NAPOLI: Negative/Low Hormone Receptor And/or HER2 POsitive Lobular Invasive Breast Carcinoma - A Real-World International Cohort Study

Invasive lobular carcinoma (ILC) is the second most common histologic subtype of breast cancer (BC), accounting for approximately 10-15% of all invasive BCs. ILC is characterized by loss or dysfunction of the E-cadherin/catenin adhesion complex, typically due to CDH1 alterations, and by a distinctive discohesive and infiltrative growth pattern. These features translate into specific and unique biological, clinical and therapeutic challenges compared with invasive carcinoma of no-special type (IC-NST).

The majority of ILCs - up to 90% - are estrogen receptor (ER)-positive, progesterone receptor (PR)-positive and HER2-negative. In contrast, hormone receptor (HR)-negative ILC (ER and PR expression <1%), HR-low ILC (1-10% HR-positive cells), and HER2-positive (any HR expression) ILC are rare, biologically and clinically heterogeneous, and markedly underrepresented in clinical trials and large translational datasets. Moreover, the absence or very low expression of hormone receptors limits the role of endocrine therapy, thereby narrowing therapeutic options and potentially affecting prognosis. The efficacy of anti-HER2 therapies in ILC remains less defined than in IC-NST, due to the rarity of HER2 overexpression in breast cancer of lobular histotype (<10% of all ILC). Consequently, clinical outcomes and response to neoadjuvant therapies across both HR-positive/HER2-positive and HR-negative/HER2-positive represent an area where clinical data are lacking.

Recent genomic and transcriptomic studies have identified alterations involving pathways such as CDH1, ERBB2, TP53, PI3K/AKT/PTEN, and DNA damage response pathways, along with other potentially actionable molecular mechanisms. These findings suggest that HR-negative/low ILC may constitute a biologically distinct entity rather than simply an uncommon variant of conventional HR-positive lobular carcinoma, raising important questions regarding prognosis, optimal treatment sequencing, indications and response to neoadjuvant therapies, and the potential role of targeted and biomarker-driven treatments.

Triple-negative ILC (TN-ILC) is exceedingly rare, accounting for approximately 1-2% of all ILC and well below 1% of all invasive BCs, which largely explains their marked underrepresentation in prospective trials, and the consequent lack of disease-specific evidence to guide clinical management. Available evidence suggests that TN-ILC is not simply the lobular counterpart of conventional basal-like triple-negative BC. Indeed, when profiled by PAM50, the majority of TN-ILC are non-basal-like, in contrast to conventional TN IC-NST. Moreover, TN-ILC appears enriched for older age at diagnosis, pleomorphic and apocrine/histiocytoid morphology, androgen receptor (AR) expression, and luminal androgen receptor (LAR)-like biology. Importantly, TN-ILC has been reported to show poor responsiveness to conventional neoadjuvant chemotherapy despite aggressive clinical behavior, raising questions about the optimal systemic treatment strategy and the potential value of biomarker-driven approaches. The few dedicated series available consistently report an unfavorable course, with a pooled pathologic complete response (PCR) rate of approximately 22.5%: in the largest early-stage cohort described to date, 5- and 10-year invasive disease-free survival were only approximately 50% and 37%, respectively. In addition, potentially actionable ERBB2 mutations have been reported in up to ~20% of TN-ILC and, together with frequent enrichment in DNA-damage-response, recurrent ESRRA mutations and PI3K/AKT/PTEN pathway alterations, may represent tractable therapeutic vulnerabilities, including HER2 tyrosine-kinase inhibitors, PARP or PI3K/AKT inhibitors.

HER2-positive ILC represents another uncommon and clinically relevant subgroup. HER2 overexpression/amplification in ILC is more frequently observed in pleomorphic and high-grade variants, and may be associated with distinct clinicopathologic features, higher proliferative activity and worse prognosis than classic HR-positive/HER2-negative ILC. However, data specific to HER2-positive ILC remain sparse, and most recommendations are extrapolated from IC-NST cohorts. Whether patterns of response to anti-HER2 neoadjuvant therapy, rates of PCR, surgical outcomes and recurrence patterns differ from those observed in IC-NST remains insufficiently defined.