Carcinoma of the breast is a histologically heterogeneous disease. Invasive lobular carcinoma (ILC) accounts for 8-14% of all breast cancers [1,2]. Data from a recent epidemiologic study [3] indicate that for unknown causes the incidence of this type of breast cancer is increasing, especially among postmenopausal women.The morphologic features of lobular carcinoma differ from those of ductal carcinoma. ILC is characterized by small, round cells that are bland in appearance and have scant cytoplasm, which infiltrate the stroma in single file and surround benign breast tissues in a targeted manner [1,4]. Infiltration typically does not destroy anatomic structures or incite a substantial connective tissue response. By virtue of their distinctive growth pattern and biology, lobular carcinomas often fail to form distinct masses that can easily be diagnosed by palpation or mammography. This can make early diagnosis challenging [5,6] and breast conservation approaches more difficult. Lobular carcinomas may have a substantially increased propensity for multifocal and multicentric distribution and for bilaterality [5,[7][8][9][10][11]. Metastatic spread with an uncommon pattern of involvement has been reported [12,13]. CNS = central nervous system; DFS = disease-free survival; EGFR = epidermal growth factor receptor; ER = estrogen receptor; IDC = infiltrating ductal carcinoma; ILC = infiltrating lobular carcinoma; OS = overall survival; PgR = progesterone receptor. AbstractIntroduction: Invasive lobular carcinoma (ILC) comprises approximately 10% of breast cancers and appears to have a distinct biology. Because it is less common than infiltrating ductal carcinoma (IDC), few data have been reported that address the biologic features of ILC in the context of their clinical outcome. In the present study we undertook an extensive comparison of ILC and IDC using a large database to provide a more complete and reliable assessment of their biologic phenotypes and clinical behaviors.

The response to endocrine therapy in breast cancer correlates with estrogen receptor (ER) and progesterone receptor (PR) status. ER-positive/PR-negative breast cancers respond less well to selective ER modulator (SERM) therapy than ER-positive/PR-positive tumors. The predictive value of PR has long been attributed to the dependence of PR expression on ER activity, with the absence of PR reflecting a nonfunctional ER and resistance to hormonal therapy. However, recent clinical and laboratory evidence suggests that ER-positive/PR-negative breast cancers may be specifically resistant to SERMs, whereas they may be less resistant to estrogen withdrawal therapy with aromatase inhibitors, which is a result inconsistent with the nonfunctional ER theory. Novel alternative molecular mechanisms potentially explaining SERM resistance in ER-positive/PR-negative tumors have been suggested by recent experimental indications that growth factors may downregulate PR levels. Thus, the absence of PR may not simply indicate a lack of ER activity, but rather may reflect hyperactive cross talk between ER and growth factor signaling pathways that downregulate PR even as they activate other ER functions. Therefore, ER-positive/PR-negative breast tumors might best be treated by completely blocking ER action via estrogen withdrawal with aromatase inhibitors, by targeted ER degradation, or by combined therapy targeting both ER and growth factor signaling pathways. In this review, we will discuss the biology and etiology of ER-positive/PR-negative breast cancer, highlighting recent data on molecular cross talk between ER and growth factor signaling pathways and demonstrating how PR might be a useful marker of these activities. Finally, we will consider the clinical implications of these observations.

When accurately measured, PgR status is an independent predictive factor for benefit from adjuvant endocrine therapy. Therefore, PgR status should be taken into account when discussing RR reductions expected from endocrine treatment with individual patients.