Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: cohort A of the phase II KEYNOTE-086 study

ABSTRACT Background Treatment options for previously treated metastatic triple-negative breast cancer (mTNBC) are limited. In cohort A of the phase II KEYNOTE-086 study, we evaluated pembrolizumab as second or later line of treatment for patients with mTNBC. Patients and methods Eligible patients had centrally confirmed mTNBC, ≥1 systemic therapy for metastatic disease, prior treatment with anthracycline and taxane in any disease setting, and progression on or after the most recent therapy. Patients received pembrolizumab 200 mg intravenously every 3 weeks for up to 2 years. Primary end points were objective response rate in the total and PD-L1–positive populations, and safety. Secondary end points included duration of response, disease control rate (percentage of patients with complete or partial response or stable disease for ≥24 weeks), progression-free survival, and overall survival. Results All enrolled patients (N = 170) were women, 61.8% had PD-L1–positive tumors, and 43.5% had received ≥3 previous lines of therapy for metastatic disease. ORR (95% CI) was 5.3% (2.7–9.9) in the total and 5.7% (2.4–12.2) in the PD-L1–positive populations. Disease control rate (95% CI) was 7.6% (4.4–12.7) and 9.5% (5.1–16.8), respectively. Median duration of response was not reached in the total (range, 1.2+–21.5+) and in the PD-L1–positive (range, 6.3–21.5+) populations. Median PFS was 2.0 months (95% CI, 1.9–2.0), and the 6-month rate was 14.9%. Median OS was 9.0 months (95% CI, 7.6–11.2), and the 6-month rate was 69.1%. Treatment-related adverse events occurred in 103 (60.6%) patients, including 22 (12.9%) with grade 3 or 4 AEs. There were no deaths due to AEs. Conclusions Pembrolizumab monotherapy demonstrated durable antitumor activity in a subset of patients with previously treated mTNBC and had a manageable safety profile. Clinical trial registration ClinicalTrials.gov, NCT0244700

Serial Analysis of Circulating Tumor Cells in Metastatic Breast Cancer Receiving First-Line Chemotherapy

BACKGROUND: We examined the prognostic significance of circulating tumor cell (CTC) dynamics during treatment in metastatic breast cancer (MBC) patients receiving first-line chemotherapy. METHODS: Serial CTC data from 469 patients (2202 samples) were used to build a novel latent mixture model to identify groups with similar CTC trajectory (tCTC) patterns during the course of treatment. Cox regression was used to estimate hazard ratios for progression-free survival (PFS) and overall survival (OS) in groups based on baseline CTCs, combined CTC status at baseline to the end of cycle 1, and tCTC. Akaike information criterion was used to select the model that best predicted PFS and OS. RESULTS: Latent mixture modeling revealed 4 distinct tCTC patterns: undetectable CTCs (56.9% ), low (23.7%), intermediate (14.5%), or high (4.9%). Patients with low, intermediate, and high tCTC patterns had statistically significant inferior PFS and OS compared with those with undetectable CTCs (P < .001). Akaike Information Criterion indicated that the tCTC model best predicted PFS and OS compared with baseline CTCs and combined CTC status at baseline to the end of cycle 1 models. Validation studies in an independent cohort of 1856 MBC patients confirmed these findings. Further validation using only a single pretreatment CTC measurement confirmed prognostic performance of the tCTC model. CONCLUSIONS: We identified 4 novel prognostic groups in MBC based on similarities in tCTC patterns during chemotherapy. Prognostic groups included patients with very poor outcome (intermediate + high CTCs, 19.4%) who could benefit from more effective treatment. Our novel prognostic classification approach may be used for fine-tuning of CTC-based risk stratification strategies to guide future prospective clinical trials in MBC

Abstract OT1-05-01: A phase I/II, single arm, non-randomized study of ribociclib (LEE011), a CDK 4/6 inhibitor, in combination with bicalutamide, an androgen receptor (AR) inhibitor, in advanced AR+ triple-negative breast cancer

Abstract Background: Triple negative breast cancer (TNBC) is a heterogeneous disease encompassing distinct intrinsic molecular subtypes, including a luminal androgen receptor (AR) subtype, characteristically dependent on AR signaling. The AR is expressed in more than 50% of TNBCs. Bicalutamide is an oral, non-steroidal, AR antagonist, which has been studied in metastatic TNBC with a clinical benefit rate of 19% at 24 weeks. In preclinical models, cyclin dependant kinase (CDK) 4/6 inhibition has been shown to restore sensitivity to AR inhibition, and may thus be an important resistance mechanism. Ribociclib is an orally bioavailable, highly specific CDK4/6 inhibitor that induces cell cycle arrest, already approved in endocrine receptor positive breast cancers. We hypothesize that inhibition of CDK inhibition can enhance the activity of anti-androgen therapy in TNBC that express AR. Methods: We designed a phase I/II, single arm, non-randomized, open label study of the combination of bicalutamide with ribociclib in women with advanced AR-positive TNBC. The primary objective of the phase I component is to determine the maximum tolerated dose of the combination, and of the phase II component to assess the clinical benefit rate at 16 weeks. Secondary objectives include progression free and overall survival, objective response rates, and safety and tolerability. Exploratory objectives will be to assess AR quantification, localization and splice variants in circulating tumor cells, as well as quantification of pan and phospho proteins of Rb. Eligible patients must have measurable metastatic or unresectable AR-positive TNBC and have had no more than 1 line of systemic therapy for metastatic disease. The phase I study will be conducted using a 3+3 dose escalation schema, 12 to 18 patients are expected to enroll. The phase II component will utilize a Simon's two stage design, enrolling 24 patients for the first stage. At least 5 subjects must have clinical benefit by 16 weeks to proceed onto the second stage, which would enroll an additional 22 subjects for a total of 46 patients. The study will be powered to detect a clinical benefit rate of 40% with a power of 80% and a type I error rate of 10%. Contact [email protected] for more information about the study. Citation Format: Santa-Maria CA, Rampurwala M, Wisinski K, Toppmeyer D, O'Regan R. A phase I/II, single arm, non-randomized study of ribociclib (LEE011), a CDK 4/6 inhibitor, in combination with bicalutamide, an androgen receptor (AR) inhibitor, in advanced AR+ triple-negative breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT1-05-01.</jats:p

Plasma cell-regulated polyadenylation at the Ig gamma 2b secretion-specific poly(A) site.

Abstract We found that the sequences downstream of the Ig gamma 2b secretory-specific (sec) poly(A) site play an important role in the preferential production of sec Ig mRNA during plasma B cell development. The Ig gamma 2b mRNA production in a deletion mutant (delta-Kpn) lacking the Ig sec poly(A) site and downstream consensus element (dsc) has been previously shown to default to the use of the downstream membrane-specific (mb) poly(A) site. In this study restoration of the Ig sec poly(A) site and dsc to the delta-Kpn gene causes a significant increase in the use of the sec poly(A) site vs mb poly(A) site in stable transfectants of plasma but not memory B cell tumors, indicating plasma cell-specific recognition of the Ig sec dsc. Restoration of the poly(A) cleavage site alone to delta-Kpn did not restore regulation. Substitution of an SV40 downstream poly(A) element for the Ig dsc in the delta-Kpn gene also does not restore regulation. The data further indicate that although the Ig dsc is clearly very important in the plasma cell-regulated expression, the difference in the processing ratios of the restored vs the intact Ig gamma 2b gene in plasma cells suggests that there are other yet to be defined sequences that may also play a role in the intact gene. Insertion of a 130-nucleotide segment of the gene containing the Ig sec poly(A) site and dsc into a heterologous, guanosyl phosphotransferase gene resulted in plasma cell-regulated polyadenylation of the sec poly(A) site. Neither the mb nor the SV40 early poly(A) sites and their respective dscs, in similar gpt chimeras, were regulated. Therefore the region downstream of the Ig sec poly(A) site plays an essential role in regulating polyadenylation at the sec poly(A) site in plasma cells but not memory cells. A model involving a plasma cell-specific recognition factor for the Ig sec dsc is presented.</jats:p

Local-regional relapse and distant metastasis in conservatively managed triple negative early stage breast cancer

594 Background: Triple negative (TN) basal-like breast cancers (Negative for ER,PR,HER2/neu) represent an aggressive phenotype, with unique clinical and pathologic features. The purpose of this study was to determine the prognostic significance of this classification with respect to local-regional relapse and distant metastasis in a cohort of conservatively managed breast cancer patients. Methods: A large data base of conservatively managed breast cancer patients with long term follow-up, in which all three immunhistochemical markers, ER,PR and HER2/neu were available was reviewed. Patients were classified as TN if they tested negative for all three markers. Of 442 patients in the data base with all three markers available, 100 were classified as TN. All clinical, pathologic, outcomes and molecular marker data were entered into a computerized database. Results: As of September 2005, with a median follow-up of 7 years, of the 442 patients in the study there have been 50 in-breast relapses, 10 nodal relapses, 68 distant relapses and 62 deaths. Compared with the other subtypes, the TN cohort had a poorer overall survival (67% vs 75%, p = .096), poorer distant metastasis-free rate (61% vs 75%, p = .002), poorer cause-specific survival (67% vs 78%, p = .03), and poorer nodal relapse-free rate (93% vs 99%, p = .021). In a multivariate Cox regression analysis, TN subtype was an independent predictor of distant metastasis (HR=2.6, CI 1.53–4.35, p = .004) and cause- specific survival (HR= 2.36, CI 1.28–4.38, p= .006). There was no significant difference in local (in-breast) control between the TN and other subtypes. BRCA testing was performed on 85 patients in this cohort, of whom 8 had deleterious mutations in BRCA1 and 6 had deleterious mutations in BRCA2. Of 8 BRCA1 mutant patients 7 were classified as TN, while only 1 of 6 BRCA2 patients were TN (p &lt; .001). Conclusions: Patients classified as TN have a poor prognosis with respect to overall, disease free and cause specific survival. However there was no evidence that these patients are at higher risk for local relapse following conservative surgery and radiation. BRCA1 mutant patients develop predominantly TN tumors. No significant financial relationships to disclose. </jats:p

Telephone disclosure of <i>BRCA1/2</i> test results? Experience and opinions of genetic counselors and consumers

1510 Background: BRCA1/2 test results have historically been disclosed in person (IPD) by a certified genetic counselor (GC). Greater consumer demand and access to BRCA1/2 testing, and greater prevalence and acceptance of telemedicine, have interested providers in conducting BRCA1/2 testing and disclosing results by telephone (TD) and internet. GC and consumer experiences and opinions about TD have not been well described. Methods: To determine experience, opinions and interest in TD of BRCA1/2 test results we conducted semi-structured interviews with 194 GC recruited via NSGC Cancer Special Interest Group and with 30 consumers (to date) less than 9 months post IPD of BRCA1/2 test results at two cancer centers. Descriptive statistics characterize GC and consumer experiences and opinions. Results: 98% GC had provided TD; 46% rarely. Most frequent reasons for TD: perceived consumer hardship of IPD (n = 190); consumer preference (n = 49) and medical benefit (n = 30). GC comfort with TD varied by test result (true negative [TN] 77%, indeterminate [IND] 49%; mutation carriers [MC] 37%; variant of unknown significance [VUS] 33%). GC cited consumer convenience (n = 132), medical (n = 71) and psychological benefit (n = 42), and greater GC counseling capacity (n = 33) as TD advantages. No nonverbal communication (n = 161), poorer communication/understanding (n = 67), and difficulty explaining complex results (n = 41) were disadvantages GC most frequently reported. 46% post-IPD consumers reported interest in TD; interest varied by test result (VUS 67%; IND, 63%; TN 57%; MC 25%). Consumers’ perceived advantages: convenience (n = 22) and medical benefit (n = 9); and disadvantage to TD; lack of visual and personal connection with GC (n = 18). Conclusions: Results of the ongoing study suggest many consumers of BRCA1/2 testing are interested in, and nearly all GC have conducted, TD. GC and consumers share perceptions of TD convenience, and of challenges of lack of visual cues, however, GC comfort with, and consumer preference for, TD vary differently by test result. Given consumer and provider interest, longitudinal study of TD impact on knowledge, risk perception, communication, and health behaviors, and their mediators will be critical to develop policy and procedures optimizing adaptive responses to TD. No significant financial relationships to disclose. </jats:p