance Strategies After Primary Treatment for Patients with Invasive Lobular Carcinoma of the Breast: Method of Local Recurrence Detection After Breast-Conserving Surgery.

BACKGROUND: Invasive lobular carcinoma (ILC) is the second most common subtype of breast cancer. Although mammography is known to have low sensitivity for ILC, there are no data to guide the optimal surveillance after treatment. We explored surveillance strategies after breast-conserving surgery (BCS) for ILC and determined the proportion of imaging-detected recurrences versus interval cancers. METHODS: From an institutional database of 813 women, we retrospectively identified patients who underwent BCS for stage I-III ILC and subsequently had a recurrence. We categorized patients by surveillance strategy and determined the modality of recurrence detection. Interval cancer rates for local recurrences were compared across surveillance strategies using the Chi-square test. We evaluated overall survival with the log-rank test and a Cox proportional hazards model. RESULTS: We included 58 patients with ILC who had a recurrence after BCS. Of these, 22 (37.9%) had local recurrence, 27 (46.6%) had distant recurrence, and 9 (15.5%) had both local and distant recurrence. Most patients underwent routine mammographic surveillance (65.2%), with 19.6% having supplemental breast magnetic resonance imaging (MRI) and 15.2% having no surveillance. The interval cancer rate was significantly higher in the mammographic surveillance group compared with the MRI surveillance group (61.9% vs. 16.7%; p < 0.001). CONCLUSION: In this study of patients with recurrence after BCS for primary treatment of stage I-III ILC, we found that most local recurrences were not detected by surveillance mammography. These data support further investigation of supplemental imaging beyond mammography specifically for patients with ILC who undergo BCS.

Invasive lobular breast cancer: Focus on prevention, genetics, diagnosis, and treatment.

Invasive lobular cancer (ILC) is the most common of the breast cancer special types, accounting for up to 15% of all breast malignancies. The distinctive biological features of ILC include the loss of the cell adhesion molecule E-cadherin, which drives the tumor's peculiar discohesive growth pattern, with cells arranged in single file and dispersed throughout the stroma. Typically, such tumors originate in the lobules, are more commonly bilateral compared to invasive ductal cancer (IDC) and require a more accurate diagnostic examination through imaging. They are luminal in molecular subtype, and exhibit estrogen and progesterone receptor positivity and HER2 negativity, thus presenting a more unpredictable response to neoadjuvant therapies. There has been a significant increase in research focused on this distinctive breast cancer subtype, including studies on its pathology, its clinical and surgical management, and the high-resolution definition of its genomic profile, as well as the development of new therapeutic perspectives. This review will summarize the heterogeneous pattern of this unique disease, focusing on challenges in its comprehensive clinical management and on future insights and research objectives.

Oncologic Safety of Immediate Oncoplastic Surgery Compared with Standard Breast-Conserving Surgery for Patients with Invasive Lobular Carcinoma.

BACKGROUND: Invasive lobular carcinoma (ILC) of the breast grows in a diffuse pattern, resulting in a high risk of positive margins at surgical resection. Oncoplastic approaches have been shown to reduce this risk, but concerns persist around the safety of immediate oncoplastic surgery for those with ILC. This study evaluated the short- and long-term oncologic outcomes of immediate oncoplastic surgery for patients with ILC. METHODS: This study retrospectively analyzed an institutional database of stages I to III ILC patients who underwent breast-conserving surgery (BCS) with or without immediate oncoplastic surgery (oncoplastic closure or oncoplastic reduction mammoplasty [ORM]). The study compared positive margin rates, rates of successful BCS, and recurrence-free survival (RFS) by type of surgery. RESULTS: For 494 patients the findings showed that the use of immediate ORM was associated with significantly lower odds of positive margins (odds ratio [OR], 0.34; 95 % confidence interval [CI], 0.17-0.66; p = 0.002). Both lumpectomy with oncoplastic closure and ORM were significantly associated with higher rates of successful BCS than standard lumpectomy (94.2 %, 87.8 %, and 73.9 %, respectively; p < 0.001). No difference in RFS was observed between those undergoing immediate oncoplastic surgery and those undergoing standard lumpectomy alone. CONCLUSIONS: The patients with stages I to III ILC who underwent immediate oncoplastic surgery had significant benefits including lower odds of positive margins and higher rates of successful BCS, with both types of immediate oncoplastic surgery showing similar RFS compared with lumpectomy alone. This supports the oncologic safety of immediate oncoplastic surgery for diffusely growing tumors such as ILC, providing it an ideal option for patients desiring BCS.

Circulating tumor cells in early lobular versus ductal breast cancer and their associations with prognosis.

This is a secondary data analysis of the TIPPING study, which included 1,121 patients with stage I-III breast cancer who had enumeration of CTCs (by either CellSearch or immunomagnetic enrichment and flow cytometry [IE/FC]) and disseminated tumor cells (DTCs) at the time of surgical resection between 1999 and 2012. The primary endpoint was mean number of CTCs by histology, taking into account method of detection and treatment type, and evaluation of histology specific prognostic cutpoints. Overall, patients with ILC had significantly higher CTC counts than those with IDC, a finding which persisted in the 382 patients with CTC enumeration by IE/FC method. Additionally, among those with primary surgery, patients with ILC had significantly higher mean CTC counts than those with IDC (mean 2.11 CTCs/mL versus 0.71 CTCs/mL respectively, p < 0.001), which persisted on multivariate analysis. Patients with ILC and CTC-high/DTC-high status trended towards reduced DRFS HR = 9.27, 95% CI 0.95-90.5, p = 0.055) and had significantly decreased BCSS (HR = 10.4, 95% CI 1.07-99.7, P = 0.043) compared with those who were CTC-low/DTC-low. In the IDC group, CTC-high/DTC-high status was not associated with either DRFS or BCSS. In neoadjvuantly treated patients, there was no significant difference in CTC counts in the ILC group versus the IDC group (mean 0.89 CTCs/mL versus 1.06 CTCs/mL respectively, p = 0.82). Our findings contribute to the limited literature on CTCs and DTCs in ILC, and suggest that clinical utility and optimal thresholds for CTC and DTC assays may differ by histologic subtype in early-stage breast cancer.

Mechanosensitive hormone signaling promotes mammary progenitor expansion and breast cancer risk.

Tissue stem-progenitor cell frequency has been implicated in tumor risk and progression, but tissue-specific factors linking these associations remain ill-defined. We observed that stiff breast tissue from women with high mammographic density, who exhibit increased lifetime risk for breast cancer, associates with abundant stem-progenitor epithelial cells. Using genetically engineered mouse models of elevated integrin mechanosignaling and collagen density, syngeneic manipulations, and spheroid models, we determined that a stiff matrix and high mechanosignaling increase mammary epithelial stem-progenitor cell frequency and enhance tumor initiation in vivo. Augmented tissue mechanics expand stemness by potentiating extracellular signal-related kinase (ERK) activity to foster progesterone receptor-dependent RANK signaling. Consistently, we detected elevated phosphorylated ERK and progesterone receptors and increased levels of RANK signaling in stiff breast tissue from women with high mammographic density. The findings link fibrosis and mechanosignaling to stem-progenitor cell frequency and breast cancer risk and causally implicate epidermal growth factor receptor-ERK-dependent hormone signaling in this phenotype.

Clinicopathologic and genetic analysis of invasive breast carcinomas in women with germline CHEK2 variants.

PURPOSE: Germline pathogenic variants in checkpoint kinase 2 (CHEK2) are associated with a moderately increased risk of breast cancer (BC). The spectrum of clinicopathologic features and genetics of these tumors has not been fully established. METHODS: We characterized the histopathologic and clinicopathologic features of 44 CHEK2-associated BCs from 35 women, and assessed responses to neoadjuvant chemotherapy. A subset of cases (n = 23) was additionally analyzed using targeted next-generation DNA sequencing (NGS). RESULTS: Most (94%, 33/35) patients were heterozygous carriers for germline CHEK2 variants, and 40% had the c.1100delC allele. Two patients were homozygous, and five had additional germline pathogenic variants in ATM (2), PALB2 (1), RAD50 (1), or MUTYH (1). CHEK2-associated BCs occurred in younger women (median age 45 years, range 25-75) and were often multifocal (20%) or bilateral (11%). Most (86%, 38/44) were invasive ductal carcinomas of no special type (IDC-NST). Almost all (95%, 41/43) BCs were ER + (79% ER + HER2-, 16% ER + HER2 + , 5% ER-HER2 +), and most (69%) were luminal B. Nottingham grade, proliferation index, and results of multiparametric molecular testing were heterogeneous. Biallelic CHEK2 alteration with loss of heterozygosity was identified in most BCs (57%, 13/23) by NGS. Additional recurrent alterations included GATA3 (26%), PIK3CA (226%), CCND1 (22%), FGFR1 (22%), ERBB2 (17%), ZNF703 (17%), TP53 (9%), and PPM1D (9%), among others. Responses to neoadjuvant chemotherapy were variable, but few patients (21%, 3/14) achieved pathologic complete response. Most patients (85%) were without evidence of disease at time of study (n = 34). Five patients (15%) developed distant metastasis, and one (3%) died (mean follow-up 50 months). CONCLUSION: Almost all CHEK2-associated BCs were ER + IDC-NST, with most classified as luminal B with or without HER2 overexpression. NGS supported the luminal-like phenotype and confirmed CHEK2 as an oncogenic driver in the majority of cases. Responses to neoadjuvant chemotherapy were variable but mostly incomplete.

The impact of histologic subtype on primary site surgery in the management of metastatic lobular versus ductal breast cancer: a population based study from the National Cancer Database (NCDB).

PURPOSE: Primary site surgery for metastatic breast cancer improves local control but does not impact overall survival. Whether histologic subtype influences patient selection for surgery is unknown. Given differences in surgical management between early-stage lobular versus ductal disease, we evaluated the impact of histology on primary site surgery in patients with metastatic breast cancer. METHODS: The National Cancer Database (NCDB, 2010-2016) was queried for patients with stage IV HR-positive, HER2-negative invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC). We compared clinicopathologic features, primary site surgery rates, and outcomes by histologic subtype. Multivariable Cox proportional hazard models with and without propensity score matching were used for overall survival (OS) analyses. RESULTS: In 25,294 patients, primary site surgery was slightly but significantly less common in the 6,123 patients with ILC compared to the 19,171 patients with IDC (26.9% versus 28.8%, p = 0.004). Those with ILC were less likely to receive chemotherapy (41.3% versus 47.4%, p < 0.0001) or radiotherapy (29.1% versus 37.9%, p < 0.0001), and had shorter OS. While mastectomy rates were similar, those with ILC who underwent lumpectomy had significantly higher positive margin rates (ILC 15.7% versus IDC 11.2%, p = 0.025). In both groups, the odds of undergoing surgery decreased over time, and were higher in younger patients with T2/T3 tumors and higher nodal burden. CONCLUSION: Lobular histology is associated with less primary site surgery, higher positive margin rates, less radiotherapy and chemotherapy, and shorter OS compared to those with HR-positive HER2-negative IDC. These findings support the need for ILC-specific data and treatment approaches in the setting of metastatic disease.

Tamoxifen or aromatase inhibitors with ovarian function suppression in pre-menopausal stage I-III lobular breast cancer.

While adjuvant treatment with the selective-estrogen receptor modulator (SERM) tamoxifen has been the standard of care for pre-menopausal patients with hormone receptor (HR) positive breast cancer, recent trials showed a benefit of aromatase inhibitors (AI) and ovarian function suppression (OFS) for some patients. The approach to endocrine therapy has not been well studied in pre-menopausal patients with invasive lobular carcinoma (ILC). We identified 202 pre-menopausal patients with HR positive stage I-III ILC in an institutional database. We investigated factors associated with endocrine therapy type and determined changes in systemic therapy from 1990-2021. We evaluated associations between endocrine therapy type and disease-free survival (DFS) with a multivariate Cox proportional hazards model. Of 202 patients, most (69.3%) were prescribed a SERM (99.3% tamoxifen). Those who received an AI had significantly higher stage disease. Over time, use of OFS and AI increased significantly in stage II or III cases (from 0% in 1990 to 56% after 2015 for stage II; from 0% to 80% after 2015 for stage III). Concurrently, adjuvant chemotherapy use significantly decreased in stage II cases (from 67% to 19%). In an exploratory multivariable model, longer duration of AI compared to tamoxifen was associated with significantly improved DFS (HR 0.31; 95% CI 0.11-0.86; p = 0.025). While most pre-menopausal patients received adjuvant tamoxifen, the use of OFS and AIs increased significantly over time. The association between AI use and improved DFS may be consistent with prior randomized trials and warrants further investigation into predictive factors to guide treatment selection.

Erratum: 53 The development of a multi-institutional prospective registry for patients with metastatic invasive lobular carcinoma: identifying new markers of disease progression - CORRIGENDUM.

[This corrects the article DOI: 10.1017/cts.2023.142.].

Impacts of a lead smelter in East Java, Indonesia: degree of contamination, spatial distribution, ecological risk, and health risk assessment of potentially toxic elements in soils.

This study investigates the characteristics of potentially toxic elements in soils collected from the vicinity of a lead smelter in East Java, Indonesia. The objective is to assess the impact of the lead smelter on the surrounding soil. The study involves chemical composition analysis, spatial distribution mapping, and potential ecological and health risk assessments. Soil samples were collected from the surface area (0-10 cm) and subsurface (15-30 cm) within radii of 1.5 km, 3 km, and 5 km from the lead smelter. The samples were analyzed for As, Cr, Cu, Ni, Pb, and Zn using energy-dispersive X-ray fluorescence. Principal component analysis (PCA) was performed to identify the sources of potentially toxic elements in the soil. The results indicate severe Pb contamination within a 1.5 km radius of the smelter, with an average contamination factor (Cf) value of 22.0, posing a high potential health risk. The contamination factor indicated that the soils were heavily polluted by As and Pb and moderately polluted by Cu, Ni, and Zn. The results of PCA showed that smelter releases are the main source of potentially toxic element contamination in the soil, accounting for 66.2%. The health risk assessment suggested that the children and adults in the study region were exposed to non-carcinogenic risks caused by As and Pb. Oral ingestion was identified as the primary exposure route impacting health risks. The carcinogenic risk from potentially toxic elements in soil was found to exceed the acceptable level for children and adults in the study region. Therefore, it is necessary for the government to take effective measures, including designing regulations and interventions, and improving lead smelter management to mitigate potential contamination and minimize the impact of lead smelter releases on the surrounding environment, especially to protect human health, particularly that of children.

Nipple-Sparing Mastectomies in Patients over the Age of 60 Years: Factors Associated with Surgical Outcomes.

BACKGROUND: Nipple-sparing mastectomy (NSM) outcomes in the elderly have not been well characterized. The goal of this study was to evaluate NSM outcomes in patients over age 60. PATIENTS AND METHODS: A single-institution retrospective cohort study was performed for NSM patients over the age of 60 from January 2004 to January 2022. Demographic, intraoperative, and postoperative variables were collected. RESULTS: We identified 136 women who underwent a total of 200 NSMs at a mean age 65.2 years and with mean body mass index of 25. Most (56%) had invasive breast cancer, requiring neoadjuvant chemotherapy in 15%, and 17.5% had radiation prior to NSM. A total of 91% had immediate tissue expander placement. The infection rate was 19%, with 11.5% requiring expander explantation in the follow-up period. In binomial logistic regression analysis, prior radiation increased the odds of any complication by 2.9 (OR 2.93, CI 1.30-6.58, p = 0.009) and increased the odds of infection by 5.7 (OR 5.70, CI 1.95-16.66, p = 0.001), but no associations were seen for other covariates including age, comorbidities, prior chemotherapy, or presence of invasive disease. Diabetes increased the odds of wound breakdown specifically by 9.0 (OR 8.97, CI 2.01-39.92, p = 0.004). Local recurrence was 3% in mean 3.4-year follow-up. CONCLUSIONS: Our data support NSM in patients over the age of 60 years with acceptable outcomes within the standard of care. Locoregional recurrence was within the cited range of 0-5%, and only diabetes and prior radiation were associated with reconstructive complications. NSM should thus be offered when appropriate regardless of increased age to achieve oncologic and reconstructive goals.

Successful Breast Conservation After Neoadjuvant Chemotherapy in Lobular Breast Cancer: The Role of Menopausal Status in Response to Treatment.

BACKGROUND: While neoadjuvant chemotherapy (NAC) has been shown to increase rates of breast conservation surgery (BCS) for breast cancer, response rates in invasive lobular carcinoma (ILC) appear lower than other histologic subtypes. Some data suggest higher response rates to NAC in premenopausal versus postmenopausal patients, but this has not been studied in ILC. We evaluated the rates of successful BCS after NAC in patients with ILC stratified by menopausal status. PATIENTS AND METHODS: We analyzed data from a single-institution cohort of 666 patients with stage I-III hormone receptor positive HER-2 negative ILC. We used t-tests, chi-squared tests, and multivariable logistic regression to investigate rates of NAC use, attempted BCS, and associations between NAC and successful BCS by menopausal status. RESULTS: In 217 premenopausal and 449 postmenopausal patients, NAC was used more often in the premenopausal group (15.2% vs. 9.8%, respectively, p = 0.041). Among those who attempted breast conservation (51.3% of pre- and 64.8% of postmenopausal cohorts), NAC was not associated with successful BCS in either group. Interestingly, for postmenopausal patients, receipt of NAC was significantly associated with increased rates of completion mastectomy in those who had positive margins at the first attempt at BCS. CONCLUSION: NAC was not associated with successful BCS in either premenopausal or postmenopausal patients with ILC. Although premenopausal patients were more likely to receive NAC, these data suggest that menopausal status may not be a good predictor of response to chemotherapy. Better predictors of response and more efficacious treatment for patients with ILC are needed.

Quantifying hormone receptor status in lobular breast cancer in an institutional series: the relationship between estrogen and progesterone receptor status and outcomes.

PURPOSE: Recent guidelines defined a new reporting category of ER-low-positive breast cancer based on immunohistochemistry (IHC). While low positivity of either hormone receptor is uncommon in invasive lobular carcinoma (ILC), we sought to investigate whether relatively low hormone receptor positivity was associated with tumor characteristics and patient outcomes in a single institutional cohort. METHODS: We searched an institutional database for cases of stage I-III ILC with available IHC reports. Based on prior published categories in ILC, ER was classified as low, medium, or high as defined by ER staining of 10-69%, 70-89%, and ≥ 90% respectively. PR low and high tumors were defined by < 20%, or ≥ 20% staining respectively. We used chi-squared tests, t-tests, and Cox proportional hazards models to evaluate associations between ER/PR categories and tumor characteristics or disease-free survival (DFS). RESULTS: The cohort consisted of 707 ILC cases, with 11% of cases categorized as ER low, 15.1% as medium, and 73.8% as high. The majority (67.6%) were PR high. Patients with ER low/medium expression were significantly younger, and more likely to also have PR low and/or HER2 positive tumors compared to those that were ER high. In a Cox proportional hazards model adjusting for age, stage, grade, pleomorphic histology, and treatment, ER category was not prognostic for DFS, but PR negative and PR low status each had significantly worse DFS compared to PR high status (HR 3.5, 95% CI 1.8-6.7, p < 0.001; and HR 2.0, 95% CI 1.1-3.5, p = 0.015, respectively). CONCLUSION: These findings highlight the relevance of quantifying ER and PR within ILC.