Triple-negative breast cancer: treatment challenges and solutions

Figures & data

Table 1 Genomic TNBC subtypes and potential therapeutic targets

Subtypes	Genetic abnormalities	Potential therapeutic target
BL1	Cell cycle gene expression DNA repair gene (ATR–BRCA pathway) Proliferation genes	PARP inhibitors Genotoxic agents
BL2	Growth factor signaling pathways (EGFR, MET, NGF, Wnt/β-catenin, IGF-1R) Glycolysis, gluconeogenesis Expression of myoepithelial markers	mTOR inhibitors Growth-factor inhibitors
Immunomodulatory	Immune cell processes (CTLA4, IL12, IL7 pathways, antigen processing/presentation) Gene signature for medullary BC (rare TNBC with a favorable prognosis)	PD1/PDL1 inhibitors
Mesenchymal-like	Cell motility Cell differentiation Growth factor signaling EMT	mTOR inhibitors EMT-and CSC-targeted treatment
Mesenchymal stem-like	Similar to M^+ Low proliferation Angiogenesis genes	PI3K inhibitors Antiangiogenic therapy Src antagonist
Luminal androgen receptor	Androgen receptor gene Luminal gene expression pattern Molecular apocrine subtype	Antiandrogen therapy

Note: Data from Lehmann et al.²⁵

Abbreviations: BC, breast cancer; BL, basal-like; CSC, cancer stem cells; DNA, deoxyribonucleic acid; EGFR, epidermal growth factor receptor; EMT, epithelial-mesenchymal-transition; IGF-1R, insulin-like growth factor I receptor; IL, interleukin; IM, immunomodulatory; LAR, luminal androgen receptor; M, mesenchymal-like; MET, hepatocyte growth factor; mTOR, mammalian target of rapamycin; MSL, mesenchymal stem-like; NGF, nerve growth factor; PARP, poly ADP ribose polymerase; PD1, programmed cell death 1; PDL1, programmed death-ligand 1; PI3K, phosphatidylinositol 3-kinase; TNBC, triple negative breast cancer.

Table 2 Carboplatin-based chemotherapy in neoadjuvant treatment: randomized Phase II results

Phase II trials	n	Standard chemotherapy	Standard chemotherapy + carboplatin	Toxicity
GeparSixto^Citation52 TNBC subgroup Weekly paclitaxel and liposomal doxorubicin ×18 weeks + bevacizumab every 3 weeks ×6 cycles ± weekly carboplatin AUC 2×18 weeks	315	pCR: 36.9% (ypT0N0) 3-year EFS 76.1%	pCR: 53.2% (ypT0N0) 3-year EFS 85.8%	Increased with carboplatin (AUC 2) More grade 3/4 anemia More grade 3/4 neutropenia More grade 3/4 thrombopenia More grade 3/4 diarrhea Reduction of carboplatin AUC to 1.5 → reduced hematological events (from 82% to 70%) and nonhematological events (78% to 59%)
CALGB 40603, only TNBC^Citation53 Weekly paclitaxel ×12 weeks ± carboplatin AUC 6 every 3 weeks ×4 cycles/dose-dense anthracycline–cyclophosphamide ×4 cycles	443	pCR 41% (ypT0/TisN0) 3-year EFS 71.6%	pCR 54% (ypT0/TisN0) 3-year EFS 76.5%	Increased with carboplatin More grade 3/4 neutropenia More grade 3/4 thrombopenia
GEICAM/2006-03^Citation54 Epirubicin–cyclophosphamide every 3 weeks ×4 cycles/docetaxel every 3 weeks ×4 cycles ± carboplatin AUC 6 every 3 weeks ×4 cycles	94	pCR 35% (ypT0N0)	pCR 30% (ypT0N0)	No difference in grade 3/4 toxicity
I-SPY arm 1^Citation55 Weekly paclitaxel ×12 weeks/dose-dense doxorubicin–cyclophosphamide ×4 cycles ± veliparib and carboplatin	62	pCR 26% (ypT0N0)	pCR 52% (ypT0N0)	More toxicity with carboplatin/veliparib ≥ Hematological grade 3 events: 26.4% versus 4.5%
Paclitaxel plus carboplatin versus paclitaxel plus epirubicin as neoadjuvant treatment in locally advanced TNBC^Citation51 Paclitaxel–carboplatin AUC 5 every 3 weeks ×4–6 cycles or epirubicin–paclitaxel every 3 weeks ×4–6 cycles	91	pCR: 14% (ypT0/TisN0) 4-year RFS 52.8%	pCR: 38.6% (ypT0/TisN0) 4-year RFS 71.1%	No difference in grade 3/4 toxicity

Abbreviations: AUC, area under curve; EFS, event-free survival; is, in situ; pCR, pathologic complete response; RFS, relapse-free survival; TNBC, triple-negative breast cancer.

Table 3 Trials in progress in the neoadjuvant and adjuvant settings for TNBC

Study, ClinicalTrials.gov identifier	Phase, design	Treatment	Primary outcome
Neoadjuvant studies
Neoadjuvant metronomic chemotherapy in TNBC NCT00542191	II Single-arm Open-label	AC/carboplatin + P	pCR rates
Two consequent chemotherapy regimens as induction preoperative therapy for patients with locally advanced TNBC NCT01969032	II Single-arm Open-label	P + carboplatin/AC + capecitabine	pCR rates
Personalized treatment of high-risk mammary cancer: the PETREMAC trial (personalized medicine) NCT02624973	II Single-arm Open-label	Neoadjuvant olaparib/olaparib + carboplatin (if lack of response to olaparib alone)	Predictive and prognostic value of mutations in cancer-related genes assessed in breast cancer tissue before starting therapy
Identification of BRCA1-associated DNA-repair dysfunction in patients with early TNBC treated with neoadjuvant platinum-based chemotherapy NCT01672671	II Single-arm Open-label	Cisplatin	pCR rates
Effect of neoadjuvant platinum-based chemoradiation therapy for locally advanced TNBC: clinical outcomes and correlation to biological parameters NCT01167192	II Single-arm Open-label	Carboplatin or cisplatin + radiotherapy	CRR
Impact of an additional four cycles of cisplatin in patients with TNBC not achieving clinical CR after four cycles of neoadjuvant adriamycin plus cyclophosphamide NCT02001519	II Single-arm Open-label	Adriamycin + cyclophosphamide/cisplatin	pCR rates
TBCRC030: preoperative cisplatin versus P in patients with TNBC: evaluating the homologous recombination-deficiency biomarker NCT01982448	II Randomized Open-label	P versus cisplatin	pCR rates
2×2 factorial trial of the addition of carboplatin ± bevacizumab to neoadjuvant weekly P followed by dose-dense AC in hormone receptor-poor/HER2-negative resectable breast cancer NCT00861705	II Randomized Open-label	P/AC versus P/AC + carboplatin versus P/AC + bevacizumab versus P/AC + bevacizumab and carboplatin	pCR rates
TBCRC 031: neoadjuvant cisplatin versus doxorubicin/cyclophosphamide in women with newly diagnosed breast cancer and germ-line BRCA mutations NCT01670500	II Randomized Open-label	AC versus cisplatin	pCR rates
Efficacy and safety of weekly P single agent and two different regimens of the PARP1 inhibitor SAR240550 (BSI-201) in combination with weekly P as neoadjuvant therapy in patients with stage II–IIIA TNBC (SOLTI NEOPARP) NCT01204125	II Randomized Open-label	Iniparib (different schedules and dosing) + P versus P alone	pCR rates
Different neoadjuvant regimens in subtypes of breast Cancer NCT02041338	II Randomized Open-label	TNBC subtype: carboplatin + P versus epirubicin + P	pCR rates
Pathologic complete response with the addition of carboplatin with and without veliparib to standard chemotherapy in the neoadjuvant treatment of TNBC NCT01818063	II Randomized Open-label	P + carboplatin/AC versus P + carboplatin/AC + veliparib	pCR rates
Predictors of response to neoadjuvant docetaxel–carboplatin chemotherapy for patients with stage II and III TNBC NCT01560663	II Observational	Carboplatin–docetaxel	Predictors of response to docetaxel–carboplatin
Individualized neoadjuvant chemotherapy in TNBC (neo-TN) NCT01057069	II/III Randomized Open-label	Platinum-based chemotherapy, but variable schedule based on HRD status and response	Average neoadjuvant response index
Neoadjuvant carboplatin plus docetaxel or carboplatin plus P followed by AC in stage I–III TNBC NCT02413320	III Randomized Open-label	Carboplatin + docetaxel/AC versus carboplatin + P/AC	pCR rates
Two dose-dense, dose-intensified approaches (ETC andPM[Cb]) for neoadjuvant treatment of patients withhigh-risk early breast cancer (GeparOcto) NCT02125344	III Randomized Open-label	Carboplatin + Myocet + P versus epirubicin + P + cyclophosphamide	pCR rates
Safety and efficacy of the addition of veliparib pluscarboplatin versus the addition of carboplatin to standardneoadjuvant chemotherapy versus standard neoadjuvantchemotherapy in subjects with early stage TNBC NCT02032277	III Randomized Double-blind	Veliparib + carboplatin + P followed by AC versus placebo + carboplatin + P followed by AC versus 2 placebos + P followed by AC	pCR rates
Neoadjuvant or adjuvant study
Anthracyclines followed by taxane versus anthracyclinesfollowed by taxane plus carboplatin as (neo)adjuvanttherapy in patients with TNBC (PEARLY trial) NCT02441933	III Randomized Open-label	AC/taxol versus AC/taxol + carboplatin	5-year EFS
Adjuvant studies, if residual disease after neoadjuvant chemotherapy
PARP inhibition after preoperative chemotherapy inpatients with TNBC or ER/PR^+, HER2^− with knownBRCA1/2 mutations NCT01074970	II Randomized Open-label	Cisplatin versus cisplatin + rucaparib	2-year DFS
Everolimus plus cisplatin in TNBC patients with residualdisease after standard chemotherapy (NECTAR trial) NCT01931163	II Single-arm Open-label	Cisplatin + everolimus	Tumor response
Postoperative trial of platinum-based chemotherapyversus observation in patients with residual TN basal-like breast cancer following neoadjuvant chemotherapy NCT02445391	III Randomized Open-label	Platinum-based chemotherapy (cisplatin or carboplatin) versus observation	IDFS
Carboplatin as adjuvant chemotherapy versusobservation in TNBC with pathologic residual cancerafter neoadjuvant chemotherapy: POST-neoadjuvant study NCT01752686	III Randomized Open-label	Carboplatin versus observation	DFS
Adjuvant studies
NRG BR-003: adjuvant therapy comparing AC followedby weekly P with or without carboplatin for node-positive or high-risk node-negative triple-negativeinvasive breast cancer NCT02488967	II Randomized Open-label	Sequential treatment AC/P versus AC/P + carboplatin	IDFS
EC followed by docetaxel given every 3 weeks, weeklyP or weekly P plus carboplatin in TNBC (TPPC) NCT02455141	II Randomized Open-label	3 arms: EC/docetaxel versus EC/P versus EC/carboplatin + P	3-year DFS
Efficacy and safety of olaparib versus placebo asadjuvant treatment in patients with germ-line BRCA1/2mutations and high-risk HER2-negative primary breastcancer who have completed definitive local treatmentand neoadjuvant or adjuvant chemotherapy (Olympia) NCT02032823	III Randomized Double-blind	Olaparib versus placebo	IDFS

Abbreviations: AC, doxorubicin + cyclophosphamide; CR, complete response; CRR, clinical response rate; DFS, disease-free survival; EC, epirubicin–cyclophosphamide; EFS, event-free survival; ETC, epirubicin–paclitaxel–cyclophosphamide; HRD, homologous recombination deficiency; IDFS, invasive DFS; PARP, poly ADP ribose polymerase; P, paclitaxel; pCR, pathologic complete response; PM(Cb), paclitaxel–Myocet (carboplatin); TNBC, triple-negative breast cancer.

Table 4 Results of trials with PARP inhibitors in triple-negative breast cancer

Study, ClinicalTrials.gov identifier	Phase, design	Drug	Primary objective	Results
Pharmacokinetic and biological evaluation of a small molecule inhibitor of PARP1 (KU-0059436) in patients with advanced tumors^Citation60 NCT00516373	I Open-label Single-arm	Olaparib	Safety, tolerability, dose-limiting toxicity, and maximum tolerated dose of olaparib	60 patients 22 germ-line BRCA1/2 Mild toxicity Durable objective response in only germ-line BRCA1/2 breast, ovarian, prostate cancers (63%)
AZD2281 in patients with known BRCA mutation status or recurrent high-grade ovarian cancer or patients with known BRCA mutation status/TNBC^Citation63 NCT00679783	II Open-label Single-arm	Olaparib 400 mg	Objective response rate (ORR) Complete response (CR)	26 patients ORR 0 CR 0
Efficacy and safety of KU-0059436 (olaparib) given orally twice daily in patients with advanced BRCA1 or BRCA2-associated breast cancer^Citation61 NCT00494234	II Open-label Single-arm	Olaparib 100 mg twice daily, 400 mg twice daily	Confirmed objective tumor response CR Overall response (OR) = CR + PR	27 patients (100 mg) ORR 22% CR 0 27 patients (400 mg) ORR 41% CR 0
Efficacy and safety of olaparib given orally twice daily in patients with advanced cancers who have a confirmed genetic BRCA1 and/or BRCA2 mutation^Citation62 NCT01078662	II Open-label Single-arm	Olaparib 400 mg twice daily	Tumor-response rate	62 patients ORR 13% CR 0

Abbreviation: TNBC, triple-negative breast cancer.

Table 5 First results with antiandrogen therapy in TNBC and studies in progress

Study, ClinicalTrials.gov identifier	Phase, design	Drug	Primary outcome	Status	Results
Bicalutamide for the treatment of AR^+, ER^−, PR^− metastatic BC patients^Citation70 NCT00468715	II Open-label Single-arm	Bicalutamide 150 mg once daily	CBR at 6 months (CR, PR, stable disease)	Closed	26 patients CBR 19% Median PFS 12 weeks
Clinical activity and safety of enzalutamide in patients with advanced, AR^+ TNBC, stage 1^Citation71 NCT01889238	II Open-label Single-arm	Enzalutamide 160 mg once daily	CBR at 16 weeks (CR, PR, stable disease)	Not recruiting	26 patients CBR16 42%
Clinical activity and safety of enzalutamide in patients with advanced, AR^+ TNBC, stage 2^Citation72 NCT01889238	II Open-label Single-arm	Enzalutamide 160 mg once daily	CBR at 16 weeks (CR, PR, stable disease)	Not recruiting	75 patients CBR16 35% Median PFS 14.7 weeks
Activity of abiraterone acetate plus prednisone in patients with a molecular apocrine HER2^− locally advanced or metastatic BC NCT01842321	II Open-label Single-arm	Abiraterone acetate 160 mg once daily	CBR at 6 months (CR, PR, stable disease)	Not recruiting	Not available
Orteronel as monotherapy in patients with metastatic BC that expresses the AR NCT01990209	II Open-label Single-arm	Orteronel 300 mg twice daily	Response rate at 36 months Disease control rate at 36 months	Recruiting	Not available
Bicalutamide as a treatment in AR-positive metastatic triple-negative breast cancer (mTNBC) patients NCT02348281	II Open-label Single-arm	Bicalutamide 150 mg once daily	CBR	Recruiting	Not available
AR inhibitor bicalutamide in treating patients with TNBC NCT02353988	II Open-label Single-arm	Bicalutamide 150 mg once daily	CBR	Recruiting	Not available
Efficacy and safety of GTx-024 in patients with AR^+ TNBC NCT02368691	II Open-label Single-arm	GTx-024 18 mg once daily	CBR	Recruiting	Not available
Safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of VT-464 in patients with advanced BC NCT02580448	I/II Open-label Single-arm	VT-464 once daily	Phase I: maximum tolerated dose Phase II: CBR16 and CBR24 for patients with AR^+ TNBC	Recruiting	Not available

Abbreviations: BC, breast cancer; CBR, clinical benefit rate; CBR₁₆, clinical benefit rate at 16; CBR₂₄, clinical benefit rate at 24; CR, complete response; mTNBC, metastatic triple-negative breast cancer; PFS, progression-free survival; PR, partial response; TNBC, triple-negative breast cancer; AR, androgen receptor; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; PR-, progesterone receptor negative.

Table 6 Immunotherapy trials in breast cancer

Study, ClinicalTrials.gov identifier	Phase, design	Drug	Primary outcome
Neoadjuvant/adjuvant
MEDI4736 (anti-PDL1 antibody) concomitant with weekly Nab-paclitaxel and dose-dense doxorubicin–cyclophosphamide chemotherapy for clinical stage I–III TNBC NCT02489448	Phase I/II Single-arm Open-label	Anti-PDL1 (MEDI4736) concomitant with Nab-paclitaxel and doxorubicin + cyclophosphamide	pCR
Triple-negative first-line study: neoadjuvant trial of Nab-paclitaxel and MPDL3280A, a PDL1 inhibitor, in patients with TNBC NCT02530489	Phase II Single-arm Open-label	Anti-PDL1 (MPDL3280A) in combination with Nab-paclitaxel	pCR
Safety and clinical activity of pembrolizumab (MK-3475) in combination with chemotherapy as neoadjuvant treatment for TNBC NCT02622074	Phase I Randomized Open-label	Anti-PD1 (MK-3475, pembrolizumab) + chemotherapy versus MK-3475 + chemotherapy + carboplatin	DLT, pCR
Metastatic
Single-agent pembrolizumab (MK-3475) versus single-agent chemotherapy as per physician’s choice for metastatic TNBC NCT02555657	Phase III Randomized Open-label	Anti-PD1 (MK-3475, pembrolizumab) versus chemotherapy	PFS OS
Pembrolizumab (MK-3475) as monotherapy for metastatic TNBC NCT02447003	Phase II Single-arm Open-label	Anti-PD1 (MK-3475, pembrolizumab) monotherapy	ORR safety
Nivolumab after induction treatment in TNBC patients: TONIC trial NCT02499367	Phase II Randomized Open-label	Anti-PD1 (nivolumab) after induction treatment (four arms: radiotherapy, doxorubicin, cisplatin, cyclophosphamide) or noninduction treatment	PFS
Atezolizumab (MPDL3280A) (anti-PDL1 antibody) in combination with Nab-paclitaxel compared with placebo with Nab-paclitaxel for patients with previously untreated metastatic TNBC NCT02425891	Phase III Randomized Double-blind	Anti-PDL1 (MPDL3280A, atezolizumab) with Nab-paclitaxel compared with placebo and Nab-paclitaxel	PFS
Tremelimumab monotherapy in patients with advanced solid tumors NCT02527434	Phase Single-arm Open-label	Anti-CTLA4 (tremelimumab) monotherapy with the option to be sequenced to MEDI4736 monotherapy or MEDI4736 + tremelimumab after progressive disease	ORR
Safety and efficacy of PDR001 administered to patients with advanced malignancies NCT02404441	Phase I/II Single-arm Open-label	Anti-PD1 (PDR001) monotherapy	Maximum tolerated dose Safety ORR
Immuno-PET imaging with ^89Zr-MPDL3280A in patients with locally advanced or metastatic non-small cell lung cancer, bladder cancer, or TNBC prior to MPDL3280A treatment NCT02453984	Phase I Single-arm Open-label	^89Zr-MPDL380A (anti-PDL1)	Description of 89Zr-MPDL380A PK by measuring SUV on the ^89Zr-MPDL380A-PET scans → to evaluate the uptake of the tracer in tumor lesions and its use as a complementary tool for patient selection
MPDL3280A treatment in patients with locally advanced or metastatic non-small cell lung, bladder, and TNBC after investigational imaging NCT02478099	Phase II Single-arm Open-label	Anti-PDL1 (MPDL380A)	ORR and efficacy
Safety and pharmacokineticsof MPDL3280A administeredintravenously as a single agent topatients with locally advanced ormetastatic solid tumors or hematologicmalignancies NCT01375842	Phase I Single-arm Open-label	Anti-PDL1 (MPDL3280A)	Incidence and nature of DLT
Neoadjuvant study with the PDL1-directed antibody in locally advancedTNBC undergoing treatment withNab-paclitaxel and carboplatin NCT02620280	Phase III Randomized Open-label	Carboplatin, Nab-paclitaxel, atezolizumab (MPDL3280A, anti-PDL1), anthracycline versus carboplatin, Nab-paclitaxel, and anthracycline	Event-free survival

Abbreviations: DLT, dose-limiting toxicity; Nab, nanoparticle albumin-bound; ORR, objective response rate; OS, overall survival; pCR, pathologic complete response; PFS, progression-free survival; SUV, standardized uptake value; PK, pharmacokinetic; TNBC, triple-negative breast cancer; CTLA4, cytotoxic T-lymphocyte-associated protein 4; PD1, programmed cell death 1; PDL1, programmed death-ligand 1.

LehmannBDBauerJAChenXIdentification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapiesJ Clin Invest201112172750276721633166

 PubMed Web of Science ®Google Scholar

von MinckwitzGSchneeweissALoiblSNeoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trialLancet201415774775624794243

 PubMed Web of Science ®Google Scholar

SikovWMBerryDAPerouCMImpact of the addition of carboplatin and-or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin an cyclophosphamide on pathologic complete response rates in stages II to III triple negative breast cancer: CALGB 40603 (Alliance)J Clin Oncol2015331132125092775

 PubMed Web of Science ®Google Scholar

AlbaEChaconJILluchAA randomized phase II trial of platinum salts in basal-like breast cancer patients in the neoadjuvant setting: results from the GEICAM/2006-03, multicenter studyBreast Cancer Res Treat2012136248749323053638

 PubMed Web of Science ®Google Scholar

No authors listedPositive results for drug combo in I-SPY 2 trialCancer Discov201442OF2

 Google Scholar

ZhangPYinYXuBCarboplatin plus paclitaxel compared with epirubicin plus paclitaxel as neoadjuvant chemotherapy for triple-negative breast cancer – a phase II clinical trialCancer Res201373P3-14-07

 Web of Science ®Google Scholar

FongPCBossDSYapTAInhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriersN Engl J Med2009361212313419553641

 PubMed Web of Science ®Google Scholar

GelmonKATischkowitzMMackayHOlaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised studyLancet Oncol201112985286121862407

 PubMed Web of Science ®Google Scholar

TuttARobsonMGarberJEOral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trialLancet2010376973723524420609467

 PubMed Web of Science ®Google Scholar

KaufmanBShapira-FrommerRSchmutzlerRKOlaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutationJ Clin Oncol201533324425025366685

 PubMed Web of Science ®Google Scholar

GucalpATolaneySIsakoffSJPhase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic breast cancerClin Cancer Res201319195505551223965901

 PubMed Web of Science ®Google Scholar

TrainaTAO’ShaughnessyJNandaRAbstract P5-19-09: preliminary results from a phase 2 single-arm study of enzalutamide, an androgen receptor (AR) inhibitor, in advanced AR+ triple-negative breast cancer (TNBC)Cancer Res201575P5-19-09

 Web of Science ®Google Scholar

TrainaTAMillerKYardleyDAResults from a phase 2 study of enzalutamide (ENZA), an androgen receptor (AR) inhibitor, in advanced AR+ triple-negative breast cancer (TNBC)J Clin Oncol201533 Suppl1003

 Web of Science ®Google Scholar