Abstract PS16-03: Clonal relatedness of LCIS with synchronous and asynchronous invasive disease
Authors: Sawyer Elinor , Sborchia Mateja , Megalios Anargyros , Shah Vandna , Nowinski Salpie , Vassart Cloe , Grigoriadis Anita , Thompson Alastair , Tomlinson Ian , Roylance Rebecca , Pinder Sarah 
Published: February 2021

Abstract
Background: Lobular carcinoma in situ (LCIS) is typically clinically undetectable but is being increasingly diagnosed as a result of breast screening mammography and is often found associated with other breast pathologies such as invasive lobular breast cancer (ILC), invasive carcinoma of ductal /no special type (IDC) and ductal carcinoma in situ (DCIS). It is also considered a risk factor for the development of subsequent invasive breast disease. The aim of this study was to understand the genetic relationship between LCIS that presents with synchronous DCIS, IDC and/or ILC in order to ascertain whether the components have common precursors and also to understand the clonal relationship between LCIS and subsequent invasive disease. Methods: 25 cases of LCIS with synchronous ILC, 7 cases of LCIS with synchronous DCIS & IDC, and 8 pure LCIS that developed a subsequent invasive recurrence were identified from the GLACIER study (MREC 06/Q1702/64). DNA was extracted from archival paraffin embedded tissue and underwent copy number analysis using either the Oncoscan™ Array (Affymetrix) or HumanCytoSNP FFPE-12 BeadChip (Illumina). Four of 7 cases of LCIS with synchronous DCIS & IDC also underwent targeted sequencing using a custom 121 breast cancer-associated gene panel (SureSelectXT HS kit, Agilent Technologies). Clonal relatedness was assessed using a novel methodology based on the presence of shared copy number aberration breakpoints and mutations. Results: Of the 25 synchronous LCIS and ILC cases, 17 appeared related, 4 were ambiguous (sharing the typical lobular signature of 1q gain and 16q loss) and 4 demonstrated no evidence of relatedness. Of the 7 cases with synchronous LCIS, DCIS and IDC, all had copy number data available and 4 had mutation data available. In 3 cases the synchronous LCIS, DCIS and IDC were clonally related according to copy number and for two there was mutation data that supported this (one sharing PIK3CA and CDH1 mutations, the other a TP53 mutation). In two cases the LCIS was not related to the DCIS or IDC, but the DCIS and IDC were related to each other; while in one case LCIS was related to IDC but not to the DCIS by copy number but all components shared the same CHEK2 mutation. Finally in one case none of the three components were related to each other by copy number but the LCIS and IDC shared a PIK3CA mutation, albeit at much lower allele frequency in LCIS than in IDC. Of the 8 patients with pure LCIS, 4 developed an ipsilateral invasive recurrence of various combinations of morphologies: 1 ILC & LCIS, 1 ILC & DCIS, 1 IDC & DCIS, 1 ILC & IDC, and 4 a contralateral recurrence (1 tubular, 1 IDC, 2 ILC), with a median time to recurrence of 69 months (range 34-175). The primary LCIS was related to at least one component of the recurrent disease in all four ipsilateral cases; in two the primary LCIS and all components of the recurrent disease were related, and in the remainder we observed a variety of putative evolutionary patterns. Conclusions: The majority (68%) of cases of synchronous LCIS and ILC appeared to be clonally related by copy number. 50% of cases of co-existing LCIS and IDC appeared to have a common clonal origin by either copy number or targeted sequencing. As these are genomically stable tumours, copy number data may also be underestimating relatedness. In the four cases of pure primary LCIS that developed an ipsilateral recurrence, different subtypes of breast cancer were noted as the recurrence morphology, supporting the historical view that LCIS is a risk lesion rather than a true precursor. However, in all cases the preceding LCIS was found to be related to at least one component of the subsequent invasive tumour including DCIS and IDC. This data shows that clonal relatedness between LCIS and both synchronous and asynchronous invasive disease and DCIS is more complex than previously thought, with LCIS acting as a precursor lesion even in some cases of IDC.
Citation Format: Elinor Sawyer, Mateja Sborchia, Anargyros Megalios, Vandna Shah, Salpie Nowinski, Cloe Vassart, Anita Grigoriadis, Alastair Thompson, Ian Tomlinson, Rebecca Roylance, Sarah Pinder. Clonal relatedness of LCIS with synchronous and asynchronous invasive disease [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS16-03.