Careful randomized clinical trial designs that incorporate biomarkers of response are key to moving forward.
—Melinda L. Telli, MD
For the treatment of triple-negative breast cancer, there is renewed interest in investigating the role of platinum chemotherapy, according to Melinda L. Telli, MD, Assistant Professor of Medicine at Stanford University, Palo Alto. At the Best of ASCO meeting in Los Angeles, Dr. Telli reviewed the results of two studies presented at the 2013 ASCO Annual Meeting, and previewed several ongoing studies that are further evaluating the role of these agents.
Old Players in a New Game
The family of platinum salts binds directly to DNA, resulting in the formation of DNA-platinum adducts and consequently intra- and interstrand DNA crosslinks that impede cell division. Interest in platinum-based chemotherapy in breast cancer has been renewed, based on the hypothesis of greater susceptibility of triple-negative and BRCA1/2-mutant tumors to DNA-damaging chemotherapy agents.
“We have all been intrigued by a small proof-of-concept neoadjuvant study from Poland, involving 25 BRCA1 mutation carriers, approximately 80% of whom had triple-negative breast cancer,” Dr. Telli said at the Best of ASCO meeting. In that study, four cycles of treatment with single-agent cisplatin at 75 mg/ m2 every 21 days yielded a pathologic complete response rate of 72%.1
“In comparison, we don’t really know the [pathologic complete response] rate for BRCA mutation carriers with triple-negative breast cancer treated with standard anthracycline/taxane chemotherapy, but a retrospective study from MD Anderson showed a 37% [pathologic complete response] rate,” she said.
Two additional studies, both from the Dana-Farber Cancer Institute, evaluated neoadjuvant cisplatin at 75 mg/m2 given every 21 days for four cycles. Silver et al reported a response rate of 21% in a study of 28 unselected patients with triple-negative breast cancer,2 whereas the larger 51-patient study by Ryan at el, in which patients also received bevacizumab (Avastin) every 3 weeks for three cycles, found a pathologic complete response rate of 15%.3
“While this is interesting activity, what we have lacked is randomized trial data,” Dr. Telli noted.
The GeparSixto trial, presented at the 2013 ASCO Annual Meeting, provided that data in a randomized phase II study of 595 patients, evaluating the addition of carboplatin to standard neoadjuvant chemotherapy in triple-negative and HER2-positive patient populations.4 Patients received weekly paclitaxel plus weekly nonpegylated liposomal doxorubicin in a dose-intensive regimen over 18 weeks, with or without the addition of carboplatin at AUC 1.5. All HER2-positive patients also received both trastuzumab (Herceptin) and lapatinib (Tykerb), and all triple-negative patients received bevacizumab.
The study met its primary endpoint by showing an increase in pathologic complete response with the addition of carboplatin. In the overall population, pathologic complete response was achieved by 46.7% in the carboplatin arm vs 37.2% in the standard arm, with a P value < .2, which met the level of statistical significance in this study.
“The interesting finding was the difference in [pathologic complete response] by subtype. Among patients with triple-negative disease, [pathologic complete response] increased by about 20% (58.7% vs 37.9%; P < .05). This impressive result is something we don’t frequently see in triple-negative breast cancer,” Dr. Telli said. “But surprisingly, for HER2-positive patients, there did not appear to be a significant advantage for the addition of carboplatin, with [pathologic complete response] rates lower than what we would have expected (33.1% vs 36.3%, respectively). The main finding is that the advantage seen with carboplatin was driven by patients with triple-negative disease.”
Disappointingly, however, the regimen was very toxic. Almost half the patients receiving carboplatin discontinued treatment, mostly due to adverse events. “This chemotherapy backbone—a dose-intense weekly anthracycline/taxane regimen—is something we don’t use in the United States. The data are exciting, but the regimen is unacceptably toxic,” she commented.
“Our own group presented the results of a platinum-containing regimen that did not include an anthracycline or taxane from a single-arm phase II study in triple-negative and BRCA1/2-mutated patients,” Dr. Telli said.5
Eighty patients were treated neoadjuvantly with carboplatin at AUC 2 on days 1 and 8, gemcitabine at 1,000 mg/m2 on days 1 and 8, and iniparib at 5.6 mg/kg on days 1, 4, 8, and 11, every 21 days for six cycles. The primary endpoint was pathologic complete response, which was achieved by 36% of the overall population but rose to 47% in the BRCA1/2-mutated population and to 56% in triple-negative patients who also had BRCA1/2 mutations.
The toxicity profile was more favorable than that of the GeparSixto regimen, she added. As expected, myelosuppression was common (grade 3/4 neutropenia in 49%) and elevations in liver enzymes were seen (grade 3 in 24%). “Some of the important quality-of-life toxicities, however, such as alopecia and neuropathy, were infrequent with this regimen,” Dr. Telli noted.
“There are exciting new assays coming down the pike to help us identify which patients may respond to platinum agents,” she said.
The homologous recombination deficiency assay was developed by Myriad Genetics to detect a genomic homologous recombination deficiency “footprint” in a tumor caused by defects in the homologous recombination pathway. It has the potential for identifying non–BRCA1/2 mutation carriers with “BRCA-like” cancers who may benefit from DNA repair-targeted strategies.
The assay was developed by looking at the association of genomic patterns of loss of heterozygosity and homologous recombination deficiency in ovarian cancer.6 Loss-of-heterozygosity regions of intermediate size were observed more frequently in tumors with defective BRCA1 or BRCA2. Greater genomic instability in the tumor is reflected by an elevated homologous recombination deficiency score, and this is believed to be related to underlying DNA repair defects in that tumor, she explained.
“We looked at this assay in the context of the PrECOG 0105 study, and we saw that the mean [homologous recombination deficiency] scores were significantly higher for responders than nonresponders,” she said.7 “But what was really interesting, and where the power of this type of assay lies, is that even if you take out the germline BRCA mutation carriers, this difference was observed.
“Patients with higher scores had much more favorable [pathologic complete response] rates (70%) than those with low homologous recombination deficiency scores (20%),” she reported.
“We know the efficacy of platinums in this patient population is influenced by BRCA mutation status, and BRCA mutation carriers achieve higher response rates, but there are certain sporadic triple-negative patients who likely stand to benefit significantly from a platinum-based approach. Tumor measures of genomic instability, such as loss of heterozygosity, may prove to be important biomarkers in these cases,” she said.
“Careful randomized clinical trial designs that incorporate biomarkers of response are key to moving forward,” she added. In the near term, trials that are ongoing or in development include:
Neoadjuvant anthracycline/cyclophosphamide vs cisplatin in BRCA1/2 mutation carriers
CALGB 40603 trial of neoadjuvant weekly paclitaxel plus anthracycline/cyclophosphamide, with or without carboplatin and with or without bevacizumab
Hoosier Oncology trial of cisplatin with or without the PARP inhibitor rucaparib as postneoadjuvant therapy in triple-negative and BRCA-positive breast cancer with residual disease after standard neoadjuvant therapy
ECOG 5112 trial of neoadjuvant anthracycline/cyclophosphamide followed by paclitaxel vs gemcitabine/carboplatin in triple-negative and BRCA-positive breast cancer, with the primary endpoint being pathologic complete response in patients with high homologous recombination deficiency score (in development) ■
Disclosure: Dr. Telli has received research support from Sanofi; she has served in a consultant or advisory role (uncompensated) with Sanofi.
1. Gronwald J, Byrski T, Huzarski T, et al: Neoadjuvant therapy with cisplatin in BRCA-positive breast cancer patients. 2009 ASCO Annual Meeting. Abstract 502. Presented May 31, 2009.
2. Silver DP, Richardson AL, Eklund AC, et al: Efficacy of neoadjuvant cisplatin in triple negative breast cancer. J Clin Oncol 28:1145-1153, 2010.
3. Ryan PD, Tung NM, Isakoff SJ, et al: Neoadjuvant cisplatin plus bevacizumab in triple negative breast cancer: Safety and efficacy. 2009 ASCO Annual Meeting. Abstract 551.
4. Von Minckwitz G, Schneeweiss A, Salat C, et al: A randomized phase II trial investigating the addition of carboplatin to neoadjuvanat therapy for triple-negative and HER2-positive early breast cancer (GeparSixto). 2013 ASCO Annual Meeting. Abstract 1004. Presented June 3, 2013.
5. Telli ML, Jensen KC, Kurian AW, et al: PrECOG 0105: Final efficacy results from a phase II study of gemcitabine and carboplatin plus iniparib (BSI201) as neoadjuvant therapy for triple-negative and BRCA1/2 mutation-associated breast cancer. 2013 ASCO Annual Meeting. Abstract 1003. Presented June 3, 2013.
6. Abkevich V, Timms KM, Hennessy BT, et al: Patterns of genomic loss of heterozygosity predicts homologous recombination repair defects in epithelial ovarian cancer. Br J Cancer 107:1776-1782, 2012.
7. 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 mutation-associated breast cancer. 2012 AACR-CTRC San Antonio Breast Cancer Symposium. Abstract PD09-04. Presented December 13, 2012.