O'Shaughnessy Provides Fresh Insights Into Specificity in TNBC Therapy

Joyce A. O’Shaughnessy, MD

Although no cytotoxic agents are currently correlated with specific subtypes of triple negative breast cancer (TNBC), recent findings indicate that targeting genomic stability, antimetastatic mechanisms, and protein expression characteristics are promising approaches for future TNBC treatments.

Joyce A. O’Shaughnessy, MD, presented an overview of recent findings on chemotherapy regimens for TNBC at the 13th Annual International Congress on the Future of Breast Cancer, which Physicians’ Education Resource (PER) sponsored on July 17-19 in Huntington Beach, California.

According to O’Shaughnessy, therapy selection for TNBC is difficult because no subtyping approach has proved clinically useful thus far and most chemotherapeutic agents are nonselective.

However, genomic analyses of TNBC subtypes are yielding clues about potential ways to identify therapies. Notably, Vanderbilt-Ingram Cancer Center researchers have identified six subtypes of TNBC using gene expression profiling,¹ and these insights help form the basis of emerging strategies, O’Shaughnessy indicated. She noted that research efforts are under way to identify assays and biomarkers to aid clinicians in matching therapies with patients.

Among unselected patients, single-agent studies indicate that a proportion of patients with TNBC respond extremely well to DNA-damaging platinum agents, such as cisplatin, doxorubicin, docetaxel, and epirubicin, in neoadjuvant therapy. Pathologic complete response (pCR) rates ranged from 9.6% among 73 patients treated with epirubicin to 27% among 28 patients who received docetaxel, said O’Shaughnessy.

The TBCRC 009 study showed that six patients who received cisplatin or carboplatin as a first-line treatment for metastatic TNBC were disease free without therapy for 22-53 months.² Although the treatment was not randomized in this study, such a long disease-free period is extremely unusual in metastatic TNBC and the tumor characteristics of these high responders should be investigated further, according to O’Shaughnessy.

HRD Scores as Markers

High homologous recombination deficiency (HRD) scores indicate genetic instability and may predict which tumors respond to platinum-based chemotherapy, according to recent findings. A single-arm trial³ led by Melinda Telli, MD, showed neoadjuvant carboplatin, gemcitabine, and iniparib led to a 70% pathologic complete response in TNBC patients with high HRD scores, compared with 20% in those with low HRD scores. Investigators used a tumor DNAbased assay to identify underlying defects in the homologous recombination pathway.

Telli will head an upcoming phase II E5112 trial that will compare a neoadjuvant dose-dense doxorubicin/ cyclophosphamide/paclitaxel regimen with carboplatin plus gemcitabine. The primary endpoint will be invasive pathologic complete response (pCR) in the breast and nodes in the high-HRD group.

First-Line Options

Eribulin Regimens

The optimal first-line chemotherapy for TNBC is a common question among clinicians, according to O’Shaughnessy. The phase III CALGB 40502 trial⁴ did not show a clear benefit from weekly 150 mg/m²O’Shaughnessy described combined treatment with eribulin mesylate and capecitabine as another promising new regimen. One phase III study⁶ showed that patients with TNBC who took eribulin as a second-line therapy tended to have a longer overall survival (median 14.4 months) than those who took capecitabine (9.4 months), and O’Shaughnessy described a personal case study of a 30-year-old woman with metastatic TNBC who achieved a near-complete response after 10 months of treatment.

O’Shaughnessy indicated that eribulin may have an antimetastatic role that makes it particularly useful in drug-resistant TNBCs. According to a preclinical in vitro study,⁷ eribulin disrupts microtubules, which form the “scaffolding” of the cancer cell and enable it to travel to other tissues through the vasculature and metastasize. An exploratory analysis of the phase III trial data,8 presented by Edith Perez, MD, at the 2013 European Cancer Congress, suggested that eribulin tended to delay the development of new metastases in the lung, liver, and central nervous system longer than capecitabine did in patients with TNBC.

Pathway Questions

O’Shaughnessy added that learning how each of these drugs is involved in the MAPK (associated with proliferation) and PI3K (associated with metastasis) pathways will help clinicians prescribe the agents appropriately.

Another question involves the role of dexamethasone pretreatment; in a TNBC cell line (MDA-MB-231 cells) the use of the corticosteroid reduced paclitaxel- induced tumor cell apoptosis,⁸ which may be a critical concern in TNBC treatment, according to O’Shaughnessy.

Dexamethasone activates SGK-1, a protein involved in cell proliferation that is overexpressed in 50% of invasive human breast cancers, through the glucocorticoid receptor (GR). O’Shaughnessy suggested that may counter the apoptotic effect of paclitaxel, although the role of GR, SGK-1, and corticosteroids should be evaluated further.

References

1. Lehmann BD, Bauer JA, Chen X, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies [published online June 1, 2011]. J Clin Invest. 2011;121(7):2750-2767.
2. Isakoff SJ, Goss PE, Mayer EL, et al. TBCRC009: a multicenter phase II study of cisplatin or carboplatin for metastatic triple-negative breast cancer and evaluation of p63/p73 as a biomarker of response. J Clin Oncol. 2011;29(suppl; abstr 1025).
3. Telli ML, Jensen KC, Abkevich V, et al. Homologous recombination deficiency score predicts pathologic response following neoadjuvant platinum-based therapy in triple-negative and BRCA1/2 mutationassociated breast cancer. Presented at 2012 AACR-CTRC San Antonio Breast Cancer Symposium; December 4-8, 2012; San Antonio, TX. Abstract PD09-04.
4. Rugo HS, Barry WT, Moreno-Aspitia A, et al. CALGB 40502/NCCTG N063H: randomized phase III trial of weekly paclitaxel (P) compared to weekly nanoparticle albumin bound nab-paclitaxel (NP) or ixabepilone (Ix) with or without bevacizumab (B) as first-line therapy for locally recurrent or metastatic breast cancer (MBC). J Clin Oncol. 2012;30(suppl; abstr CRA1002).
5. Yardley DA, Brufsky A, Coleman RE, et al. tnAcity: a phase II/III trial of weekly nab-paclitaxel (nab-P) plus gemcitabine (gem) or carboplatin (carbo) versus gem/carbo as first-line treatment for metastatic triple-negative breast cancer (mTNBC). J Clin Oncol. 2014;32:5s (suppl; abstr TPS1146).
6. Kaufman PA, Awada A, Twelves C, et al. A phase III, open-label, randomized, multicenter study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines and taxanes. Presented at 2012 AACRCTRC San Antonio Breast Cancer Symposium; December 4-8, 2012; San Antonio, TX. Abstract S6-6.
7. Jordan MA, Kamath K, Manna T, et al. The primary antimitotic mechanism of action of the synthetic halichondrin E7389 is suppression of microtubule growth. Mol Cancer Ther. 2005;4(7):1086-1095.
8. Pang D, Kocherginsky M, Krausz T, et al. Dexamethasone decreases xenograft response to Paclitaxel through inhibition of tumor cell apoptosis [published online August 2, 2006]. Cancer Biol Ther. 2006;5(8):933-940.