Lobular Breast Cancer: Different Disease, Different Algorithms?

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Key points

  • 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.

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.

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