Invasive lobular breast cancer (ILC) is the second most common subtype of breast carcinoma, comprising approximately 15 % of all cases. ILC is increasingly acknowledged as a unique pathological and molecular entity. Clinically, ILCs are often harder to detect, as they can be missed on physical exam and imaging. Most ILCs are estrogen receptor (ER)-positive (commonly luminal A subtype) and tend to have lower observed responses to chemotherapy and slightly lower sensitivity to tamoxifen compared to ductal carcinomas, although they usually respond to endocrine therapy (Mouabbi et al., 2022). ILC is also known for its propensity for late recurrences (An et al., 2018) and metastases to unusual sites such as the gastrointestinal tract or peritoneum (McCart Reed et al., 2021a). These differences have raised the question of whether ILC should be managed differently from the more common invasive ductal carcinoma (IDC).

The most common genetic alteration in ILC is the loss of function of the CDH1 gene (encoding E-cadherin). To our knowledge, until now, no targeted therapy specifically for CDH1-mutated ILC has been established. However, recent research has identified a synthetic lethal interaction between E-cadherin loss and ROS1 inhibition, providing a potential targeted approach for CDH1-mutant cancers (Bajrami et al., 2018). The second most common mutations associated with ILC (often co-occurring with CDH1 loss) are those in the PI3K/AKT/mTOR signaling pathway, in particular mutations of the PIK3CA gene, which encodes the p110α catalytic subunit of PI3K. The frequency of PIK3CA mutation has ranged from 8 % to 40 % in human breast cancers (Kalinsky et al., 2009). Most of these mutations occur at three hotspots: E542K and E545K at exon 9, which encode the helical domain (HD), and H1047R at exon 20, which encodes the kinase domain (Kalinsky et al., 2009). It is hypothesized that somatic PIK3CA mutations induce a growth advantage to cancer cells, including resistance to antiestrogen therapy, stimulation of angiogenesis and increased invasiveness (Kalinsky et al., 2009). An Y et. al have shown in vitro that CDH1 and PIK3CA mutations cooperate to induce a molecular subtype of lobular cancer known as immune related. In addition, they found that these tumors show sensitivity to PI3K inhibitors (An et al., 2018). Another study by Elangovan et al. showed that a cell line created by pleural effusion from a patient with lung metastases from lobular breast cancer is sensitive to alpelisib (Elangovan et al., 2023).

There have been multiple clinical trials targeting this pathway in hormone receptor-positive breast cancer – for example, the BOLERO-1, -2, and -3 trials of the mTOR inhibitor everolimus (André et al., 2014, Piccart et al., 2014, Royce et al., 2018, Shao et al., 2024, Toi et al., 2017), the CAPItello-291 trial of the AKT inhibitor capivasertib (Oliveira et al., 2024), and the SOLAR-1 trial of the PI3Kα inhibitor alpelisib (André et al., 2021). None of these trials discriminated between histology focused on ILC specifically. However, an exploratory subgroup analysis of BOLERO-2 (which included both ILC and IDC patients) suggested that everolimus added to endocrine therapy had greater efficacy in metastatic lobular carcinoma than in ductal carcinoma (Hortobagyi et al., 2014). This highlights a potential differential benefit of PI3K pathway targeting in ILC, although prospective validation is needed.

Data directly evaluating predictive significance of PIK3CA mutations in ILC (i.e., whether mutation status predicts differential benefit from a treatment) are limited. One insight comes from a retrospective exploratory analysis of the BIG 1–98 trial, which compared adjuvant letrozole vs. tamoxifen in early breast cancer. Investigators found that postmenopausal women with lobular carcinoma seemed to derive greater benefit from aromatase inhibitor (letrozole) therapy than those with ductal carcinoma27 Additionally, a post - hoc analysis of BIG 1–98 reported that tumors harboring PIK3CA mutations had a better outcome on letrozole compared to tamoxifen, regardless of histologic subtype (Luen et al., 2018). This suggests a possible interaction between PIK3CA status and endocrine therapy effectiveness. Mouabbi et. al. examined real-world outcomes of HR+/HER2– metastatic breast cancer treated with various targeted agents (CDK4/6 inhibitors, everolimus, or alpelisib) and found no difference in benefit between ILC and IDC subtypes (Mouabbi et al., 2022) In that series, the addition of these targeted therapies to endocrine treatment improved progression outcomes similarly in both lobular and ductal cancers, suggesting that ILC responds to PI3K-pathway inhibitors in a manner comparable to IDC. Thus, the current evidence for a predictive role of PIK3CA in guiding therapy specifically for ILC is inconclusive: while targeted pathway inhibitors are effective in PIK3CA-mutant breast cancers generally (as demonstrated by trials like SOLAR-110), there is no clear proof yet that ILC histology modifies this effect.

Given these considerations, we set out to review comprehensively the role of PIK3CA mutations in lobular breast cancer. The goals of this review are: (1) to precisely estimate the prevalence of PIK3CA mutations in ILC by integrating data from the literature, (2) to determine whether ILC differs from IDC in the frequency of PIK3CA mutations, (3) to assess any evidence that PIK3CA mutations impact the prognosis of ILC patients, and (4) to evaluate whether PIK3CA mutations predict response (or lack of response) to specific therapies in ILC. By addressing these questions, we aim to clarify the significance of this common mutation in lobular breast cancer and guide future research and management in the era of precision oncology.