- •
Invasive lobular breast cancer is a biologically unique entity, distinct from invasive ductal cancer.
- •
The characteristic molecular features of invasive lobular carcinoma (ILC) include its largely ER-positive and low-grade nature, and loss of E-cadherin protein expression.
- •
Tumor biology is of key importance in designing treatment approaches.
- •
Harnessing the growing knowledge of the molecular features inherent to lobular cancer holds promise for the next generation of tailored therapies.
Lobular Breast Cancer: Different Disease, Different Algorithms?
Section snippets
Key points
Epidemiology
The mean age of diagnosis of ILC is 57 years.2 Risk factors include age at menarche, age at first birth, and use of hormone therapy, emphasizing the role of estrogen exposure in pathogenesis. This relationship is also observed for most IDCs, but is more pronounced for ILC.3 The incidence of ILC in the Western world has generally mirrored trends in use of hormone replacement therapy, with a steep increase between 1975 and 2000 and a decline between 2000 and 2004, but now increasing since 2005
Histology
Classic ILC is histologically characterized by discohesive cells infiltrating the breast stroma in a single-file pattern2 with a limited host inflammatory response (Fig. 1A).6 Observed loss of membranous E-cadherin staining by immunohistochemistry may be a useful adjunct to confirm the diagnosis (see Fig. 1B). Several nonclassic forms of ILC have also been described, distinguished by morphology (alveolar, solid, dispersed, trabecular, and mixed) and cytology (apocrine, pleomorphic, signet ring,
Molecular biology
More than 90% of ILCs are estrogen receptor (ER) positive and they are largely classified as luminal A at the level of the transcriptome, although this proportion is lower in more aggressive variants,5 with highest rates of ER positivity observed in the classic form and alveolar variants, and lowest rates of ER positivity observed in pleomorphic ILCs (10%).2 HER2 overexpression is rare, seen in only 3% to 5% of classic ILCs, but present in up to 80% of the more aggressive pleomorphic subgroup.2
Clinical presentation and diagnosis
ILC may pose a diagnostic challenge because of its inherently insidious and infiltrative growth pattern. Although some patients present with an ill-defined palpable mass, others may display only vague skin thickening or diffuse nodularity, or disease may be clinically occult.2 In keeping with their indolent phenotype, ILCs are not frequently associated with calcifications and have an innately discohesive growth pattern. As such, ILCs frequently display a scattered radiological appearance.
Management
The contemporary, multidisciplinary approach to the treatment of breast cancer includes individually tailored surgery, radiotherapy (RT), and systemic therapy. Although the overarching concepts of treatment are common among all breast cancer types, the largely ER-positive phenotype of ILC is central to the principles of management and the observed responses.
Surgery and RT provide locoregional control. The course of surgery, regardless of histology, is determined by the TNM stage at
Upfront surgery
Patients with early-stage breast cancer are generally candidates for upfront surgery, either with BCT or mastectomy. BCT involves lumpectomy with negative margins followed by RT.
Factors that determine eligibility for BCT are shared between ILC and IDC. To be a candidate for BCT, patients must have tumors that can be removed with negative margins and acceptable cosmesis and must be able to receive RT thereafter. Accordingly, contraindications to BCT include cancers that are too large or diffuse
Surgery following neoadjuvant therapy
Patients with locally advanced cancers should generally receive neoadjuvant therapy before proceeding to surgery. This approach affords an opportunity for downstaging of locally advanced disease without compromising survival and allows BCS in more patients who would otherwise need mastectomy. Neoadjuvant therapy also decreases the need for ALND42 and provides insight into in vivo tumor chemosensitivity.
Patients with ILC are significantly less likely than those with IDC to experience a
Radiotherapy
BCT by definition includes margin negative lumpectomy followed by adjuvant RT. Adjuvant whole-breast RT reduces the risk of both LRR and death from breast cancer after BCS.24 Additional regional nodal irradiation may be indicated for those with involved lymph nodes or high-risk features. It is noteworthy that omission of RT may be considered in elderly women with early-stage ER-positive tumors, with small increases in absolute risk of LRR but no difference in mastectomy-free survival,
Adjuvant systemic treatment
Systemic adjuvant therapy is driven largely by tumor biology, rather than histology. Generally, patients with hormone receptor–positive cancers receive endocrine therapy, applicable to the vast majority of ILCs. Chemotherapy is offered for locally advanced cancers and considered for early-stage cancers with high-risk features such as large size, nodal involvement, high grade, high 21-gene recurrence scores, and more aggressive tumor biology, including triple-negative and HER2-positive receptor
Outcomes
In keeping with the luminal A phenotype, outcomes and prognosis in ILC are generally favorable. In a large SEER study of 263,408 women (27,639 with ILC and 235,769 with IDC) treated between 1993 and 2003, a stage-matched analysis showed that the 5-year disease-free survival was significantly better for ILC than IDC, with an overall 14% survival benefit (HR 0.86) on multivariate analysis.19 Although overall stage-corrected prognosis is favorable, some think that this may be offset by a higher
Summary and future directions
Lobular breast cancer is increasingly recognized as a distinct disease from ductal cancer, with a unique molecular pathogenesis and differing genomic profile. Presently, locoregional and systemic treatment approaches remain shared among all breast cancer types. Continual discoveries of the molecular basis of this disease hold potential for advances in therapy and will pave the way for development of treatment algorithms tailored specifically to lobular disease.
Acknowledgments
The authors thank Dr Stuart J. Schnitt for providing the histologic images for Fig. 1.
References (69)
- et al.
Lobular breast carcinoma and its variants
Semin Diagn Pathol
(2010) - et al.
Comprehensive molecular portraits of invasive lobular breast cancer
Cell
(2015) - et al.
Lobular breast cancer: clinical, molecular and morphological characteristics
Pathol Res Pract
(2016) - et al.
Lobular neoplasia
Surg Oncol Clin N Am
(2014) - et al.
Infiltrating lobular carcinoma–a comparison of diagnosis, management and outcome with infiltrating duct carcinoma
Breast
(2004) - et al.
The sensitivity of pre-operative axillary staging in breast cancer: comparison of invasive lobular and ductal carcinoma
Eur J Surg Oncol
(2014) - et al.
Utility of ultrasound and fine-needle aspiration biopsy of the axilla in the assessment of invasive lobular carcinoma of the breast
Am J Surg
(2007) - et al.
The diagnosis of invasive lobular breast carcinoma. Does MRI have a role?
Breast
(2001) - et al.
Dynamic contrast enhanced magnetic resonance imaging aids the surgical management of invasive lobular breast cancer
Eur J Surg Oncol
(2003) - et al.
Correlation of magnetic resonance imaging and pathologic size of infiltrating lobular carcinoma of the breast
Am J Surg
(2005)
Invasive lobular carcinoma predicts micrometastasis in breast cancer
J Surg Res
Sentinel lymph node biopsy and isolated tumor cells in invasive lobular versus ductal breast cancer
Clin Breast Cancer
Patient selection for breast conservation therapy with magnification mammography
Surgery
Comparison of mastectomy with breast-conserving surgery in invasive lobular carcinoma: 15-year results
Rep Pract Oncol Radiother
Clinical-pathologic features, long term-outcome and surgical treatment in a large series of patients with invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC)
Eur J Surg Oncol
Society of Surgical Oncology-American Society for Radiation Oncology consensus guideline on margins for breast-conserving surgery with whole-breast irradiation in stages I and II invasive breast cancer
Int J Radiat Oncol Biol Phys
Sentinel lymph node dissection provides axillary control equal to complete axillary node dissection in breast cancer patients with lobular histology and a negative sentinel node
Am J Surg
Axillary dissection versus no axillary dissection in patients with sentinel-node micrometastases (IBCSG 23-01): a phase 3 randomised controlled trial
Lancet Oncol
Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS): a randomised, multicentre, open-label, phase 3 non-inferiority trial
Lancet Oncol
Different responses to preoperative chemotherapy for invasive lobular and invasive ductal breast carcinoma
Eur J Surg Oncol
Response to neoadjuvant chemotherapy in lobular and ductal breast carcinomas: a retrospective study on 860 patients from one institution
Ann Oncol
The poor responsiveness of infiltrating lobular breast carcinomas to neoadjuvant chemotherapy can be explained by their biological profile
Eur J Cancer
Accelerated partial breast irradiation: executive summary for the update of an ASTRO evidence-based consensus statement
Pract Radiat Oncol
Post-mastectomy radiation therapy for invasive lobular carcinoma: a comparative utilization and outcomes study
Clin Breast Cancer
Influence of semi-quantitative oestrogen receptor expression on adjuvant endocrine therapy efficacy in ductal and lobular breast cancer - a TEAM study analysis
Eur J Cancer
Effect of adjuvant chemotherapy in postmenopausal patients with invasive ductal versus lobular breast cancer
Ann Oncol
Collective wisdom: lobular carcinoma of the breast
Am Soc Clin Oncol Educ Book
Risk factors for ductal and lobular breast cancer: results from the Nurses' Health Study
Breast Cancer Res
Risk factors for ductal, lobular, and mixed ductal-lobular breast cancer in a screening population
Cancer Epidemiol Biomarkers Prev
Genomic characterization of primary invasive lobular breast cancer
J Clin Oncol
Role of magnetic resonance imaging in the diagnosis and single-stage surgical resection of invasive lobular carcinoma of the breast
Br J Surg
The role of MRI in invasive lobular carcinoma
Breast Cancer Res Treat
Preoperative magnetic resonance imaging in breast cancer: meta-analysis of surgical outcomes
Ann Surg
Cited by (0)
The authors have nothing to disclose.