The key to moving forward [in the treatment of triple-negative breast cancer] is to look at biomarkers of response.
—Priyanka Sharma, MD
Combination chemotherapy for triple-negative breast cancer is anthracycline- and taxane-based and has not really changed much in the past 10 years, but “we are starting to see emerging data with selective activity of platinum agents,” Priyanka Sharma, MD, told participants at the Best of ASCO Chicago session she moderated on triple-negative breast cancer.
Dr. Sharma, Associate Professor of Medicine, University of Kansas School of Medicine, Kansas City, reported on four randomized phase II studies showing improvement in pathologic complete response in early-stage triple-negative breast cancer when carboplatin is added to the anthracycline/taxane treatment backbone. The magnitude of long-term benefit from carboplatin is still not known, Dr. Sharma noted, and the survival data are “eagerly awaited.”
Dr. Sharma also reviewed biomarker studies showing that germline BRCA1/2 status does influence systemic treatment response in triple-negative breast cancer. Higher pathologic complete response rates occurred among patients with genetic mutations and those with a family history of breast or ovarian cancer.
Greater Risk of Relapse
“Women with [triple-negative breast cancer] are at greater risk of relapse for every stage of breast cancer, so it is clear that we need to improve on systemic therapy,” Dr. Sharma stated. “The relationship between BRCA defects and triple-negative breast cancer has been established,” she noted. There are phenotypic and molecular similarities between BRCA1-associated breast cancer and sporadic triple-negative breast cancer, and 10% to 20% of triple-negative breast cancers harbor germline BRCA mutations. Moreover, nongermline BRCA1/homologous recombination defects may be present in up to 50% of triple-negative breast cancer cases.
The relationship between BRCA defects and triple-negative breast cancer has therapeutic implications. “BRCA1 deficient and basal-like cell lines demonstrate unique chemosensitivities,” Dr. Sharma said. They include a greater sensitivity to platinum agents and gemcitabine, a lack of selective sensitivity to anthracyclines, and a decreased sensitivity to taxanes. Platinum agents are being explored for use in women with triple-negative breast cancer, with most of the insights into their use coming from neoadjuvant trials.
Neoadjuvant Carboplatin With Paclitaxel
Women with stage II/IIIa HER2-negative breast cancer treated neoadjuvantly with weekly paclitaxel and carboplatin followed by CEF (cyclophosphamide/epirubicin/fluorouracil) had a significantly improved pathologic complete response compared to those who received paclitaxel alone before CEF, in a study by Tamura et al.1 Among the 181 eligible patients, there were 75 with triple-negative breast cancer.
The pathologic complete response rate was 31.8% among 88 patients receiving carboplatin with paclitaxel vs 17.6% for 91 patients receiving paclitaxel without carboplatin (P = .01). In the triple-negative subgroup, the pathologic complete response rate was 61.2% with carboplatin vs 26.3% without carboplatin (P = .003).
Dr. Sharma pointed out the differences in EGFR expression among the tumor samples obtained from 46 patients. Overall, 45% of EGFR-positive patients had pathologic complete response, compared to 11.5% of EGFR-negative patients (P = .010). Among those receiving carboplatin with paclitaxel, the pathologic complete response rate was 63.8% for EGFR-positive patients vs 18.2% for EGFR-negative patients (P = .040). However, EGFR was more likely to be a surrogate for triple-negative status rather than a response biomarker.
Neoadjuvant Carboplatin With Docetaxel
Neoadjuvant carboplatin with docetaxel produced encouraging pathologic complete response rates, which were similar to observed rates for neoadjuvant doxorubicin/cyclophosphamide/taxane plus carboplatin combinations, but without the potential cardiac and secondary leukemia toxicities, according to a study led by Dr. Sharma.2 Following neoadjuvant therapy and surgery, 32 out of 49 patients with triple-negative breast cancer (65%) had achieved pathologic complete response, including 22 out of the 36 patients (61%) with BRCA1/2 wild-type disease vs 10 out of 13 patients (77%) with a BRCA mutation (P = .50).
Rates for near–pathologic complete response were based on a residual cancer burden score of 0 or 1 following neoadjuvant therapy and surgery. Overall, 38 patients (78%) achieved near–pathologic complete response, including 27 patients (75%) with BRCA1/2 wild-type disease and 11 patients (85%) with a BRCA mutation (P = .70).
Residual disease predicts high risk of relapse, Dr. Sharma observed, but due to lack of data on efficacy of alternative agents in this setting, the current standard is no further therapy. Carefully designing and conducting residual disease adjuvant trials is a valuable opportunity for patients and science, she said. Alternative ways of thinking about residual disease include the possibility that the wrong neoadjuvant chemotherapy agents were chosen and it might be beneficial to investigate something different, or perhaps blood markers can be used to identify patients with residual disease who are likely to experience early relapse.
A study by Turner et al3 concluded that patients with detectable mutations in circulating free DNA following treatment for primary breast cancer “are at high risk of relapse and may be suitable candidates for therapeutic trials of novel agents.” Results of this study discussed by Dr. Sharma showed that among 31 patients with early-stage breast cancer, who received neoadjuvant chemotherapy, mutation tracking in blood predicted early relapse in 4 of the 5 patients who relapsed (detected on the 6-month postsurgery specimen). Among the five patients who developed recurrence, three were HER2-positive, one was estrogen receptor–positive, and one had triple-negative breast cancer.
The median follow-up of this study was short at 17 months, so the ability to detect late relapse is still unknown, Dr. Sharma noted. She added, however, that the study is “an important proof-of-concept study with the potential to guide patient selection in postneoadjuvant therapy trials.”
Based on preclinical data suggesting that the combination of DNA-damaging chemotherapy and inhibition of poly(ADP-ribose)polymerase (PARP) is synergistic in BRCA-deficient and triple-negative breast cancer cell lines, Dwadasi et al4 compared postoperative cisplatin with or without the investigational PARP inhibitor rucaparib among women with triple-negative breast cancer or known BRCA mutation–associated breast cancer. Eligible patients had residual lymph node involvement or > 2 cm invasive disease after anthracycline- or taxane-based neoadjuvant therapy.
Prior treatment with cisplatin was not allowed, but prior treatment with carboplatin was. Among the 128 patients enrolled, the median tumor size at surgery was 1.9 cm (range, 0–11.5 cm) and the median number of lymph nodes involved was 1 (range, 0–38).
Disease-free survival at 1 year was similar at 82% in the two arms. Dr. Sharma pointed out that the dose of rucaparib used in this trial was much lower than the currently recommended phase II single-agent dose of 600 mg orally twice daily. An “interesting observation,” according to Dr. Sharma, was the underutilization of clinical BRCA testing, with only 30% of BRCA mutations identified as part of routine clinical care. Another interesting
observation was that there have been no recurrences among eight BRCA mutation carriers treated on the rucaparib arm.
Another investigational PARP inhibitor, olaparib, is being tested as adjuvant therapy in BRCA mutation carriers in the OlympiA trial, Dr. Sharma reported. That trial includes patients with residual disease following neoadjuvant therapy with six cycles of anthracycline-based and/or taxane-based therapy.
Biomarkers of Response
“The key to moving forward,” Dr. Sharma said, “is to look at biomarkers of response,” and two biomarker analyses from the GeparSixto trial did that. Building on previous findings that tumor-infiltrating lymphocytes are linked to response to carboplatin-based chemotherapy and prognosis among patients with triple-negative breast cancer, Denkert et al5 evaluated 12 immunologically relevant genes in 481 core biopsies (83% of GeparSixto samples).
The investigators reported that all 12 of the immune markers “were significantly linked” to increased pathologic complete response rates in univariate analysis, and 11 “were also significant in multivariate analysis, including clinical parameters.” In addition, some markers “showed a significant interaction with treatment.”
The 12 immune mRNA markers were measured by quantitative reverse transcription–polymerase chain reaction assay and correlated well with tumor-infiltrating lymphocytes. Dr. Sharma remarked that the visual assessment is inexpensive and tissue-efficient. The use of tumor-infiltrating lymphocytes and immune genes as biomarkers of response in triple-negative breast cancer “has potential therapeutic implications” for other targeted agents like PD-1 and PD-L1 antibodies, she stated.
The use of immune marker mRNAs in addition to tumor-infiltrating lymphocytes to identify patients with increased response to carboplatin requires further validation in other breast cancer trials. Future studies should seek to correlate tumor-infiltrating lymphocytes/immune genes with other potential predictors of platinum response, such as germline BRCA mutations and genomic instability, Dr. Sharma added.
Another GeparSixto correlative study by von Minckwitz et al6 found that germline BRCA1/2 and RAD mutations as well as a family history of breast and/or ovarian cancer can identify patients most likely to benefit from carboplatin. “This is the first randomized study to report on germline BRCA status,” Dr. Sharma stated. She anticipated that 8 to 10 more germline BRCA alterations are likely to be identified by GeparSixto and said that survival data are expected in 2015. (Details of that study were reported in the August 15, 2014, issue of The ASCO Post.)
Despite the established benefit of germline BRCA testing in women newly diagnosed with breast cancer, “the reality in clinics,” Dr. Sharma noted, is that only about 44.5% of women are tested. “Insurance coverage can be denied for up to 20% of triple-negative breast cancer patients meeting National Comprehensive Cancer Network (NCCN) criteria for testing,” Dr. Sharma reported. “We capture a complete family history in less than one-third of these cancer patients. So obviously one of the take-home messages is that we need to improve family history–taking and genetic counseling and testing efforts,” she remarked.
“Looking beyond germline BRCA1/2 mutations, there are other factors” that might influence systemic treatment response among patients with triple-negative breast cancer, Dr. Sharma said. They include tumor genomic instability, BRCA 1 epigenetic silencing, and germline and somatic mutations in other homologous recombination pathway genes.
Ongoing and Upcoming Trials
Dr. Sharma is serving as principal investigator of a correlative study that will evaluate “BRCAness” as a prognostic marker in patients with triple-negative breast cancer treated with adjuvant anthracycline-based chemotherapy. A panel of BRCAness markers will be performed on tumor tissue genomic DNA and RNA taken from tumor tissue samples from 443 patients. Each marker will be evaluated individually and an exploratory analysis performed of interaction between all the markers.
A SWOG phase II study in development will be investigating whether the addition of a PARP inhibitor to platinum-based therapy improves progression-free survival for patients with germline BRCA mutation–associated breast cancers and sporadic triple-negative breast cancers that express the BRCAness phenotype. Patients with metastatic triple-negative breast cancer and BRCA mutation–associated breast cancer will be randomly assigned between cisplatin/vinorelbine with or without veliparib. All patients will have germline BRCA testing after randomization and will then be assigned to the BRCA–confirmed negative or BRCA–confirmed positive group.
Two upcoming randomized, phase III trials involve patients with triple-negative breast cancer who have residual disease after treatment with neoadjuvant chemotherapy. One trial will compare postoperative platinum-based chemotherapy to observation. The other trial, which is in development, will evaluate the efficacy and safety of PD-1 antibody MK-3475 as adjuvant therapy in patients with > 1 cm residual invasive cancer or any positive lymph nodes after neoadjuvant chemotherapy. ■
Disclosure: Dr. Sharma reported no potential conflicts of interest.
1. Tamura K, Hashimoto J, Tsuda H, et al: Randomized phase II study of weekly paclitaxel with or without carboplatin followed by cyclophosphamide/epirubicin/5-fluorouracil as neoadjuvant chemotherapy for stage II/IIIA HER2-negative breast cancer. ASCO Annual Meeting. Abstract 1017. Presented June 2, 2014.
2. Sharma P, Stecklein S, Klemp JR, et al: Efficacy of neoadjuvant carboplatin/docetaxel based chemotherapy in sporadic and BRCA mutation associated triple-negative breast cancer. ASCO Annual Meeting. Abstract 1022. Presented June 2, 2104.
3. Turner NC, Garcia-Murillas I, Schiavon G, et al: Tracking tumor specific mutations in circulating-free DNA to predict early relapse after treatment of primary breast cancer. ASCO Annual Meeting. Abstract 511. Presented May 31, 2014.
4. Dwadasi S, Tong Y, Walsh T, et al: Cisplatin with or without rucaparib after preoperative chemotherapy in patients with triple-negative breast cancer (TNBC): Hoosier Oncology Group BRE09-146. ASCO Annual Meeting. Abstract 1019. Presented June 2, 2104.
5. Denkert C, von Minckwitz, Brase JC, et al: Expression of immunologic genes in triple-negative and HER2-positive breast cancer in the neoadjuvant GeparSixto trial: Prediction of response to carboplatin-based chemotherapy. ASCO Annual Meeting. Abstract 510. Presented May 31, 2014.
6. von Minckwitz G, Hahnen E, Fasching PA, et al: Pathological complete response (pCR) rates after carboplatin-containing neoadjuvant chemotherapy in patients with germline BRCA (gBRCA) mutation and triple-negative breast cancer (TNBC): Results from GeparSixto. ASCO Annual Meeting. Abstract 1005. Presented June 2, 2104.
Transformations in the treatment of early-stage breast cancer have shifted the therapeutic approach from a “stage-centered treatment algorithm” to a “tumor biology-centered treatment algorithm,” Priyanka Sharma, MD, Associate Professor of Medicine, University of Kansas School of Medicine, Kansas...