Clinicopathological Features and Outcomes Comparing Patients With Invasive Ductal and Lobular Breast Cancer

Steffi Oesterreich, PhD; Azadeh Nasrazadani, MD, PhD; Jian Zou, MS; Neil Carleton, BS; Tiffany Onger, MD; Matthew D. Wright, MD; Yujia Li, BS; Kathryn Demanelis, PhD; Bhuvaneswari Ramaswamy, MD; George Tseng, PhD; Adrian V. Lee, PhD; Nicole Williams, MD; Megan Kruse, MD


J Natl Cancer Inst. 2022;114(11):1511-1522. 

In This Article

Abstract and Introduction


Background: There is increasing interest in better understanding the biology and clinical presentation of invasive lobular cancer (ILC), which is the most common special histological subtype of breast cancer. Limited large contemporary data sets are available allowing comparison of clinicopathologic features between ILC and invasive ductal cancer (IDC).

Methods: The Great Lakes Breast Cancer Consortium was formed to compare clinical behavior of ILC (n = 3617) and IDC (n = 30 045) from 33 662 patients treated between 1990 and 2017 at 3 large clinical centers. We used Kaplan-Meier analysis, Cox proportional hazards modeling, and propensity score matching to evaluate treatment differences and outcomes. All statistical testing used 2-sided P values.

Results: Compared with IDC, patients with ILC were more frequently diagnosed at later stages and with more lymph node involvement (corrected P < .001). Estrogen receptor–positive ILCs were of lower grade (grade 1 and 2: 90% in ILC vs 72% in IDC) but larger in size (T3 and 4: 14.3% in ILC vs 3.4% in IDC) (corrected P < .001), and since 1990, the mean ILC size detected at diagnosis increased yearly. Patients with estrogen receptor (ER)–positive ILC underwent statistically significantly more mastectomies compared with ER-positive IDC (57% vs 46%). Using Kaplan-Meier analysis, patients with ER-positive ILC had statistically significantly worse disease-free survival and overall survival than ER-positive IDC although 6 times more IDCs were classified as high risk by OncotypeDx Breast Recurrence Score assay.

Conclusions: This large, retrospective, collaborative analysis with 3 clinical centers identified meaningful differences in clinicopathological features between ILC and IDC, providing further evidence that these are 2 different entities requiring different clinical management.


Invasive lobular carcinoma (ILC) is the most common special subtype of breast cancer, accounting for 10%-15% of all breast cancers, which represents approximately 26 000-40 000 cases annually in the United States.[1] There is an increasing recognition that ILC has distinct clinical, histologic, molecular, and biological characteristics compared with invasive ductal cancer (IDC) [reviewed in].[1–6]

The hallmark of ILC is the loss of E-cadherin, resulting in a more linear growth pattern of cells as compared with round masses usually seen in IDC. This unique growth pattern is associated with challenges in detection of ILC and, hence, larger, lobulated, and more spiculated tumors at the time of detection. This, together with increased rates of multifocality, is associated with an increased rate of mastectomy.[7]

ILC is more often estrogen receptor (ER) positive compared with IDC,[8–11] and hence, hormonal therapy is given in the majority of cases. The use of chemotherapy remains an open question, with limited data on efficacy in ILC. Further complicating use of chemotherapy is the limited data on the utility of multigene prognostic tests in ILC. Some assays have been tested in ILC with mixed results,[12–20] and there are efforts to develop assays specifically based on information from ILC.[21] These studies are necessary given the large number of ILC variants,[22] which may harbor unique mutations that change clinical phenotype.

ILC outcome is similar to ER-positive IDC in that the majority of patients experience a favorable outcome. Recurrence sites are shared with IDC such as bone, brain, lung, and liver, but lobular metastases can also be found in less well-characterized sites such in the gastrointestinal and urogenital tracts.[23,24] There is evidence that patients with ILC have worse long-term outcome compared with IDC because of late recurrences.[25–27]

It is promising to see overall progress in the understanding of ILC; nevertheless, many open questions remain. Many previous studies comparing clinicopathological features and outcomes have been based on relatively small numbers of patients with ILC or larger numbers of patients but seen at a large number of hospitals,[8,11,23,27–29] thereby limiting granular detail. We set out to investigate the clinicopathologic features, treatment trends, and outcomes for ILC and IDC across a large cohort of patients using cancer registries from 3 high-volume cancer centers.