NcXHF

MOLECULAR SUBTYPES AND NEW TARGETS FOR TRIPLE-NEGATIVE BREAST CANCER
clonal antibody, hRS7, against Trop-2, which is linked to the
active metabolite of irinotecan, 7-ethyl-10-hydroxycamptothecin
(SN-38). The antibody moiety of IMMU-132 selectively binds
to Trop-2. After internalization and proteolytic cleavage,
SN-38 is delivered preferentially to the tumor cells. Preclinical
data shows that IMMU-132 resulted in increased tumor
regression in MDA-MD-468 TNBC xenograft models, compared
to irinotecan or to the antibody-drug conjugate control.
76 IMMU-132 received Fast Track designation in January
2015 from the FDA for treatment of patients with TNBC who
have progressed on prior therapies for metastatic disease. A
phase I/II trial of IMMU-132 was conducted in advanced epithelial
cancers, including TNBC. There was no prescreening
for Trop-2 expression. The recommended phase II dose of
IMMU-132 was 10 mg/kg intravenously on days 1 and 8 of a
21-day cycle. The toxicity was mostly neutropenia, and diarrhea
was low grade. 76 An expansion cohort enrolled 23 patients
with pretreated metastatic TNBC (prior number of
median regimens was 4) with a response rate of 30% consisting
of 7 partial responses, and a CBR (partial response stable
disease 6 months) of 40%. 77 Immunohistochemical
data on Trop-2 scoring is being collected. A phase II trial will
treat 80 patients with metastatic TNBC who have received
two or more prior regimens with IMMU-132 alone or in
combination with carboplatin (NCT02161679). 78 Further research
is necessary to evaluate the strategy of using antitrop-2
therapeutics for breast cancer and the relationship of Trop-2
expression to response.
CONCLUSION
TNBC is a heterogeneous disease. The identifıcation of several
specifıc subtypes characterized by different biologic
pathways and various sensitivities to chemotherapy is instrumental
in delivering more personalized therapy for TNBC.
Ongoing and future clinical research in selected subsets of
TNBC will validate the effıcacy of such novel treatment
strategies.
Disclosures of Potential Conflicts of Interest
Relationships are considered self-held and compensated unless otherwise noted. Relationships marked “L” indicate leadership positions. Relationships marked “I” are those held by an immediate
family member; those marked “B” are held by the author and an immediate family member. Institutional relationships are marked “Inst.” Relationships marked “U” are uncompensated.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: None.
Speakers’ Bureau: None. Research Funding: Antoinette R. Tan, Abbvie (Inst), Bayer/Onyx (Inst), Eisai (Inst), Genentech (Inst), GlaxoSmithKline (Inst),
ImClone Systems (Inst), Merck (Inst), Nektar Therapeutics (Inst). Patents, Royalties, or Other Intellectual Property: Brian D. Lehmann, Intellectual
property for TNBCtype licensed by Insight Genetics LLC. (Inst). Jennifer Pietenpol, Insight Genetics. Expert Testimony: None. Travel, Accommodations,
Expenses: Jennifer Pietenpol, Roche. Other Relationships: None.
References
1. Carey LA, Perou CM, Livasy CA, et al. Race, breast cancer subtypes, and
survival in the Carolina Breast Cancer Study. JAMA. 2006;295:2492-
2502.
2. Amirikia KC, Mills P, Bush J, et al. Higher population-based incidence
rates of triple-negative breast cancer among young African-American
women: implications for breast cancer screening recommendations.
Cancer. 2011;117:2747-2753.
3. Dent R, Trudeau M, Pritchard KI, et al. Triple-negative breast cancer:
clinical features and patterns of recurrence. Clin Cancer Res. 2007;13:
4429-4434.
4. Silver DP, Richardson AL, Eklund AC, et al. Effıcacy of neoadjuvant cisplatin
in triple-negative breast cancer. J Clin Oncol. 2010;28:1145-1153.
5. Byrski T, Gronwald J, Huzarski T, et al. Pathologic complete response
rates in young women with BRCA1-positive breast cancers after neoadjuvant
chemotherapy. J Clin Oncol. 2010;28:375-379.
6. Tutt A, Ellis P, Kilburn L, et al. TNT: a randomized phase III trial of carboplatin
compared with docetaxel for patients with metastatic or recurrent
locally advanced triple-negative or BRCA1/2 breast cancer. 37th Annual
San Antonio Breast Cancer Symposium. December 2014. Abstract S3-01.
7. Gonzalez-Angulo AM, Timms KM, Liu S, et al. Incidence and outcome
of BRCA mutations in unselected patients with triple receptor-negative
breast cancer. Clin Cancer Res. 2011;17:1082-1089.
8. Shah SP, Roth A, Goya R, et al. The clonal and mutational evolution
spectrum of primary triple-negative breast cancers. Nature. 2012;486:
395-399.
9. Cancer Genome Atlas Network. Comprehensive molecular portraits of
human breast tumours. Nature. 2012;490:61-70.
10. Curtis C, Shah SP, Chin SF, et al. The genomic and transcriptomic
architecture of 2,000 breast tumours reveals novel subgroups. Nature.
2012;486:346-352.
11. Mieog JS, van der Hage JA, van de Velde CJ. Preoperative chemotherapy
for women with operable breast cancer. Cochrane Database Syst Rev.
2007;CD005002.
12. Carey LA, Dees EC, Sawyer L, et al. The triple negative paradox: primary
tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res.
2007;13:2329-2334.
13. Liedtke C, Mazouni C, Hess KR, et al. Response to neoadjuvant therapy
and long-term survival in patients with triple-negative breast cancer.
J Clin Oncol. 2008;26:1275-1281.
14. Wetterskog D, Lopez-Garcia MA, Lambros MB, et al. Adenoid cystic
carcinomas constitute a genomically distinct subgroup of triplenegative
and basal-like breast cancers. J Pathol. 2012;226:84-96.
15. Tognon C, Knezevich SR, Huntsman D, et al. Expression of the ETV6-
NTRK3 gene fusion as a primary event in human secretory breast carcinoma.
Cancer Cell. 2002;2:367-376.
16. Huober J, Gelber S, Goldhirsch A, et al. Prognosis of medullary breast
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e37