Abstract P2-03-06: FoundationOne profiling of TSC1 and TSC2-mutated advanced breast cancers
Authors: Palma Norma A , Chmielecki Juliann , Frampton Garrett , Ali Siraj , Levin Maren , Ross Jeffrey S , Morosini Deborah , Palmer Gary , Miller Vincent A , Stephens Phil , O'Shaughnessy Joyce 
Published: May 2015

Abstract
Background: The TSC1/TSC2 complex inhibits the mTOR pathway. Loss of function of this complex leads to hyperperactivation of the mTOR pathway which promotes growth and survival. Few studies have examined the role of TSC1 and TSC2 mutations in breast cancer and as a clinically relevant target for molecularly targeted therapy, such as everolimus, a rapamycin analog.
Methods: Hybridization capture of 3769 exons of 236 cancer-related genes and 47 introns from 19 genes that are frequently rearranged in cancer were fully sequenced to high, uniform coverage from a commercial CLIA-certified laboratory (Foundation Medicine).
Results: 30 of 2,208 breast cancer pt samples (1.3%) harbored either TSC1 (13/30, 43%) or TSC2 (17/30, 56%) genomic alterations (GAs). The samples with TSC1/2 consisted of breast carcinoma n.o.s. (17/30) and invasive ductal carcinoma (12/30); one invasive lobular carcinoma (ILC) harbored a TSC2 alteration. Sequencing was performed on metastatic (18/30, 60%) and primary (12/30, 40%) tumors. All TSC1 alterations resulted in truncation of the protein product; TSC2 GA consisted of truncations (14/17) and point mutations (3/17). TSC1/2 GAs frequently co-occurred with GAs in TP53 (19/30; 63%) and amplifications of MYC (9/30; 30%) and FGFR1 (7/30; 23%). Of the TSC1/2-mutant cases where hormone receptor and HER2/neu status was known (23/30), 65% were ER-/PR-/HER2- (TNBC), 26% were ER+/HER2- and 9% were ER-/HER2+.
Patient case: We describe a postmenopausal node positive ILC (ER+/PR+/HER2-) pt who received adjuvant chemotherapy followed by 9 yrs adjuvant anastrazole then with disease recurrence. On FoundationOne testing a TSC2 A1141T missense mutation, along with GAs in CDH1, ETV6, and CSF1R, were found in her metastatic disease in the soft tissues of her left orbit associated with substantial swelling resulting in loss of vision. While TSC2 A1141T has not been functionally characterized, in vitro and in vivo data suggest sensitivity to mTOR inhibitors. Her disease stabilized but did not decrease in size with vinorelbine + capecitabine. She was treated with letrozole + everolimus and had a near clinical complete response with restoration of vision for 5 + months. Collection of clinical data on additional pts is currently ongoing.
Conclusion: 1.3% of breast cancer cases harbored GAs in either TSC1 orTSC2. The majority of TSC1/2 GAs cause inactivation of these negative regulatory proteins leading to activation of the mTOR signaling pathway. TSC1/2 GAs were enriched for TNBC (65%) versus non-TNBC (35%) (p= 0.077; Fisher’s exact test). Truncation of TSC1/2 occurred at multiple codons, underscoring the importance of examining the entire coding region of tumor suppressor genes for these inactivating events. Comprehensive genomic profiling has the potential to identify the broad spectrum of these inactivating events, a subset of which may be clinically relevant.
Citation Format: Norma A Palma, Juliann Chmielecki, Garrett Frampton, Siraj Ali, Maren Levin, Jeffrey S Ross, Deborah Morosini, Gary Palmer, Vincent A Miller, Phil Stephens, Joyce O'Shaughnessy. FoundationOne profiling of TSC1 and TSC2-mutated advanced breast cancers [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-03-06.