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

The NAPOLI Study is a retrospective multicenter observational study designed to characterize hormone receptor-negative/low invasive lobular carcinoma of the breast. The study will collect real-world clinicopathological, molecular, therapeutic and outcome data from patients diagnosed and treated at participating centers. The aim is to describe the clinical behavior, pathological features, receptor profile, treatments received and oncologic outcomes of this rare breast cancer subtype.

Sex

All

Minimum age

18 Years

Inclusion Criteria:

* Female or male patients aged ≥18 years;
* Histologically confirmed ILC, confirmed by E-cadherin loss/aberrant expression and/or p120 cytoplasmic relocalization and/or CDH1 alteration;
* HR-negative (ER \<1% and PR \<1%) or HR-low (ER and/or PR 1-10%) disease, as defined by ASCO/CAP guidelines, is eligible regardless of HER2 status (assessed according to 2025 ASCO/CAP criteria, with HER2-low and HER2-ultralow status recorded where assessable);
* HR-positive (ER\>10% according to the ASCO/CAP guidelines) ILC is eligible only if HER2 status is positive;
* Mixed ductal-lobular carcinomas are eligible provided that a clearly identified invasive lobular component is present and predominant (\>50% lobular) and HR-negative/low criteria are met;
* Stage I-III disease at diagnosis; Patients with de novo stage IV disease who underwent surgery of the primary tumor will not be included in the main study cohort but may be captured in a separate exploratory cohort for dedicated analysis;
* Patients who underwent surgery of the primary tumor at the participating institution, either upfront or after neoadjuvant systemic treatment;
* Diagnosis occurred between 1 January 2000 and 31 December 2025;
* Minimum follow-up of 12 months for patients without an event, unless recurrence or death occurred earlier;
* Local review by a dedicated breast pathologist to confirm the diagnosis and the related molecular features, with particular attention to the confirmation of apocrine morphology.

Exclusion Criteria:

* Pure IC NST without any lobular invasive component;
* ER or PR expression \>10% in the invasive component, in cases with negative HER2 status;
* In situ lobular neoplasia (lobular carcinoma in situ) without an invasive component;
* De novo stage IV disease (such patients, if they underwent surgery of the primary tumor, will be captured in a separate exploratory cohort for a dedicated analysis)
* Synchronous invasive BC of another dominant histology requiring systemic treatment that precludes attribution of outcomes to HR-negative/low ILC;
* Prior invasive BC under active systemic treatment at the time of diagnosis, unless clearly documented as unrelated and not expected to confound outcomes;
* Insufficient data or follow up

• BACKGROUNDVan Baelen K, Nguyen HL, Richard F, Zels G, Karsten MM, Nader-Marta G, Vermeulen P, Dirix L, Dordevic AD, de Azambuja E, Larsimont D, Maetens M, Biganzoli E, Wildiers H, Smeets A, Nevelsteen I, Neven P, Floris G, Desmedt C. Association of HER2-low with clinicopathological features in patients with early invasive lobular breast cancer: an international multicentric study. Breast Cancer Res. 2025 Jun 13;27(1):106. doi: 10.1186/s13058-025-02058-x. PMID 40514709
• BACKGROUNDLehmann BD, Bauer JA, Schafer JM, Pendleton CS, Tang L, Johnson KC, Chen X, Balko JM, Gomez H, Arteaga CL, Mills GB, Sanders ME, Pietenpol JA. PIK3CA mutations in androgen receptor-positive triple negative breast cancer confer sensitivity to the combination of PI3K and androgen receptor inhibitors. Breast Cancer Res. 2014 Aug 8;16(4):406. doi: 10.1186/s13058-014-0406-x. PMID 25103565
• BACKGROUNDAktas A, Gurleyik MG, Akkus D, Ucur Z, Aker F. Invasive lobular breast carcinoma variants; clinicopathological features and patient outcomes. Breast Cancer Res Treat. 2025 Jul;212(2):347-359. doi: 10.1007/s10549-025-07729-z. Epub 2025 May 21. PMID 40397321
• BACKGROUNDBorella F, Gallio N, Giurdanella M, Capella G, Cassoni P, Castellano I. Triple-negative lobular breast cancer: focus on pathology and clinical challenges. Hum Pathol. 2025 Aug;162:105871. doi: 10.1016/j.humpath.2025.105871. Epub 2025 Jul 8. PMID 40639624
• BACKGROUNDAllison KH, Hammond MEH, Dowsett M, McKernin SE, Carey LA, Fitzgibbons PL, Hayes DF, Lakhani SR, Chavez-MacGregor M, Perlmutter J, Perou CM, Regan MM, Rimm DL, Symmans WF, Torlakovic EE, Varella L, Viale G, Weisberg TF, McShane LM, Wolff AC. Estrogen and Progesterone Receptor Testing in Breast Cancer: ASCO/CAP Guideline Update. J Clin Oncol. 2020 Apr 20;38(12):1346-1366. doi: 10.1200/JCO.19.02309. Epub 2020 Jan 13. PMID 31928404
• BACKGROUNDConforti F, Pala L, Pagan E, Rocco EG, Bagnardi V, Montagna E, Peruzzotti G, De Pas T, Fumagalli C, Pileggi S, Pesenti C, Marchini S, Corso G, Marchio' C, Sapino A, Graffeo R, Collet L, Aftimos P, Sotiriou C, Piccart M, Gelber RD, Viale G, Colleoni M, Goldhirsch A. Biological and clinical features of triple negative Invasive Lobular Carcinomas of the breast. Clinical outcome and actionable molecular alterations. Breast. 2021 Oct;59:94-101. doi: 10.1016/j.breast.2021.06.011. Epub 2021 Jun 26.