Distinct Strategies Needed for Treating Lobular Breast Cancer

Jennifer Yuchen Shih, MD, MS

Although patients with invasive lobular carcinoma (ILC) are typically treated with the same therapeutic strategies as those with infiltrating ductal malignancies, ILC is emerging as a molecularly complex and distinct tumor type that suggests different approaches may be effective.

Three abstracts presented at the 2014 San Antonio Breast Cancer Symposium (SABCS) offer a window into the evolving understanding of ILC, which comprises an estimated 10% to 15% of all breast cancers, according to Jennifer Yuchen Shih, MD, MS, an attending physician at Fox Chase Cancer Center in Philadelphia who specializes in ILC research.

While it is known that ILC is histologically different from invasive ductal carcinoma (IDC), Shih said the recent research demonstrates that lobular breast cancers “are a molecularly distinct entity as well.” This has opened the door for researching targeted therapies aimed at the mutations uncovered in these studies and for analyzing current modalities more specifically for ILC.

“This is an evolving trend of personalizing and treating breast cancers—not just saying that you are hormone positive as a whole but, depending on your type of breast cancer, treating it differently,” Shih said in an interview with OncologyLive. She discussed the research in an SABCS symposium that Fox Chase presented in Philadelphia in January.

In recent years, researchers have been able to characterize differences among patients with ILC and IDC. Shih and colleagues determined through a retrospective analysis of 537 patients that those with ILC (n = 179) were more likely to be hormone-receptor-positive/HER2-negative than those with IDC (90% vs 69%, respectively; P <.00001).¹ Although surgical and medical outcomes were comparable for ILC and IDC tumors, ILC were more likely than IDC tumors to recur in the abdominal cavity (24.3% vs 4.1%, respectively; P = .001).

Key Mutations Identified

The underlying molecular characteristics of ILC are becoming evident through multiplatform tumor analyses.

Ciriello et al examined a dataset of 817 breast tumors from The Cancer Genome Atlas project, including 490 IDC, 127 ILC, and 88 of mixed histology.² The incidence of PTEN inactivating events, both mutations and copy number changes, was greater in ILC tumors (13%) than with estrogen receptor—positive IDC (7%).

Other notable differences between ILC and IDC tumors included the incidence of mutations in FOXA1 (9% vs 2%, respectively) and GATA3 (5% vs 19%, respectively). Investigators concluded that therapies targeted at AKT, which helps activate FOXA1, are ILC a potential avenue for attacking ILC tumors.

Similarly, Desmedt et al³ analyzed mutational data from the tumors of 499 patients with ILC. They found a median of six non-silent mutations across all primary tumors. The investigators then correlated the most frequent mutations (>3%) with the characteristics of patients in five ILC histologic subtypes (Table). They also compared survival data at a median follow-up of 9.8 years with molecular abnormalities observed in the specimens.

Table. Genomic Alterations in Invasive Lobular Cancer Subtypes³

ER indicates estrogen receptor.

“The genomic analyses show that invasive lobular cancers have more mutations in the PI3 kinase pathway—AKT foci, or the ERBB2/ERBB3,” said Shih. “These mutations are potential treatment targets in the future. There are investigations going on right now using AKT pathway inhibitors and other inhibitors that could potentially work better in this type of breast cancer than in other types for that reason.”

Translating Results

A glimpse into the future of managing patients with ILC based on a more granular understanding of their tumors was offered by Knauer et al⁴ in a molecular-based analysis of outcomes among 3714 women who had participated in the phase III ABCSG-8 trial.

The study evaluated 5 years of tamoxifen versus 2 years of tamoxifen followed by 3 years of anastrozole in postmenopausal patients with grade 1/2 disease who had undergone surgery and radiotherapy but were not receiving adjuvant chemotherapy. Inves- tigators concluded that patients with ILC (n = 694) experienced a greater 3-year overall survival (OS) benefit from anastrozole, verifying results from earlier trials, said Shih.

Using the PAM50 (Prosigna) multigene assay, researchers then analyzed patients based on whether their tumors were luminal A or luminal B. “They found that in luminal A patients, those with ductal cancers benefitted more from anastrozole, while in luminal B’s, those with lobular cancers benefitted more,” said Shih.

“The study researchers are suggesting that, in the future, clinicians could rely more on these multigene assays, such as PAM50, to further subgroup breast cancers, and then provide treatment options for our patients,” said Shih.

References

1. Shih Y-C, Dillon P. Retrospective database review of outcomes in invasive lobular carcinoma and invasive ductal carcinoma of the breast. Poster presented at: 2012 San Antonio Breast Cancer Symposium; December 6, 2012; San Antonio, TX. P3-07-11.
2. Ciriello G, Gatza ML, Hoadley KA, et al. Comprehensive molecular characterization of invasive lobular breast tumors. Presented at: 2014 San Antonio Breast Cancer Symposium; December 10, 2014; San Antonio, TX. Abstract S2-04.
3. Desmedt C, Gundem G, Zoppoli G, et al. Characterization and clinical relevance of the genomic alterations defining lobular breast cancer. Presented at: 2014 San Antonio Breast Cancer Symposium; December 10, 2014; San Antonio, TX. Abstract S2-05.
4. Knauer M, Gruber C, Dietze O, et al. Survival advantage of anastrozol compared to tamoxifen for lobular breast cancer in the ABCSG-8 study. Presented at: 2014 San Antonio Breast Cancer Symposium; December 10, 2014; San Antonio, TX. Abstract S2-06.