As a relatively rare subtype, lobular breast cancer is not well understood by many oncologists. At the 2023 Miami Breast Cancer Conference, Tari A. King, MD, FASCO, described how it differs from its more common counterpart, ductal breast cancer, in terms of characteristics, prognosis, and optimal management.1 Dr. King is Vice Chair for Multidisciplinary Oncology and Chief of the Division of Breast Surgery, Dana-Farber/Brigham Cancer Center, and the Anne E. Dyson Professor of Surgery in the Field of Women’s Cancers at Harvard Medical School.
Classic invasive lobular cancer is characterized by small, monomorphic cells; rounded nuclei; and an infiltrative, “dyscohesive” growth pattern that spreads diffusely through the breast. As lobular cancer became better recognized as its own entity in the 1970s and 1980s, surgeons of that era asked whether it should be treated differently from ductal cancer. Retrospective studies sought a better understanding of this malignancy, but the first prospective examination was not published until 2008.
Tari A. King, MD, FASCO
Comparing Histologic Subtypes
The International Breast Cancer Study Group (IBCSG) compiled the results of 15 trials involving more than 13,000 patients with histology documented by central pathology review.2 Corresponding with results from the older retrospective studies, the IBCSG found lobular cancer as compared with ductal cancer to be largely associated with older age, larger tumors, and the performance of more mastectomies, but a new finding emerged: Histologic type had significant time-dependent effects on both disease-free and overall survival, whereby lobular cancers were associated with an early but not long-lasting advantage. By 6 years, the disease-free survival rate of those with lobular cancer was significantly lower than that of those with ductal cancer, and by 10 years, overall survival rates were significantly inferior.
Most lobular cancers are estrogen receptor–positive, and late recurrences are known to be more common in such patients, but this did not explain the difference. “The shape of the curves was similar for the estrogen receptor–positive and estrogen receptor–negative patients, suggesting the time-dependent effect on prognosis is independent of estrogen receptor status,” Dr. King said.
The IBCSG study also revealed another histology-dependent difference: Although local recurrence rates were similar for lobular and ductal cancers, patients with ductal cancers experienced more regional recurrences, whereas those with lobular cancers had more distant recurrences. In disease that metastasized, ductal cancers tended to spread to the bone, whereas lobular cancers tended to spread to the peritoneum, ovaries, and gastrointestinal tract. Recurrence in the lungs was less common with lobular cancers.
Risk Factors May Also Differ
Risk factors for lobular cancer may also differ from those associated with ductal cancer. In a meta-analysis of 25 observational studies of hormone exposure, there was a stronger association with hormone replacement therapy, age at menarche, and age at menopause for lobular vs ductal cancer.3,4 Among ever-users or current users of hormone replacement therapy, the relative risk for lobular cancer was 2.0, compared with 1.5 for ductal cancer; some individual studies found a threefold increased risk associated with lobular cancer.
Despite the tendency toward increased use of MRI in patients with lobular cancer, there is no demonstrated improvement in surgical outcomes.— Tari A. King, MD, FASCO
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Perhaps the strongest risk factor for lobular cancer is a preceding diagnosis of lobular carcinoma in situ; it shares the same cytologic features as infiltrating lobular carcinoma, but the cells are confined to the terminal duct lobular units. Surveillance, Epidemiology, and End Results data showed that the risk for subsequent breast cancer after a diagnosis of lobular carcinoma in situ is 11% at 10 years and 20% at 20 years—or approximately 1% per year.5 Although lobular carcinoma in situ is a risk factor for both ductal and lobular cancers, lobular cancers are overrepresented in this group, with about 30% of these subsequent cancers being pure lobular carcinomas or mixed ductal and lobular carcinomas.
Closer Look at the Phenotype
“Pathologists have known for a long time that the hallmark of the lobular phenotype is loss of functional E-cadherin, which is encoded by CDH1. It is the loss of this protein that is responsible for the dyscohesive growth pattern of these cells.
Most lobular cancers are of the luminal phenotype, predominantly luminal A—ie, estrogen receptor–positive, HER2-negative—and have a very low rate of proliferation. A comparison of luminal A invasive lobular cancers and luminal A invasive ductal cancers in The Cancer Genome Atlas data set showed “a striking” enrichment for CDH1 mutations in lobular cancer: 68% vs 2% in ductal tumors.6 FOXA1 aberrations are also overrepresented in lobular cancers, and FOXA1 activity in lobular cancers was recently described as having an important impact on estrogen receptor signaling, potentially impacting treatment.7
Considerations in Imaging
Dr. King continued: “We often hear concerns about determining the extent of disease. What are the proper margins in breast-conserving surgery, and what is the role of preoperative therapy?” She did not discuss nodal management, because it does not differ from that of ductal cancer. However, patients with lobular disease seem to be more likely to have micrometastatic nodal disease, and ultrasound-guided, fine-needle aspiration may have reduced sensitivity in these lesions.
Magnetic resonance imaging (MRI) is the best imaging modality for determining tumor size. For MRI, the correlation coefficient is approximately 0.8, which reflects much more accuracy than other approaches.
“But we know that not all of our imaging modalities are perfect,” acknowledged Dr. King. A Mayo Clinic series of 59 patients undergoing MRI examined the rates of concordance, underestimation, and overestimation of size with final pathologic tumor size. Of note, estimations by clinical breast exam were the same as those achieved with MRI.8 “We still have work to do with our imaging modalities, but generally, we know that when used for evaluating invasive breast cancer results, preoperative MRI increased the use of mastectomy,” she said.
One meta-analysis of the preoperative use of MRI in invasive breast cancer (lobular and ductal), involving almost 86,000 patients, calculated odds ratios for surgical outcomes.9 Use of MRI was associated with increased receipt of mastectomy but did not reduce the rate of positive margins or the need for reoperation. MRI use was also associated with a near doubling in contralateral prophylactic mastectomy. A subgroup analysis of six studies involving lobular cancers alone showed that unlike the primary analysis, there was no increased use of mastectomy—but also no reduction in reoperations—in patients after breast-conserving surgery.
“So, despite the tendency toward increased use of MRI in patients with lobular cancer, which we’ve all heard about, there is, in fact, no demonstrated improvement in surgical outcomes,” Dr. King noted.
Recurrence Risk After Treatment
Published series from 2004 to 2015 have found very low and “acceptable” rates of local recurrence, no different from those of patients with ductal cancers. The largest study, by Galimberti et al in 2011, showed the local recurrence rate was 5.7% at a median follow-up of 8.4 years,10 with 3.9% in the same quadrant as the surgery and 1.8% elsewhere. There was no difference in locoregional recurrence for patients with “more widely clear margins,” she added, which was defined as margin widths greater than 10 mm.
The question of margin width in lobular cancer was also assessed in a series of 736 patients treated from 1997 to 2007 at Dr. King’s institution, Brigham and Women’s Hospital/Dana Farber.11 Half the patients underwent breast-conserving surgery, and all were followed for at least 5 years. At a median follow-up of 72 months, there was no difference in locoregional recurrence rates between breast conservation and mastectomy, each being less than 5%. And although locoregional recurrence was associated with tumor size, grade, and final margin status, it was not associated with the width of the final margin.
It’s likely we’ll need lobular-specific assays to better refine prognostics and predictions in this group [those with lobular breast cancer].— Tari A. King, MD, FASCO
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Events occurred in 2.4% of cases with negative margins, defined as “no ink on tumor,” in 4.8% of cases with “close” margins, defined as 1 to 3 mm, and in 7% of cases with margins defined within 1 mm; in contrast, 18.2% of cases with positive margins had locoregional recurrence (P = .02 vs negative margins). These findings supported the validity of the 2014 consensus of ASCO, the American Society for Radiation Oncology (ASTRO), and the Society of Surgical Oncology (SSO) that “no ink on tumor” should be the definition of a “negative” margin in lobular cancers, she said.
Neoadjuvant Therapy Considerations
Pathologic complete response rates are very low in patients with lobular cancer—1% to 6% in published series—which is even lower than the 9% to 20% seen in those with estrogen receptor–positive ductal cancer. In the largest study to evaluate response to neoadjuvant chemotherapy, Loibl et al compiled the results of nine German trials of patients with estrogen receptor–positive tumors.12 Overall, the pathologic complete response rate was 6% among the 1,051 patients with lobular cancers, as compared with 17% for those with ductal cancers (P < .001). Of note, pathologic complete response was not associated with distant disease–free or overall survival in the lobular subset but did impact subsequent outcomes of patients with nonlobular cancers.
“So, if pathologic complete response is not prognostic in lobular cancer, what about genomic assays? All the most common commercially available ones have been shown to be prognostic in lobular cancers. The use of the Oncotype DX 21-gene Recurrence Score is controversial right now, as it has not demonstrated utility in predicting the benefit of chemotherapy in this cohort,” Dr. King said.
One of the larger studies included 6,467 patients with early-stage lobular cancer and known Recurrence Scores; 19% received chemotherapy.13 For 5-year breast cancer–specific survival, the Recurrence Score “stratified nicely” between the low-intermediate and high-intermediate risk groups, but it did not define a subset who derived benefit from chemotherapy. This was true even for the high-risk group, although that subset included just 177 patients. Also, HER2 status was not available for most patients, she acknowledged.
“I think that although there are some similarities between lobular and ductal cancers, there are also many differences that we are just beginning to understand. It’s likely we’ll need lobular-specific assays to better refine prognostics and predictions in this group,” Dr. King maintained.
The emerging LobSig multigene predictor, a 194-gene set and integrative analysis of gene expression and DNA copy number, may address this need. “LobSig has been shown to outperform all other available assays when looking at prognosis, so I suspect we’ll see more from this group in the future,” she said.
DISCLOSURE: Dr. King has served as a speaker and advisor for Exact Sciences.
REFERENCES
1. King TA: Unraveling the Lobular Phenotype. Invited Lecture. 2023 Miami Breast Cancer Conference. Presented March 3, 2023.
2. Pestalozzi BC, Zahrieh D, Mallon E, et al: Distinct clinical and prognostic features of infiltrating lobular carcinoma of the breast: Combined results of 15 International Breast Cancer Study Group clinical trials. J Clin Oncol 26:3006-3014, 2008.
3. Dossus L, Benusiglio PR: Lobular breast cancer: Incidence and genetic and non-genetic risk factors. Breast Cancer Res 17:37, 2015.
4. Collaborative Group on Hormonal Factors in Breast Cancer: Menarche, menopause, and breast cancer risk: Individual participant meta-analysis, including 118,964 women with breast cancer from 117 epidemiological studies. Lancet Oncol 13:1141-1151, 2012.
5. Wong SM, Stout NK, Punglia RS, et al: Breast cancer prevention strategies in lobular carcinoma in situ: A decision analysis. Cancer 123:2609-2617, 2017.
6. Ciriello G, Gatza ML, Beck AH, et al: Comprehensive molecular portraits of invasive lobular breast cancer. Cell 163:506-519, 2015.
7. Nardone A, Qiu X, Spisak S, et al: A distinct chromatin state drives therapeutic resistance in invasive lobular breast cancer. Cancer Res 82:3673-3686, 2022.
8. McGhan LJ, Wasif N, Gray RJ, et al: Use of preoperative magnetic resonance imaging for invasive lobular cancer: Good, better, but maybe not the best? Ann Surg Oncol 17(suppl 3):255-262, 2010.
9. Houssami N, Turner RM, Morrow M: Meta-analysis of pre-operative magnetic resonance imaging and surgical treatment for breast cancer. Breast Cancer Res Treat 165:273-283, 2017.
10. Galimberti V, Maisonneuve P, Rotmensz N, et al: Influence of margin status on outcomes in lobular carcinoma: Experience of the European Institute of Oncology. Ann Surg 253:580-584, 2011.
11. Sagara Y, Barry WT, Mallory MA, et al: Surgical options and locoregional recurrence in patients diagnosed with invasive lobular carcinoma of the breast. Ann Surg Oncol 22:4280-4286, 2015.
12. Loibl S, Volz C, Mau C, et al: Response and prognosis after neoadjuvant chemotherapy in 1,051 patients with infiltrating lobular breast carcinoma. Breast Cancer Res Treat 144:153-162, 2014.
13. Chen XH, Zhang WW, Wang J, et al: 21-gene recurrence score and adjuvant chemotherapy decisions in patients with invasive lobular breast cancer. Biomark Med 13:83-93, 2019.
