Invasive lobular carcinoma (ILC) accounts for 10% to 15% of breast cancers in the United States, 80% of which are estrogen receptor (ER)-positive, with an unusual metastatic pattern of spread to sites such as the serosa, meninges, and ovaries, among others. Lobular cancer presents significant challenges in detection and clinical management given its multifocality and multicentricity at presentation. Despite the unique features of ILC, it is often lumped with hormone receptor-positive invasive ductal cancers (IDC); consequently, ILC screening, treatment, and follow-up strategies are largely based on data from IDC. Despite both being treated as ERpositive breast cancer, querying the Cancer Genome Atlas database shows distinctive molecular aberrations in ILC compared with IDC, such as E-cadherin loss (66% vs. 3%), FOXA1 mutations (7% vs. 2%), and GATA3 mutations (5% vs. 20%).Moreover, compared with patients with IDC, patients with ILC are less likely to undergo breast-conserving surgery, with lower rates of complete response following therapy as these tumors are less chemosensitive. Taken together, this suggests that ILC is biologically distinct, which may influence tumorigenesis and therapeutic strategies. Long-term survival and clinical outcomes in patients with ILC are worse than in stage-and grade-matched patients with IDC; therefore, nuanced criteria are needed to better define treatment goals and protocols tailored to ILC's unique biology. This comprehensive review highlights the histologic and clinicopathologic features that distinguish ILC from IDC, with an in-depth discussion of ILC's molecular alterations and biomarkers, clinical trials and treatment strategies, and future targets for therapy. The Oncologist 2021;25:1-11 Implications for Practice: The majority of invasive lobular breast cancers (ILCs) are hormone receptor (HR)-positive and low grade. Clinically, ILC is treated similar to HR-positive invasive ductal cancer (IDC). However, ILC differs distinctly from IDC in its clinicopathologic characteristics and molecular alterations. ILC also differs in response to systemic therapy, with studies showing ILC as less sensitive to chemotherapy. Patients with ILC have worse clinical outcomes with late recurrences. Despite these differences, clinical trials treat HR-positive breast cancers as a single disease, and there is an unmet need for studies addressing the unique challenges faced by patients diagnosed with ILC.

Background: Invasive Lobular Carcinoma (ILC) is a molecular subtype of breast cancer that is usually hormone receptor (HR) positive and E-cadherin negative. Ninety percent of ILC carry CDH1 mutations. Although ILC patients have a seemingly favorable outlook at diagnosis, they suffer from late recurrences and hence the long-term outcomes are not as favorable suggesting resistance to conventional therapies. In vitro and in vivo studies have demonstrated cross talk between EGFR/HER2 with HR in inducing endocrine resistance1. Increase in HER2 expression at the time of recurrence has been reported, while HER2 activating mutations occur in approximately 15.4% of ILC’s2. Importantly, HER2 mutations are associated with significantly worse prognosis in patients with CDH1 mutated ILC3. We believe that HER2 is a viable target in ILC, and endocrine resistant IDC when combined with endocrine therapy. HER2 targeted therapy, such as Trastuzumab is not currently used to treat patients with normal HER2 expression as a recent clinical trial NSAPB B-47 found that Trastuzumab has very little effect on these patients. We hypothesize that ONT-380 (Tucatinib), a tyrosine kinase inhibitor (TKI) that is currently in clinical trials for HER2 overexpressing metastatic breast cancer, will be effective in treating normal HER2 expressing ILC and HR positive IDC that are relatively endocrine resistant. Combined treatment with TKI and anti-estrogen could improve responses to endocrine therapy. Methods: We have studied effects of ONT-380 in combination with Tamoxifen on cell proliferation using in vitro cell culture models. We used ERα positive cell lines with varying levels of HER2 expression BT474 (HER2+), and cell lines expressing basal level of HER2, ZR-75-1 (IDC), T47D (IDC), SUM44PE (ILC), and MDA-MB-134-VI (ILC) to understand the effects of simultaneous targeting of HER2 and ERα. We have used MTT assay (Promega) to compare cell proliferation in drug treated and untreated cells. Western blot analysis was used to measure the levels of pHER2Y877, pHER2Y1221/1222,pAKTS473, total HER2 and total AKT. Basal level and drug induced alteration in phosphorylation status of downstream targets of HER2 and ERα signaling will be assessed using Human RTK (Receptor Tyrosine Kinase) phosphorylation antibody array (Abcam). Results: Western blot analysis of whole cell extracts showed that the designated HER2 positive cells (BT474) have higher level of HER2 protein, while the other cells (ZR-75-1, T47D, SUM44PE, MDA-MB-134) have significantly lower level of HER2 protein. HER2 was not detectable in MCF7 cells. Similarly, pAKT, a downstream effector of EGFR/ HER2 signaling was higher in the HER2 positive cell lines. Treatment of ILC cell line MDA-MB-134-VI with ONT-380 (100nM) or Tamoxifen (10 μM) alone or in combination showed additive inhibition of cell proliferation when the two drugs were combined as opposed to single drug treatment. We have observed similar effect of ONT-380 and Tamoxifen on SUM44PE, BT474 and ZR-75-1 cells. Furthermore, treatment of ZR-75-1 cells with ONT-380 and Tamoxifen markedly reduced pAKT level, while the effect of treatment with individual drugs was barely detectable. Similar studies are underway for endocrine resistant ILC and additional IDC cell lines. Conclusion: Targeting HER2 kinase activity in normal HER2 expressing ILC and endocrine resistant IDC with small molecule inhibitors of tyrosine kinase could be a viable option for treating these cancers. Further in vitro and in vivo studies are underway to study the efficacy of this drug combination. 1. Schafer et.al. 2002 (PMID: 12650703) 2. Deniziaut et.al. 2016 (PMID: 27602491) 3. Ping et.al. 2016 (PMID: 27811364) Citation Format: Nikhil Pramod, Sivanesan Dhandayuthapani, Sarmila Majumder, Bhuvaneswari Ramaswamy. Unlocking Her2 as a target in invasive lobular cancer and endocrine resistant invasive ductal carcinoma [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 P1-18-22.