In addition to our regular coverage of the 2019 San Antonio Breast Cancer Symposium, the following reports from the meeting include studies you may have missed. We hope you find them of interest.
Ribociclib/Letrozole as Neoadjuvant Therapy
As neoadjuvant therapy in women with high-risk hormone receptor–positive/HER2-negative breast cancer, the combination of ribociclib and letrozole was as effective as standard multidrug chemotherapy and better tolerated, in the exploratory phase II SOLTI-1402/CORALLEEN trial.1 It was the first trial testing the activity of this combination vs multiagent chemotherapy using a standardized combined biomarker that integrates pathologic, biologic, and prognostic information. The study results were published simultaneously online in The Lancet Oncology.2
“We believe these results suggest that in clinically high-risk luminal B disease, a chemotherapy-free treatment strategy based on inhibition of [cyclin-dependent kinases 4 and 6 (CDK4/6)] is worth exploring in future neoadjuvant trials,” said Joaquín Gavilá, MD, of the Valencia Institute of Oncology in Spain.
“We believe these results suggest that in clinically high-risk luminal B disease, a chemotherapy-free treatment strategy based on inhibition of CDK4/6 is worth exploring in future neoadjuvant trials.”— Joaquín Gavilá, MD
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SOLTI-1402/CORALLEEN was an open-label, multicenter trial involving 106 postmenopausal women with hormone receptor–positive, HER2-negative stage I to IIIA breast cancer. Women had an operable tumor size ≥ 2 cm and high-risk luminal B disease, as defined via the Prosigna (formerly PAM50) genomic tumor-profiling test (median risk-of-recurrence [ROR] score of 74 out of a possible 100 points).
Women were randomly assigned to 6 months of neoadjuvant therapy with ribociclib and letrozole or four cycles of doxorubicin and cyclophosphamide followed by weekly paclitaxel for 12 weeks. The primary study endpoint was achievement of a low ROR score at the time of surgery.
The endpoint was met by 47% of the ribociclib/letrozole group and 46% of the chemotherapy group. The median ROR score improved from 74 points at baseline to 18 in the investigational treatment arm and to 25 in the standard chemotherapy arm. More than 80% of both arms converted from luminal B to the less aggressive luminal A subtype.
“Nearly half the patients were downstaged from high risk to low risk in both treatment arms,” Dr. Gavilá noted.
The study showed not only that a novel nonchemotherapy neoadjuvant strategy is a good alternative to chemotherapy in this population, but that a molecular subtyping tool can be used to assess the efficacy of neoadjuvant treatment.
Endocrine Therapy Plus Palbociclib in the Metastatic Setting
For patients with hormone receptor–positive, HER2-negative metastatic breast cancer, endocrine therapy plus palbociclib did not offer a progression-free survival advantage over capecitabine in the phase III PEARL study.3
“The PEARL study did not meet its two co-primary endpoints [improved progression-free survival in all patients and in those lacking ESR1 mutations],” said Miguel Martín, MD, PhD, of the Instituto de Investigación Sanitaria Gregorio Marañón, Madrid and GEICAM chairman.
Miguel Martín, MD, PhD
The study enrolled 601 patients previously treated with aromatase inhibitors. There were two randomized treatment cohorts: cohort 1 compared exemestane plus palbociclib vs capecitabine alone, whereas cohort 2 randomly assigned patients to fulvestrant plus palbociclib or capecitabine alone.
At a median follow-up of 13.5 months, the median progression-free survival for patients who received fulvestrant/palbociclib was not significantly different from those who received capecitabine: 7.5 vs 10 months, respectively (hazard ratio [HR] = 1.09; P = .537). At a median follow-up of 19.0 months for patients without an ESR1 mutation, findings were similar, with median progression-free survival times of 8.0 months for endocrine therapy plus palbociclib vs 10.6 months for capecitabine (HR = 1.08; P = .526). Response rates were numerically higher with capecitabine than the endocrine arms. In an exploratory analysis by breast cancer intrinsic subtypes, no differences were found in patients with luminal disease, whereas capecitabine provided a significantly better progression-free survival in patients with nonluminal disease.
Patients who received endocrine therapy plus palbociclib had higher rates of grade 3 or 4 neutropenia (approximately 56%) than patients who received capecitabine (5%) and lower rates of treatment discontinuation (4% vs 13%, respectively). “Therapy with palbociclib plus endocrine therapy was generally better tolerated than capecitabine,” Dr. Martín said.
Cisplatin No Better Than AC as Neoadjuvant Therapy in BRCA Mutation Carriers
In the randomized phase II INFORM trial (TBCRC-031), the use of cisplatin as neoadjuvant treatment in germline BRCA-mutated early breast cancer did not increase the rate of pathologic complete response, compared with standard doxorubicin/cyclophosphamide (AC).4 This was true both for patients with triple-negative disease and for those with estrogen receptor–positive/HER2-negative tumors, according to Nadine M. Tung, MD, of Beth Israel Deaconess Medical Center, Boston.
The 117 patients had germline BRCA1 or BRCA2 mutations, T1–3/N0–2 HER2-negative invasive breast cancer and tumors ≥ 1.5 cm or with positive lymph nodes. They were randomly assigned to neoadjuvant therapy with four cycles of cisplatin at 75 mg/m2 every 3 weeks or standard AC every 2 to 3 weeks, followed by surgery. Enrollment was stopped early due to slow accrual.
“BRCA deficiency (ie, homologous recombination deficiency) may be a marker of sensitivity to DNA-damaging chemotherapy rather than to platinum agents specifically.”— Nadine M. Tung, MD
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With regard to the possibility that cisplatin may be particularly effective in BRCA-mutated tumors, Dr. Tung offered, “BRCA deficiency (ie, homologous recombination deficiency) may be a marker of sensitivity to DNA-damaging chemotherapy in general rather than to platinum agents specifically.” Commenting on the size of the study, she added, “There is almost no chance that the pathologic complete response with cisplatin would have been significantly greater than with AC had the study met its target accrual [170 patients].”
The pathologic complete response rate with cisplatin, in all patients, was 18%, compared with 26% for AC. Among patients with triple-negative breast cancer, pathologic complete response rates were 22% and 28%, respectively, and among hormone receptor–positive patients, they were 6% and 21%, respectively. The frequency of patients with residual cancer burden 0 or 1 scores combined was also numerically but not statistically higher with AC than cisplatin, for all subtypes.
Dr. Tung noted the pathologic complete response rate with cisplatin was substantially lower than in some previous reports in BRCA mutation carriers. This may reflect differences in the study populations—especially the fact that more patients in the INFORM trial had higher-stage or estrogen receptor–positive disease, she said.
Docetaxel, Paclitaxel Equivalent in Combination With Pertuzumab/
Real-world findings from a retrospective study suggest that choice of taxane (either paclitaxel or docetaxel) does not affect outcome in the treatment of patients with HER2-positive breast cancer.5 The U.S. nationwide Flatiron Health electronic health record–derived database was used to identify 1,054 patients who received a taxane with pertuzumab/trastuzumab as initial systemic therapy after diagnosis of metastatic breast cancer between June 1, 2012, and April 30, 2019. Among all patients, 29.3% received paclitaxel as part of therapy (26.9% paclitaxel and 2.4% nab-paclitaxel) and 70.7% received docetaxel.
“In the real world, it still seems like docetaxel is the preferred option, but paclitaxel is increasingly being used together with pertuzumab and trastuzumab,” Dr. Polito said.
Patients who received paclitaxel as the taxane were significantly older (P = .001), had an Eastern Cooperative Oncology Group performance status of 0 less often (P = .001), and were likely to have more metastatic sites (P = .006) than those treated with docetaxel. “The choice of taxane in the real world is influenced by patients’ baseline characteristics with paclitaxel being the preferred options for older patients and for those with worse clinical conditions.”
The unadjusted median real-world, progression-free survival was 12.9 months (95% confidence interval = 11.2–15.8 months) for pertuzumab, trastuzumab, and paclitaxel vs 14.9 months (95% CI = 13.2–16.9 months) for pertuzumab, trastuzumab, and docetaxel. No statistically significant difference was found between the two regimens for treatment duration (time to last administration of the index taxane or the pertuzumab-based regimen) and for real-world progression-free survival in both unadjusted models and models adjusted for potential confounders.
Letizia Polito, PhD
“These results support the evidence from the PERUSE trial,6 suggesting that paclitaxel appears to be a valid alternative taxane backbone to docetaxel, and extending the evidence to a more heterogeneous population,” reported the investigators, led by Letizia Polito, PhD, a data scientist at F. Hoffmann-La Roche in Basel, Switzerland.
“This study adds the evidence that no substantial difference in effectiveness is observed between the two treatments when used in the real world, which is what we expected,” said Dr. Polito. “We know that paclitaxel has a better safety profile.”
A limitation of the study is that only patients in the Flatiron Health network were included, which could have led to selection bias.
DISCLOSURE: The SOLTI-1402/CORALLEEN trial was sponsored by Novartis, the Breast Cancer Research Foundation, The American Association for Cancer Research, and the Breast Cancer Now Career Catalyst. Dr. Gavilá has served as a consultant for Novartis, Roche, and Pfizer. Dr. Martin has received honoraria or consulting fees from AstraZeneca, Amgen, Taiho Oncology, Roche/Genentech, Novartis, PharmaMar, Lilly, Puma, Pfizer, and Daiichi Sankyo and has received institutional research funding from Roche, Novartis, and Puma. Dr. Tung has received research funding from AstraZeneca. Dr. Polito is an employee of F. Hoffmann-La Roche.
1. Gavila J, Saura C, Pascual T, et al: Primary results of SOLTI-1402/CORALLEEN phase II trial of neoadjuvant ribociclib plus letrozole vs chemotherapy in PAM50 luminal B early breast cancer: An open-label, multicenter, two-arm, randomized study. 2019 San Antonio Breast Cancer Symposium. Abstract GS2-06. Presented December 11, 2019.
2. Prat A, Saura C, Pascual T, et al: Ribociclib plus letrozole vs chemotherapy for postmenopausal women with hormone receptor-positive, HER2-negative, luminal B breast cancer (CORALLEEN): An open-label, multicenter, randomized, phase II trial. Lancet Oncol 21:33-43, 2020.
3. Martín M, Zielinski C, Ruíz-Borrego M, et al: Results from PEARL study (GEICAM/2013-02_CECOG/BC.1.3.006): A phase III trial of palbociclib in combination with endocrine therapy vs capecitabine in hormonal receptor-positive/human epidermal growth factor receptor (HER)2-negative metastatic breast cancer patients whose disease progressed on aromatase inhibitors. 2019 San Antonio Breast Cancer Symposium. Abstract GS2-07. Presented December 11, 2019.
4. Tung N, Arun B, Hofstatter E, et al: Cisplatin vs doxorubicin/cyclophosphamide as neoadjuvant treatment in germline BRCA mutation carriers with HER2-negative breast cancer: Results from the INFORM trial (TBCRC-031). 2019 San Antonio Breast Cancer Symposium. Abstract GS6-03. Presented December 13, 2019.
5. Polito L, Shim J, Du Toit Y, et al: Use of pertuzumab in combination with taxanes for HER2+ metastatic breast cancer: Analysis of U.S. electronic health records. 2019 San Antonio Breast Cancer Symposium. Abstract P1-18-14. Presented December 11, 2019.
6. Bachelot T, Ciruelos E, Schneeweiss A, et al: Preliminary safety and efficacy of first-line pertuzumab combined with trastuzumab and taxane therapy for HER2-positive locally recurrent or metastatic breast cancer (PERUSE). Ann Oncol 30:766-773, 2019.