Invasive Lobular Carcinoma Comes Into Sharper Focus

Sibylle Loibl, MD, PhD

Although invasive lobular carcinoma (ILC) is the second most-common subtype of breast cancer, the understanding of the clinical implications of its distinct pathological and genomic profile remains a work in progress. Research groups in the United States and Europe are seeking to build the knowledge base about ILC in hopes that therapy can be tailored for patients with this diagnosis.

Outcomes among patients with ILC may differ from those for patients with invasive ductal carcinoma (IDC), the most common breast cancer subtype, with frequently used treatment regimens. Neoadjuvant chemotherapy is not effective for carcinomas classified as purely lobular and these patients should not be offered this approach routinely, according to Sibylle Loibl, MD, PhD. Upfront therapy with an aromatase inhibitor (AI) may be beneficial for patients with hormone receptor–positive ILC, Loibl said.¹

Loibl, chair of the German Breast Group, shared her insights on ILC during the 2022 San Antonio Breast Cancer Symposium (2022 SABCS) in December. She is CEO of the GBG Forschungs GmbH in Neu-Isenburg and an associate professor of obstetrics and gynecology at Goethe University Frankfurt, both in Germany.

Loibl’s presentation was one of more than 20 posters, abstracts, and discussions about ILC at 2022 SABCS, a sign of the growing awareness of the tumor subtype and of advocacy efforts to improve understanding about it.² She noted several ongoing studies testing treatment strategies in cohorts that include patients with ILC (Table).¹

Table. Ongoing Studies of Therapeutic Options for Patients With ILC¹

Moving forward, the distinctive genomic profile of ILC may warrant changes in testing strategies, according to Loibl. “Some of the genomic alterations are associated with endocrine resistance and might play a role in today’s modern treatment options,” she said.¹ “When we look at invasive lobular carcinoma, we might consider testing those patients more often. We might find more mutations and also more mutations that play a role in endocrine- resistant pathways.”

Biological Profile Reveals Distinctions

Lobular carcinoma as a distinct subtype of breast cancer was first described in 1941 as an in situ carcinoma in isolated cells or groups of cells in the lobule or terminal lobular duct.³ Today, lobular carcinoma in situ is classified as a benign entity whose presence indicates an elevated risk of breast cancer; risk-reduction endocrine therapy is the preferred approach for most individuals.^4,5

In contrast, 10% to 15% of all breast cancers (approximately 40,000 cases annually in the United States) are ILC, making it the second most common subtype after IDC.^1,6,7 The incidence of ILC increased from 1987 to 1999, possibly because of improved diagnostic techniques and the use of combined hormone replacement therapy. However, a sharp decrease in the use of hormone replacement therapy did not translate into a marked decline in ILC; the rates decreased from 2002 to 2006, but not significantly.¹

In terms of histology, ILC is among 20 subtypes of breast cancer defined by their distinct biological features, according to Jorge S. Reis-Filho, MD, PhD, FRCPath, director of the experimental pathology service at Memorial Sloan Kettering Cancer Center in New York, New York, and co-administrative core director of its Specialized Programs of Research Excellence in Genomic Instability in Breast Cancer. Although these other subtypes are often called “special types” of breast cancer, the diagnosis of the predominant IDC subtype is made after the pathologist “has ruled out all the other histologic subtypes,” Reis-Filho said during a presentation at 2022 SABCS.⁸

“Special histologic types of breast cancer have not only distinct histologic appearances but also different genomic features and biological characteristics. Understanding these tumors and subtyping them can be challenging. Subtyping does indicate different biology and, likely going forward, different therapeutic approaches.”

The histologic characteristics of ILC include monomorphic cells, single cell files, intracytoplasmic lumina, round nuclei, and varying degrees of atypia, with more than 85% classified as grade I or II. Delving deeper into the subtype, ReisFilho described 8 variants of ILC: classic, alveolar, trabecular, solid, mixed, pleomorphic, histiocytoid, and signet ring.⁸

More than 90% of ILCs are estrogen receptor (ER)– or progesterone receptor–positive, are HER2 negative, and have a low Ki67 proliferation index.8 Metastases are more likely to occur in the gastrointestinal tract, ovary, peritoneum, and bone, and less likely to affect the lungs.¹

The tumors are distinguished by a loss of E-cadherin, a transmembrane glycoprotein encoded by the CDH1 gene with varied roles in the processes of cell migration and invasion.⁹ The adhesion molecule is essential to the maintenance of cell viability, and its dysregulation results in the distinctive growth patterns evident in ILC.⁷ Inactivation of E-cadherin is associated with ILC as well as atypical lobular hyperplasia and lobular carcinoma in situ.⁸ Mutations in CDH1 have been observed in approximately 80% of ILCs.⁸

Overall, CDH1 aberrations have been detected in approximately 65% of ILC specimens, followed by PIK3CA in 43% to 48% of samples.⁸ Together, mutations in PIK3CA, AKT, and PTEN make up more than 50% of the aberrations in ILC, suggesting that AKT inhibition might have a place in the treatment algorithm.¹ There also are genomic differences in the profiles of ILC variants; pleomorphic ILC, a less common but more aggressive subtype, had a higher frequency of ERBB2 and PIK3CA alterations in addition to CDH1 aberrations in one analysis.¹ (Figure ^1,7,8)

Figure. Characteristics of ILC^1,7,8

Large Study Provides Clues

Investigators have found that clinical characteristics of patients with ILC also differ from those of patients with IDC. In November 2022, Steffi Oesterreich, PhD, and colleagues published findings from a large retrospective study of women treated for breast cancer from 1990 to 2017 at the University of Pittsburgh Medical Center in Pennsylvania, Cleveland Clinic in Ohio, and The Ohio State University Comprehensive Cancer Center—Arthur G. James Cancer Hospital and Richard J. Solove Research Institute in Columbus.⁶

Oesterreich is Shear Family Foundation Chair in Breast Cancer Research, professor and vice chair in the Department of Pharmacology and Chemical Biology at University of Pittsburgh School of Medicine, and co-director of Women’s Cancer Research Center at Hillman Cancer Center, Magee Women’s Research Institute. She also is former chair of the scientific advisory board of the Lobular Breast Cancer Alliance (LBCA), an advocacy group.

Among 33,662 patients included in this Great Lakes Breast Cancer Consortium analysis, 10.7% had ILC and 89.3% had IDC. Patients with ILC were older at diagnosis than those with IDC (aged 61 years vs aged 57 years, respectively). Patients with ILC vs those with IDC were more likely to have tumors classified as grades 1 and 2 (88% vs 60%, respectively), more frequently classified as stages III and IV (20.7% vs 10.4%), and more often diagnosed with de novo metastatic disease stage IV disease (3.7% vs 2.4%).⁶

Moreover, patients with ILC had tumors that were larger in size than patients with IDC, with 14.7% at T3 and T4 vs 4.0%, respectively, and had more nodal involvement, with 9.9% vs 5.5% having N2 and N3 tumors at diagnosis. ILC tumors also were more likely than IDC malignancies to be ER positive (96% vs 77%, respectively) and progesterone receptor–positive (81% vs 67%, respectively).⁶

Patients with ILC are candidates for the same treatment regimens as those with IDC, according to National Comprehensive Cancer Network guidelines.5 In the Great Lakes Breast Cancer Consortium data set, patients with ILC were less likely than those with IDC to receive radiation therapy (52% vs 57%, respectively) and chemotherapy (44% vs 47%) and more like to receive hormonal therapy (78% vs 61%). Mastectomy rates were significantly higher among patients with ILC compared with those with IDC (60% vs 50%, respectively).⁶

Outcomes May Differ

Although the same treatment strategies are used for patients with ILC and IDC, differences in outcomes have emerged. In the Great Lakes Breast Cancer Consortium data set, there was no difference in disease-free survival (DFS) when patients in the entire cohort were compared by subtype, but overall survival (OS) was significantly worse for patients with ILC (HR, 1.17; 95% CI, 1.09-1.25; P < .001).⁶

Of note, both DFS and OS were significantly worse for patients with ILC vs those with IDC in cohorts with ER-positive, HER2-negative breast cancer. The HRs were 1.18 for DFS (95% CI, 1.011.38; P = .03) and 1.32 for OS (95% CI, 1.19-1.45; P < .001). Additionally, the probability of DFS diverged between the 2 subtypes over a 20-year period, showing an increase of late recurrences among patients with ILC vs those with IDC.⁶

Other studies have shown a similar deterioration in outcomes for patients with ILC over time. Patients with ILC had an early advantage over those with IDC in DFS and OS, according to a 2008 analysis of findings from 15 International Breast Cancer Study Group trials. The curves started to diverge after 6 years for DFS and after 10 years for OS, when an advantages began to emerge for IDC. After 6 years, the risk of a DFS event was 54% higher for patients with ILC vs those with IDC (HR, 1.54; 95% CI, 1.31-1.81; P < .01). After 10 years, the risk of death was 50% higher for patients with ILC (HR, 1.50; 95% CI, 1.22-1.86; P < .01). The pattern was similar regardless of ER status.¹⁰

In a more recent study, investigators analyzed outcomes among 171,881 patients with breast cancer, approximately 84.2% of which had IDC, 9.6% had ILC, and 6.3% had a mixed invasive ductal and lobular carcinoma histology. The findings showed that OS was better for patients with ILC or mixed histology than for those with IDC, with HRs of 0.84 (95% CI, 0.77-0.90) and 0.91 (95% CI, 0.83-1.00), respectively.¹¹

However, Loibl noted during her presentation that the follow-up period of this study, at less than 6 years, is shorter than the longer periods of time analyzed in the earlier research.

Which Treatments to Choose?

Although recommendations for treating patients with ILC often are similar to those for IDC, investigators are seeking to determine whether therapy choices should take histology into account.¹² During her 2022 SABCS presentation, Loibl sorted through study results for several strategies, noting that the data at times provide a mixed verdict on optimal treatments for ILC.¹

Although neoadjuvant chemotherapy frequently is used for patients with substantial nodal involvement, this approach has mixed results for patients with ILC. In 2014, Loibl and colleagues showed that pathologic complete response (pCRs) rates were significantly lower for patients with ILC vs those with non-ILC histology in 9020 patients with breast cancer treated during neoadjuvant trials in Germany (6.2% vs 17.4%, respectively; P < .001).¹³

However, the pCR rate differed for patients with ILC when analyzed by tumor grade and hormone receptor status. The pCR rates were 4.2% among patients with ILC hormone receptor–positive, grade 1 or 2 tumors; 7.0% in ILC hormone receptor–positive, grade 3 tumors or hormone receptor–negative, grade 1 or 2 tumors; and 17.8% in ILC with hormone receptor–negative, grade 3 tumors. OS was higher among patients who achieved pCR in ILC and non-ILC groups.¹³

By comparison, adjuvant chemotherapy showed a benefit in findings from a retrospective study of 2318 patients with hormone receptor–positive, HER2-negative ILC who received primary surgery followed by endocrine therapy with or without chemotherapy.

The addition of chemotherapy demonstrated improved outcomes for patients who received combination therapy (n = 823) compared with those who had endocrine therapy alone (n = 1485). The HRs favoring combination therapy were 0.61 for DFS (95% CI, 0.41-0.90; P = .01) and 0.52 for OS (95% CI, 0.31–0.87; P = .01). However, subgroup analysis showed that patients with low-risk disease did not significantly benefit from the addition of chemotherapy.¹⁴

One of the more interesting therapeutic questions involves adjuvant endocrine therapy for patients with ILC, because mixed results have been reported in several large clinical trials, Loibl said. The phase 3 TEAM trial (NCT00036270) compared the AI exemestane with tamoxifen, a nonsteroidal selective estrogen receptor modulator, as endocrine therapy, followed by exemestane for postmenopausal women with hormone receptor–positive nonmetastatic breast cancer. A comparison of participants by histology showed similar rates of relapse-free survival for patients with ILC and those with IDC.¹

However, data from the phase 3 BIG 1-98 study (NCT00004205) indicated a greater benefit with letrozole, an AI inhibitor, compared with tamoxifen in patients with early-stage classic ILC or IDC, with differences in treatment effect associated with histology.

The 8-year estimate for DFS was 66% with tamoxifen vs 82% with letrozole in patients with ILC (HR, 0.48; 95% CI, 0.31-0.74). Among patients with IDC, the DFS rate was 75% for tamoxifen and 82% for letrozole (HR, 0.80; 95% CI, 0.68-0.94). Similarly, the OS rate was 74% for tamoxifen vs 89% for letrozole in the ILC cohort (HR, 0.40; 95%CI, 0.23-0.69) and 84% for tamoxifen vs 88% for letrozole in the IDC group (HR, 0.73; 95% CI, 0.60-0.89).¹⁵

In this trial, DFS and OS rates also were associated with histology for the luminal A–like and luminal B–like subtypes. For ILC, HRs favored letrozole for patients with both luminal Alike (HR, 0.50) and luminal B–like (HR, 0.34) subtypes, whereas in IDC, an advantage was observed for luminal B–like group (HR, 0.65) but not the luminal A–like cohort (HR, 0.95).¹⁵

“The BIG 1-98 trial was the first trial indicating that there might be a higher benefit for an up-front aromatase inhibitor in patients who have lobular carcinoma,” Loibl said. “This was, for awhile, thought to be the standard of care.... It was actually the first treatment decision made based on the histologic subtype for the patient.”

The findings, however, were not repeated in the ABCSG 8 trial (NCT00291759), which evaluated outcomes among postmenopausal women with hormone receptor–positive early breast cancer who received adjuvant therapy with tamoxifen for 2 years, followed by either tamoxifen or anastrozole for 3 years. In the overall population, there was no significant difference in DFS and OS in terms of ILC and IDC, Loibl said. However, when results were analyzed by luminal status, investigators observed a greater benefit in the ILC cohort for luminal B subtype with anastrozole vs tamoxifen for DFS (HR, 0.35) than in the IDC luminal B group (HR, 0.86) and for OS (HR, 0.32 vs 1.09, respectively).¹

In terms of immunotherapy, the first clinical study designed for patients with ILC, the GELATO trial (NCT03147040), was terminated prematurely after failing to show sufficient benef it, Loibl noted. The study evaluated combination therapy with atezolizumab (Tecentriq), a PD-L1 inhibitor, plus carboplatin in patients with metastatic ILC. The objective response rate in 21 evaluable patients was 19% (95% CI, 5%-42%), with a median duration of response of 12 weeks (95% CI, 7.1-not reached).¹

Next Steps For ILC Research

Although several prospective studies are testing treatment strategies for patients with ILC, investigators cite a range of outstanding questions that should be explored.

An improved understanding of the tumor microenvironment in ILC is among the most pressing research questions.¹² Other questions involve whether there is “a greater propensity for tumor dormancy” in ILC, as suggested by the Great Lakes Breast Cancer Consortium findings, according William J. Gradishar, MD.¹⁶

“Long-term follow-up and novel therapeutic strategies are required for [patients with ILC],” wrote Gradishar, chief of Hematology and Oncology in the Department of Medicine and the Betsy Bramsen Professor of Breast Oncology at Northwestern University Feinberg School of Medicine in Chicago, Illinois.

LBCA and other groups are seeking to raise awareness about ILC and advance a research agenda into the subtype. At 2022 SABCS, investigators reported results from a survey of practicing oncologists, researchers, patients, and advocates.¹⁷

Only 46% of clinicians (n = 413), mostly medical oncologists and surgeons, and 48% of researchers (n = 376) said they felt confident in being able to describe the differences between ILC and breast cancer of no special type. Respondents identified the most important research questions for the ILC field as determining mechanisms of endocrine resistance and identifying novel therapeutic targets, repurposing existing drugs, and testing them in clinical trials.¹⁷

The survey was an international collaboration developed with input from breast cancer clinicians and researchers, laboratory-based researchers, and advocates and patients led by Oesterreich and Leigh Pate, an ILC survivor who founded LBCA. Pate died of complications from ovarian cancer in June 2022. Laurie Hutcheson, MS, executive director of LBCA, and Flora Migyanka, chair of The Dynami Foundation and an LBCA patient advisory board member, were among many investigators and clinicians contributing to the research.

In responding to the survey, only 46% of clinicians (n = 413), mostly medical oncologists and surgeons, and 48% of researchers (n = 376) said they felt confident in being able to describe the differences between ILC and breast cancer of no special type. Respondents identified the most important research questions for the ILC field as determining mechanisms of endocrine resistance and identifying novel therapeutic targets, repurposing existing drugs, and testing them in clinical trials.

At 2022 SABCS, the LBCA reported findings from the organization’s survey of patients diagnosed with metastatic ILC. A total of 241 patients submitted complete responses; 77% of respondents live in the United States or Canada.

Overall, 48% of respondents said their metastatic ILC diagnosis was an unexpected or incidental finding during another medical procedure. For 41% of respondents, the diagnosis of metastatic ILC was de novo.

Additionally, 36% said at least 1 imaging modality had failed to detect 1 or more of their metastatic sites at diagnosis; 54% of respondents with bone metastases and 19% of participants with gastrointestinal metastases said their metastatic sites were not depicted on standard imaging.

Investigators said the findings show that early detection of ILC is challenging, and that routine breast cancer screening methods may not be sensitive enough to detect ILC.¹⁸

References

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