Risk Of Invasive Lobular Carcinoma Research Articles

Defining features of hereditary lobular breast cancer due to CDH1 with magnetic resonance imaging and tumor characteristics

Women with germline pathogenic variants in CDH1, which encodes E-cadherin protein, are at increased lifetime risk of invasive lobular carcinoma (ILC). The associated tumor characteristics of hereditary lobular breast carcinoma (HLBC) in this high-risk population are not well-known. A single-center prospective cohort study was conducted to determine the imaging and pathologic features of HLBC compared to population-based ILC using Surveillance, Epidemiology, and End Results (SEER) data. One hundred fifty-eight women with CDH1 variants were evaluated, of whom 48 (30%) also had an ILC diagnosis. The median age at CDH1 diagnosis was 45 years [interquartile range, IQR 34–57 years] whereas the median age at diagnosis of CDH1 with concomitant ILC (HLBC) was 53 [IQR 45–62] years. Among women with HLBC, 83% (40/48) were identified with CDH1 mutation after diagnosis of ILC. Among 76 women (48%, 76/158) undergoing surveillance for ILC with breast magnetic resonance imaging (MRI), 29% (22/76) had an abnormal MRI result with available biopsy data for comparison. MRI detected ILC in 7 out of 8 biopsy-confirmed cases, corresponding with high sensitivity (88%), specificity (75%), and negative predictive value (98%); however, false-positive and false-discovery rates were elevated also (25% and 68%, respectively). HLBC was most frequently diagnosed at age 40–49 years (44%, 21/48), significantly younger than the common age of diagnosis of ILC in SEER general population data (most frequent age range 60–69 years, 28%; p < 0.001). HLBC tumors were smaller than SEER-documented ILC tumors (median 1.40 vs. 2.00 cm; p = 0.002) and had a higher incidence of background lobular carcinoma in situ (88% vs. 1%; p < 0.001) as well as progesterone receptor positivity (95% vs. 81%, p = 0.032). These findings suggest that HLBC is often detected via conventional screening methods as an early-stage hormone receptor-positive tumor, thus the clinical benefit of intensive screening with MRI may be limited to a subset of women with germline CDH1 variants.

Adherence to a western dietary pattern and risk of invasive ductal and lobular breast carcinomas: a case\u2013control study

Little is known about the role of diet in the risk of invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) of the breast, the most common histological subtypes of breast cancer (BC). This is because, the majority of studies on the association of diet and the risk of BC are focused on single food items, and studies considering the overall diet in terms of dietary patterns are limited. Also, the potential heterogeneity in the impact of Western diet (WD) on histological subtypes of BC is not established. This, the age-frequency-matched case–control study included 1009 incident BC cases and 1009 healthy controls. The required data was obtained from the patients’ medical files and interviews using a previously validated researcher-designed questionnaire for collecting data on socio-economic and anthropometric statuses and a valid food frequency questionnaire (FFQ) to measure the participants’ dietary intake. We used multinomial logistic regression, and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. A positive and significant association was observed between higher adherence to a WD and risk of IDC (OR comparing highest with the lowest tertile: 2.45, 95% CI 1.88, 3.17; p-trend < 0.001), whereas no significant association was observed between adherence to the WD and the risk of ILC (OR comparing highest with the lowest tertile: 1.63, 95% CI 0.63, 3.25) (p for heterogeneity = 0.03). The results of an analysis stratified by menopausal status suggested a similar pattern. We provided evidence that adherence to a WD raises the risk of IDC, but not ILC, suggesting different etiological mechanisms for IDC and ILC.

Abstract P6-08-04: Germline mutations in cancer predisposition genes in patients with invasive lobular carcinoma of the breast

Abstract Background: Invasive lobular carcinoma (ILC) of the breast accounts for approximately 10-15% of all histologic subtypes of breast cancer. However, apart from germline mutations in CDH1, the contributions of mutations in other cancer predisposition genes to ILC are largely unknown. Methods: The study population included 3,893 women with ILC of the breast who underwent germline multigene panel testing of cancer predisposition genes at Ambry Genetics from March 2012 to December 2016. The prevalence of predisposition gene mutations in women with ILC was assessed relative to 38,004 women with invasive ductal carcinoma (IDC) who underwent germline multigene panel testing at Ambry Genetics during the same timeframe. Associations between mutations in each gene and risk of ILC were evaluated using reference controls. Results: Of the 3,893 women with ILC included in this study, 70.7% were non-Hispanic white, 65.1% had a family history of breast cancer, and 96.4% had estrogen receptor (ER) positive breast cancer. The overall frequency of germline mutations in cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CDKN2A, CHEK2, MLH1, MRE11A, MSH2, MSH6, NBN, NF1, PALB2, PTEN, RAD51C, RAD51D and TP53) was 7.8% for women with ILC and 10.7% for women with IDC. Mutations in CDH1 were significantly more frequent (Odds Ratio (OR)=12.1, p&amp;lt;0.001), whereas mutations in BRCA1 (OR=0.1; p&amp;lt;0.001) and PALB2 (OR=0.4; p&amp;lt;0.001)were less frequent in women with ILC, compared to women with IDC. When restricting the analysis to ER positive cases only, significant differences in frequencies of ATM (OR=0.6, p=0.03), BRCA1 (OR=0.3, p&amp;lt;0.001), CDH1 (OR=7.7, p&amp;lt;0.001) and PALB2 (OR=0.3, p&amp;lt;0.001) were observed in ILC compared to IDC. By comparison with gnomAD reference controls, ATM, BRCA2, CDH1, CHEK2, PALB2 and PTEN mutations were significantly associated with an increased risk of lLC and IDC (OR&amp;gt;2), NBN mutations were associated with ILC (OR=3.4; p&amp;lt;0.001) but not IDC, and BRCA1 mutations were not associated with increased risk of ILC. Among 274 women with ILC over the age of 50 without history of any other cancer or a family history of breast or ovarian cancer, 14 (5.1%) were found to carry a mutation in one of the genes evaluated. Conclusions: In a large cohort of patients with ILC, the frequencies of germline mutations in cancer predisposition genes were similar between ILC and IDC except for ATM, BRCA1, CDH1 and PALB2. Six genes, in addition to CDH1, were found to be germline predisposition genes for ILC. A substantial proportion of patients older than 50 with ILC without a family history of breast or ovarian cancer or a personal history of other cancers were found to be mutation carriers. These findings improve our understanding of germline genetic drivers of ILC and suggest that multigene genetic testing should be considered for all ILC patients. Citation Format: Siddhartha Yadav, Holly LaDuca, Eric C. Polley, Chunling Hu, Steven N. Hart, Jie Na, Rohan Gnanaolivu, Brandon Smith, David E Goldgar, Tina Pesaran, Jill S. Dolinsky, Fergus J. Couch. Germline mutations in cancer predisposition genes in patients with invasive lobular carcinoma of the breast [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 P6-08-04.

Abstract P6-05-03: Exogenous steroid hormone exposure and the biology of lobular breast cancer

Abstract Introduction. Invasive lobular carcinoma (ILC) accounts for 10-15% of breast cancer diagnoses and is characterized by a high rate of estrogen and progesterone receptor (ER and PR) expression, low rate of HER2 amplification, and a defining lack of e-cadherin expression. Multiple population-based, observational studies have shown that the risk of ILC is significantly elevated with the intake of combined estrogen/progestin (E+P) hormone replacement therapy (HRT) but not with estrogen-alone (E alone) HRT. In addition, recent studies have revealed that ILCs might respond differently to hormone therapies than IDCs. We sought to understand the influence of exogenous hormone exposure in the form of HRT on biological pathways in ILCs compared to the more common histologic subtype, ER+ invasive ductal carcinoma (IDC). Specimens and Methods. We assessed 297 ER+/HER2- FFPE breast carcinomas, 165 IDCs and 132 ILCs, previously collected from an epidemiological study of HRT use and breast cancer in post-menopausal women. These tumors were characterized for histopathological features and protein marker expression by immunohistochemistry along with the extensive clinical and demographic data, including HRT use, collected in the parent study. Using the Nanostring nCounter assay, we measured expression of ~1000 genes representing canonical cancer-promoting pathways and steroid hormone-associated pathways to determine the relationship between HRT use and pathway alterations in ER+ breast cancer subtypes. Results. From the histopathological assessment, we observed that ILCs had lower overall lymphocyte response than IDCs (p=0.005), but HRT use shifted the lymphocyte response higher than what was observed in ILCs from never/former HRT users (p=0.002). In the gene expression analysis, we found that IDCs and ILCs have distinct expression profiles after adjusting for HRT use, including genes in cell cycle, steroid hormone-response pathways, and cytokine/cytokine receptor interactions, with increased signaling seen in the IL6/12-like family. When comparing gene expression between the HRT-use groups, adjusting for histology, we observed that E+P and E alone are both associated with down-regulation of cell cycle and DNA repair genes compared to the never/former use group. When we focused on expression patterns specific to progestin exposure, (i.e., E+P versus all others), we found decreased expression of genes related to DNA replication initiation and G1/S transition and WNT4. Unsupervised hierarchical clustering revealed additional subgroups within each histologic subtype including a group of low-grade, low-proliferating IDCs enriched for E+P exposure, which clusters with the majority of the ILCs. While many gene expression changes with HRT use are shared across the tumors, we observed alterations that are specific to either ILCs or IDCs, suggesting different steroid hormone-responsive pathways between the subtypes. Conclusions. Our study demonstrates there are potentially specific pathways differentially activated between ILCs and IDCs dependent on the type of hormone exposure. Further, while our study is focused on tumor molecular pathways modulated in response to HRT use, steroid hormone exposure can come from multiple sources, and we propose that the results from this study can provide insight into hormonally-driven breast cancers that develop with excess estrogen and/or progesterone exposure. This could have implications in clinical management of ILCs and IDCs that arise in HRT users. Citation Format: Jamie Guenthoer, Isaac C Jenkins, Beti Thompson, Mei-Tzu C Tang, Nancy E Davidson, Ryan L Ashley, Christopher I Li, Li Hsu, Peggy L Porter. Exogenous steroid hormone exposure and the biology of lobular breast cancer [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 P6-05-03.

CDH1 Gene and Hereditary Diffuse Gastric Cancer Syndrome: Molecular and Histological Alterations and Implications for Diagnosis And Treatment.

Gastric cancer, a group of common malignancies, results in the most cancer mortality worldwide after only lung and colorectal cancer. Although familial gastric cancers have long been recognized, it was not until recently that they were discovered to be associated with mutations of specific genes. Mutations of CDH1, the gene encoding E-cadherin, are the most common germline mutations detected in gastric cancer and underlie hereditary diffuse gastric cancer (HDGC) syndrome. All reported HDGCs are the pure diffuse type by Lauren classification and are associated with dismal prognosis once the tumor invades the submucosa. Because CDH1 germline mutations are inherited in an autosomal-dominant fashion and have high penetrance, the International Gastric Cancer Linkage Consortium (IGCLC) developed criteria to facilitate the screening of CDH1 mutation carriers; these criteria have been proven to have excellent sensitivity and specificity. Recent histologic studies suggest that HDGC progresses through several stages. Even when the tumor becomes “invasive” in lamina propria, it may stay indolent for a long time. However, the molecular mechanisms that induce the transitions between stages and determine the length of the indolent phase remain to be determined. Although the standard management for CDH1 mutation carriers is prophylactic total gastrectomy, many questions must be answered before the surgery can be done. These include the optimal surveillance strategy, the best strategy to choose surgical candidates, and the ideal time to perform surgery. In addition to increasing the risk of gastric cancer, CDH1 germline mutations also increase the risk of invasive lobular carcinoma of the breast, and possibly colorectal adenocarcinoma, and are associated with blepharocheilodontic syndrome (a congenital development disorder). However, the optimal management of these conditions is less established owing to insufficient data regarding the risk of cancer development. This review focuses on molecular and histological findings in HDGC, as opposed to sporadic diffuse gastric cancer, and their implications for the management of CDH1 mutation carriers and the diagnosis and treatment of HDGC. Other conditions associated with CDH1 germline mutations and future research directions are also discussed.

Low risk of invasive lobular carcinoma of the breast in carriers of BRCA1 (hereditary breast and ovarian cancer) and TP53 (Li-Fraumeni syndrome) germline mutations.

Invasive lobular carcinoma (ILC) of the breast has epidemiological, molecular and clinical specificities, and should likely be considered a unique entity. As for genetic susceptibility, CDH1 germline mutations predispose exclusively to ILC. Data are however scarce regarding ILC in women with BRCA1/2 (Hereditary Breast and Ovarian Cancer) and TP53 (Li-Fraumeni syndrome) germline mutations. We included all breast cancers from female patients tested at our institute between 1992 and 2016 (n=3469) for which pathology data were available. ILC proportion comparison according to mutational status was performed by a chi-squared test. The impact of susceptibility genes on ILC proportion was investigated by univariate logistic regression with wild-type patients as reference. There were 265 (7.64%) ILC: 2/342 (0.58%) in BRCA1 patients, 24/238 (10%) in BRCA2 patients, 1/57 (1.75%) in TP53 patients and 238/2832 (8.4%) in non-carriers. The majority of breast cancers in all groups were invasive ductal and ductal in situ carcinomas. The difference in ILC proportion was highly significant (P<0.001). Compared to wild-type patients, BRCA1 was associated with a lower ILC proportion (OR 0.064 [95% CI 0.016;0.259], P<0.0001). BRCA2 OR was 1.222 [95%CI 0.785;1.902] (P=0.374), TP53 OR was 0.195 [95%CI 0.027;1.412] (P=0.105). ILC are therefore underrepresented in BRCA1 and TP53 mutation carriers. Formal significance (P=0.05) was not reached for TP53, but statistical power was only 38%. Based on ILC incidence in the general population, we make the hypothesis that BRCA1 and TP53 do not predispose to ILC, as the few occurrences of ILC in mutation carriers could be attributed to chance and not to germline mutations. Our observations will be useful to clinical cancer geneticists managing patients with ILC, as a BRCA1 or TP53 mutation in these patients would be unlikely. Genetic counseling should be adapted accordingly.

Alcohol Intake and Risk of Breast Cancer by Histologic Subtype and Estrogen Receptor Status Among Women Aged 55 to 74Years.

Previous studies suggest that alcohol consumption and risk of breast cancer may differ by histologic subtype and hormone receptor status, though results are not entirely consistent. In this population-based case-control study, we evaluated the association between alcohol consumption and risk of invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), and invasive ductal-lobular carcinoma (IDLC) overall and by estrogen receptor (ER) status, among women aged 55-74years of age. Using polytomous regression, associations between current alcohol consumption, overall and by type of alcohol, and breast cancer risk were evaluated in 891 controls and 905 IDC, 567 ILC, and 489 IDLC cases. Current alcohol use was moderately associated with risk of ILC (odds ratio=1.25, 95% confidence interval 0.99, 1.58) with a positive dose-response relationship based on average number of drinks per week consumed (P trend=0.0005). When further stratified by ER status, alcohol use was positively associated with risk of ER+ ILC (P trend = 0.002) and ER+ IDC (P trend = 0.02), but inversely associated with risk of ER-IDC (P trend = 0.01). No association between alcohol and risk of IDLC tumors was observed. While the link between alcohol consumption and breast cancer risk is well established, our results suggest that the increased risk associated with alcohol is largely limited to ER+ ILC and ER+ IDC. Thus, avoiding or moderating alcohol consumption may be one way that women can lower their risks of these forms of breast cancer.

Lobular breast cancer: incidence and genetic and non-genetic risk factors.

While most invasive breast cancers consist of carcinomas of the ductal type, about 10% are invasive lobular carcinomas. Invasive lobular and ductal carcinomas differ with respect to risk factors. Invasive lobular carcinoma is more strongly associated with exposure to female hormones, and therefore its incidence is more subject to variation. This is illustrated by US figures during the 1987 to 2004 period: after 12 years of increases, breast cancer incidence declined steadily from 1999 to 2004, reflecting among other causes the decreasing use of menopausal hormone therapy, and these variations were stronger for invasive lobular than for invasive ductal carcinoma. Similarly, invasive lobular carcinoma is more strongly associated with early menarche, late menopause and late age at first birth. As for genetic risk factors, four high-penetrance genes are tested in clinical practice when genetic susceptibility to breast cancer is suspected, BRCA1, BRCA2, TP53 and CDH1. Germline mutations in BRCA1 and TP53 are predominantly associated with invasive ductal carcinoma, while BRCA2 mutations are associated with both ductal and lobular cancers. CDH1, the gene coding for the E-cadherin adhesion protein, is of special interest as mutations are associated with invasive lobular carcinoma, but never with ductal carcinoma. It was initially known as the main susceptibility gene for gastric cancer of the diffuse type, but the excess of breast cancers of the lobular type in CDH1 families led researchers to identify it also as a susceptibility gene for invasive lobular carcinoma. The risk of invasive lobular carcinoma is high in female mutation carriers, as about 50% are expected to develop the disease. Carriers must therefore undergo intensive breast cancer screening, with, for example, yearly magnetic resonance imaging and mammogram starting at age 30 years.

Long-term Statin Use and Risk of Breast Cancer—Letter

We read with great interest the work of McDougall and colleagues recently appeared on your journal reporting that current users of statins for 10 years or longer had a 1.83-fold increased risk of invasive ductal carcinoma (IDC) and a 1.97-fold increased risk of invasive lobular carcinoma (ILC)

Relationship Between Long Durations and Different Regimens of Hormone Therapy and Risk of Breast Cancer

The influence of the duration of combined hormone replacement therapy (CHRT) with estrogen and progestin and of different patterns of treatment was examined in 975 women 65 to 79 years of age who had invasive breast cancer. A large majority of tumors were ductal carcinomas, and most cancers were positive for both estrogen and progesterone receptors. Control subjects were age-matched women from the same general population. For women given unopposed estrogen therapy, even for 25 years or longer, the breast cancer risk was not notably greater than for those reporting no use of any form of HRT, although a small effect could not be ruled out. Women using CHRT at any time had a 1.7-fold increase in all breast cancers and a 2.7-fold increase in risk of invasive lobular carcinoma. Risk was increased 1.5-fold for invasive ductal carcinoma, and there was a 2.0-fold increase in risk of estrogen receptor (ER)/progesterone receptor (PR)-positive cancers. The most marked increase in risk was in women using CHRT for 5 years or longer. Comparable results were found in women who had used CHRT sequentially or continuously. Current CHRT was associated with 1.9-fold, 1.7-fold, and 3.1-fold increases in the risk of all histologic types of breast cancer, ductal carcinomas, and lobular breast cancers, respectively. There was no apparent increase in the risk of ER+/PR- or ER-/PR- tumors. Patterns of progestin use were not closely associated with cancer risk in either women using CHRT at any time or current users. These findings reinforce the increase in breast cancer risk observed when progestin is added to HRT, whether CHRT is used sequentially or continuously.

Relationship between long durations and different regimens of hormone therapy and risk of breast cancer.

Women using combined estrogen and progestin hormone replacement therapy (CHRT) have an increased risk of breast cancer; however, data on use for long durations and on risk associated with patterns of use are lacking. To evaluate relationships between durations and patterns of CHRT use and risk of breast cancer by histological type and hormone receptor status. Population-based case-control study. Three counties in western Washington State. Nine hundred seventy-five women 65-79 years of age diagnosed with invasive breast cancer from April 1, 1997, through May 31, 1999 (histology: 196 lobular cases, 656 ductal cases, 114 cases with other histological type, and 9 cases with an unspecified histological type; estrogen receptor (ER)/progesterone receptor (PR) status: 646 ER+/PR+ cases, 147 ER+/PR- cases, and 101 ER-/PR- cases [6 ER-/PR+ cases and 75 cases with unknown ER/PR status were not included in the analyses herein]) and 1007 population controls. Risks of invasive lobular, ductal, ER+/PR+, ER+/PR-, and ER-/PR- breast carcinomas. Women using unopposed estrogen replacement therapy (ERT) (exclusive ERT use), even for 25 years or longer, had no appreciable increase in risk of breast cancer, although the associated odds ratios were not inconsistent with a possible small effect. Ever users of CHRT (includes CHRT users who also had used ERT) had a 1.7-fold (95% confidence interval [CI], 1.3-2.2) increased risk of breast cancer, including a 2.7-fold (95% CI, 1.7-4.3) increased risk of invasive lobular carcinoma, a 1.5-fold (95% CI, 1.1-2.0) increased risk of invasive ductal carcinoma, and a 2.0-fold (95% CI, 1.5-2.7) increased risk of ER+/PR+ breast cancers. The increase in risk was greatest in those using CHRT for longer durations (users for 5-14.9 years and >or=15 years had 1.5-fold [95% CI, 1.0-2.3] and 1.6-fold [95% CI, 1.0-2.6] increases in risk of invasive ductal carcinoma, respectively, and 3.7-fold [95% CI, 2.0-6.6] and 2.6-fold [95% CI, 1.3-5.3] increases in risk of invasive lobular carcinoma, respectively. Associations of similar magnitudes were seen among users of both sequential and continuous CHRT. Risks of ER+/PR- and ER-/PR- tumors were not increased by use of any form of hormone replacement therapy; however, small numbers of these tumors limited power to detect possible associations. These data suggest that use of CHRT is associated with an increased risk of breast cancer, particularly invasive lobular tumors, whether the progestin component was taken in a sequential or in a continuous manner.