TBCRC 031: Randomized Phase II Study of Neoadjuvant Cisplatin Versus Doxorubicin-Cyclophosphamide in Germline BRCA Carriers With HER2-Negative Breast Cancer (the INFORM trial)

Abstract

Purpose: Platinum compounds have activity in triple-negative breast cancer (TNBC) in germline BRCA mutation carriers (BRCA carriers). Limited data exist for estrogen receptor (ER)-positive (+) breast cancer among BRCA carriers. INFORM is a randomized, multicenter, phase II trial comparing pathologic complete response (pCR) rates (ypT0/is, N0) after neoadjuvant single-agent cisplatin (CDDP) versus doxorubicin-cyclophosphamide (AC) in BRCA carriers with stage I-III human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Secondary objectives included residual cancer burden scores (RCB) of 0 or 1 (combined) and toxicity. The goal was to determine whether pCR was ≥ 20% higher with CDDP than AC.

Patients and methods: BRCA carriers with cT1-3 (≥ 1.5 cm), cN0-3 HER2-negative breast cancer were randomly assigned to preoperative CDDP (75 mg/m2 every 3 weeks × 4 doses) or AC (doxorubicin 60 mg/m2; cyclophosphamide 600 mg/m2 every 2-3 weeks × 4 doses) followed by surgery. Pathologic responses were confirmed by central review.

Results: A total of 118 patients were randomly assigned; 117 were included in outcome analyses. Mean age was 42 years (range, 24-73 years); 69% were BRCA1+, 30% were BRCA2+, and 2% had both mutations. Clinical stage was I for 19%, II for 63%, and III for 18%; 45% had nodal involvement at baseline. Seventy percent had TNBC. Clinical and tumor characteristics were well matched between treatment arms. The pCR rate was 18% with CDDP and 26% with AC, yielding a risk ratio (RR) of 0.70 (90% CI, 0.39 to 1.2). The risk of RCB 0 or 1 (RCB 0/1) was 33% with CDDP and 46% with AC (RR, 0.73; 90% CI, 0.50 to 1.1). Both regimens were generally well tolerated without unexpected toxicities.

Conclusion: pCR or RCB 0/1 is not significantly higher with CDDP than with AC in BRCA carriers with stage I-III HER2-negative breast cancer for both TNBC and ER+/HER2-negative disease.

Trial registration: ClinicalTrials.gov NCT01670500.

Conflict of interest statement

TBCRC 031: Randomized Phase II Study of Neoadjuvant Cisplatin Versus Doxorubicin-Cyclophosphamide in Germline

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/journal/jco/site/ifc.

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Nadine Tung

Research Funding: AstraZeneca, Myriad Genetics (Inst)

Banu Arun

Consulting or Advisory Role: Bright Pink, AbbVie

Research Funding: AbbVie (Inst), PharmaMar (Inst), AstraZeneca (Inst), InVitae (Inst)

Travel, Accommodations, Expenses: AstraZeneca

Erin Hofstatter

Consulting or Advisory Role: Teledoc Health

Other Relationship: UpToDate

Deborah L. Toppmeyer

Employment: Novartis (I), Merck (I)

Stock and Other Ownership Interests: Novartis (I), Merck (I)

Honoraria: Novartis

Consulting or Advisory Role: Merck, Novartis

Steven J. Isakoff

Consulting or Advisory Role: AbbVie, Genentech, Myriad Genetics, Hengrui Therapeutics, Puma Biotechnology, Immunomedics

Research Funding: Genentech (Inst), PharmaMar (Inst), AbbVie (Inst), OncoPep (Inst), Merck (Inst), AstraZeneca/MedImmune (Inst)

Virginia Borges

Research Funding: Abbott/AbbVie (Inst), Seattle Genetics (Inst)

Robert D. Legare

Consulting or Advisory Role: Unum Therapeutics

Claudine Isaacs

Honoraria: Genentech, AstraZeneca, Pfizer

Consulting or Advisory Role: Pfizer, Genentech, Novartis, AstraZeneca, PUMA, Context Therapeutics

Speakers' Bureau: Genentech, Pfizer, AstraZeneca

Research Funding: Novartis (Inst), Pfizer (Inst), Genentech (Inst), Tesaro (Inst)

Patents, Royalties, Other Intellectual Property: McGraw Hill Publishing; UpToDate - Wolters Kluwer, author of chapters; Elsevier, editor of book

Antonio C. Wolff

Consulting or Advisory Role: Ionis Pharmaceutical

Research Funding: Biomarin (Inst), Celldex (Inst)

Patents, Royalties, Other Intellectual Property: Antonio C. Wolff has been named as inventor on one or more issued patents or pending patent applications relating to methylation in breast cancer and has assigned his rights to Johns Hopkins University (JHU) and participates in a royalty sharing agreement with JHU

Open Payments Link: https://openpaymentsdata.cms.gov/physician/357301/summary

Paul Kelly Marcom

Consulting or Advisory Role: Genentech, Merck, Celltrion, Immunomedics

Speakers' Bureau: Catamount Medical Education, Clinical Care Options

Research Funding: AbbVie (Inst), Novartis (Inst), Genentech (Inst), Veridex (Inst), Innocrin Pharma (Inst), AstraZeneca (Inst), Verily (Inst)

Erica L. Mayer

Consulting or Advisory Role: Eli Lilly, Eisai, Pfizer, Novartis

Research Funding: Myriad Genetics (Inst), Pfizer (Inst)

Ian E. Krop

Employment: AMAG Pharmaceuticals (I)

Leadership: AMAG Pharmaceuticals (I)

Stock and Other Ownership Interests: AMAG Pharmaceuticals (I)

Honoraria: Genentech

Consulting or Advisory Role: Genentech, Daiichi Sankyo, Context Therapeutics, Macrogenics, Taiho Pharmaceutical

Research Funding: Genentech (Inst), Seattle Genetics (Inst), Pfizer (Inst), Daiichi Sankyo (Inst)

Eric P. Winer

Stock and Other Ownership Interests: Verastem

Honoraria: Genentech, Tesaro, Genomic Health

Consulting or Advisory Role: Leap Therapeutics, Seattle Genetics, Jounce Therapeutics, GlaxoSmithKline, Carrick Therapeutics, Eli Lilly, Genomic Health

Research Funding: Genentech (Inst), Novartis (Inst), Merck (Inst)

Judy E. Garber

Consulting or Advisory Role: Novartis (I), GTx (I), Helix BioPharma, Konica Minolta, Aleta BioTherapeutics (I), H3 Biomedicine (I), Kronos Bio (I)

Research Funding: Novartis (I), Ambry Genetics, Invitae Genetics, Myriad Genetics

Other Relationship: Susan G. Komen for the Cure (I), AACR, Diane Helis Henry Medical Foundation (I), James P. Wilmot Foundation (I), Adrienne Helis Malvin Medical Research Foundation (I), Breast Cancer Research Foundation, Facing Our Risk of Cancer Empowered

No other potential conflicts of interest were reported.

Figures

FIG 1.

Schema of randomized phase II INFORM trial (TBCRC 031). (*) Granulocyte colony–stimulating factor (G-CSF) mandatory for dose-dense AC (once-every-2-weeks schedule). G-CSF optional for AC once every 3 weeks and cisplatin. AC, doxorubicin plus cyclophosphamide; BC, breast cancer; CDDP, cisplatin; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; LN, lymph node; T, tumor size; TNBC, triple-negative breast cancer.

FIG 2.

CONSORT diagram. (*) Two patients had residual disease at biopsy performed before additional chemotherapy or at definitive tumor resection after additional chemotherapy; for 3 patients, residual cancer was not seen at either biopsy before additional chemotherapy or tumor resection after additional chemotherapy. (**) Both patients had residual disease demonstrated by biopsy before additional nonstudy-assigned chemotherapy.

FIG 3.

(A) Pathologic complete response (pCR) breast/axilla (ypT0/is, N0); (B) residual cancer burden (RCB) 0 or 1; risk ratio with 90% CI for (A) pCR or for (B) RCB 0/1 with cisplatin (CDDP) compared with doxorubicin-cyclophosphamide (AC) is shown. ER, estrogen receptor; PR, progesterone receptor; TNBC, triple-negative breast cancer.

FIG 4.

The likelihood (risk ratio [RR]) of pathologic complete response with cisplatin compared with doxorubicin-cyclophosphamide is shown for various patient and tumor characteristics. ER, estrogen receptor; PR, progesterone receptor.