Joyce O'Shaughnessy M.D.

Quist, J., H. Mirza, M. C. U. Cheang, M. L. Telli, J. A. O’Shaughnessy, C. J. Lord, A. N. J. Tutt and A. Grigoriadis (2019). “A Four-gene Decision Tree Signature Classification of Triple-negative Breast Cancer: Implications for Targeted Therapeutics.” Mol Cancer Ther 18(1): 204-212.

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The molecular complexity of triple-negative breast cancers (TNBCs) provides a challenge for patient management. We set out to characterize this heterogeneous disease by combining transcriptomics and genomics data, with the aim of revealing convergent pathway dependencies with the potential for treatment intervention. A Bayesian algorithm was used to integrate molecular profiles in two TNBC cohorts, followed by validation using five independent cohorts (n = 1,168), including three clinical trials. A four-gene decision tree signature was identified, which robustly classified TNBCs into six subtypes. All four genes in the signature (EXO1, TP53BP2, FOXM1, and RSU1) are associated with either genomic instability, malignant growth, or treatment response. One of the six subtypes, MC6, encompassed the largest proportion of tumors ( approximately 50%) in early diagnosed TNBCs. In TNBC patients with metastatic disease, the MC6 proportion was reduced to 25%, and was independently associated with a higher response rate to platinum-based chemotherapy. In TNBC cell line data, platinum sensitivity was recapitulated, and a sensitivity to the inhibition of the phosphatase PPM1D was revealed. Molecularly, MC6-TNBCs displayed high levels of telomeric allelic imbalances, enrichment of CD4(+) and CD8(+) immune signatures, and reduced expression of genes negatively regulating the MAPK signaling pathway. These observations suggest that our integrative classification approach may identify TNBC patients with discernible and theoretically pharmacologically tractable features that merit further studies in prospective trials.

Di Leo, A., J. O’Shaughnessy, G. W. Sledge, Jr., M. Martin, Y. Lin, M. Frenzel, M. C. Hardebeck, I. C. Smith, A. Llombart-Cussac, M. P. Goetz and S. Johnston (2018). “Prognostic characteristics in hormone receptor-positive advanced breast cancer and characterization of abemaciclib efficacy.” NPJ Breast Cancer 4: 41.

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CDK4 & 6 inhibitors have enhanced the effectiveness of endocrine therapy (ET) in patients with advanced breast cancer (ABC). This paper presents exploratory analyses examining patient and disease characteristics that may inform in whom and when abemaciclib should be initiated. MONARCH 2 and 3 enrolled women with HR+, HER2- ABC. In MONARCH 2, patients whose disease had progressed while receiving ET were administered fulvestrant+abemaciclib/placebo. In MONARCH 3, patients received a nonsteroidal aromatase inhibitor+abemaciclib/placebo as initial therapy for advanced disease. A combined analysis of the two studies was performed to determine significant prognostic factors. Efficacy results (PFS and ORR in patients with measurable disease) were examined for patient subgroups corresponding to each significant prognostic factor. Analysis of clinical factors confirmed the following to have prognostic value: bone-only disease, liver metastases, tumor grade, progesterone receptor status, performance status, treatment-free interval (TFI) from the end of adjuvant ET, and time from diagnosis to recurrence. Prognosis was poorer in patients with liver metastases, progesterone receptor-negative tumors, high grade tumors, or short TFI (<36 months). Benefit (PFS hazard ratio, ORR increase) from abemaciclib was observed in all patient subgroups. Patients with indicators of poor prognosis had the largest benefit from the addition of abemaciclib. However, in MONARCH 3, for patients with certain good prognostic factors (TFI >/= 36 months, bone-only disease) ET achieved a median PFS of >20 months. These analyses identified prognostic factors and demonstrated that patients with poor prognostic factors derived the largest benefit from the addition of abemaciclib.

Adams, S., P. Schmid, H. S. Rugo, E. P. Winer, D. Loirat, A. Awada, D. W. Cescon, H. Iwata, M. Campone, R. Nanda, R. Hui, G. Curigliano, D. Toppmeyer, J. O’Shaughnessy, S. Loi, S. Paluch-Shimon, A. R. Tan, D. Card, J. Zhao, V. Karantza and J. Cortes (2018). “Pembrolizumab Monotherapy for Previously Treated Metastatic Triple-Negative Breast Cancer: Cohort A of the Phase 2 KEYNOTE-086 Study.” Ann Oncol Nov 26. [Epub ahead of print].

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Background: Treatment options for previously treated metastatic triple-negative breast cancer (mTNBC) are limited. In cohort A of the phase 2 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 endpoints were objective response rate (ORR) in the total and PD-L1-positive populations, and safety. Secondary endpoints included duration of response, disease control rate (DCR; percentage of patients with complete or partial response or stable disease for >/=24 weeks), progression-free survival (PFS), and overall survival (OS). 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. DCR (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, 7.7-11.2), and the 6-month rate was 69.1%. Treatment-related adverse events (AEs) 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, NCT02447003.

Quist, J., H. Mirza, M. C. U. Cheang, M. L. Telli, J. O’Shaughnessy, C. J. Lord, A. N. J. Tutt and A. Grigoriadis (2018). “A four-gene decision tree signature classification of triple-negative breast cancer: Implications for targeted therapeutics.” Mol Cancer Ther Oct 10. [Epub ahead of print].

Full text of this article.

The molecular complexity of triple-negative breast cancers (TNBCs) provides a challenge for patient management. We set out to characterise this heterogeneous disease by combining transcriptomics and genomics data, with the aim of revealing convergent pathway dependencies with the potential for treatment intervention. A Bayesian algorithm was used to integrate molecular profiles in two TNBC cohorts, followed by validation using five independent cohorts (n = 1,168), including three clinical trials. A four-gene decision tree signature was identified which robustly classified TNBCs into six subtypes. All four genes in the signature (EXO1, TP53BP2, FOXM1 and RSU1) are associated with either genomic instability, malignant growth, or treatment response. One of the six subtypes, MC6, encompassed the largest proportion of tumours (~50%) in early diagnosed TNBCs. In TNBC patients with metastatic disease, the MC6 proportion was reduced to 25%, and was independently associated with a higher response rate to platinum-based chemotherapy. In TNBC cell line data, platinum-sensitivity was recapitulated, and a sensitivity to the inhibition of the phosphatase PPM1D was revealed. Molecularly, MC6-TNBCs displayed high levels of telomeric allelic imbalances, enrichment of CD4+ and CD8+ immune signatures, and reduced expression of genes negatively regulating the mitogen-activated protein kinase (MAPK) signalling pathway. These observations suggest that our integrative classification approach may identify TNBC patients with discernible and theoretically pharmacologically tractable features that merit further studies in prospective trials.

Eustace, A. J., N. T. Conlon, M. S. J. McDermott, B. C. Browne, P. O’Leary, F. A. Holmes, V. Espina, L. A. Liotta, J. O’Shaughnessy, C. Gallagher, L. O’Driscoll, S. Rani, S. F. Madden, N. A. O’Brien, C. Ginther, D. Slamon, N. Walsh, W. M. Gallagher, R. Zagozdzon, W. R. Watson, N. O’Donovan and J. Crown (2018). “Development of acquired resistance to lapatinib may sensitise HER2-positive breast cancer cells to apoptosis induction by obatoclax and TRAIL.” BMC Cancer 18(1): 965.

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BACKGROUND: Lapatinib has clinical efficacy in the treatment of trastuzumab-refractory HER2-positive breast cancer. However, a significant proportion of patients develop progressive disease due to acquired resistance to the drug. Induction of apoptotic cell death is a key mechanism of action of lapatinib in HER2-positive breast cancer cells. METHODS: We examined alterations in regulation of the intrinsic and extrinsic apoptosis pathways in cell line models of acquired lapatinib resistance both in vitro and in patient samples from the NCT01485926 clinical trial, and investigated potential strategies to exploit alterations in apoptosis signalling to overcome lapatinib resistance in HER2-positive breast cancer. RESULTS: In this study, we examined two cell lines models of acquired lapatinib resistance (SKBR3-L and HCC1954-L) and showed that lapatinib does not induce apoptosis in these cells. We identified alterations in members of the BCL-2 family of proteins, in particular MCL-1 and BAX, which may play a role in resistance to lapatinib. We tested the therapeutic inhibitor obatoclax, which targets MCL-1. Both SKBR3-L and HCC1954-L cells showed greater sensitivity to obatoclax-induced apoptosis than parental cells. Interestingly, we also found that the development of acquired resistance to lapatinib resulted in acquired sensitivity to TRAIL in SKBR3-L cells. Sensitivity to TRAIL in the SKBR3-L cells was associated with reduced phosphorylation of AKT, increased expression of FOXO3a and decreased expression of c-FLIP. In SKBR3-L cells, TRAIL treatment caused activation of caspase 8, caspase 9 and caspase 3/7. In a second resistant model, HCC1954-L cells, p-AKT levels were not decreased and these cells did not show enhanced sensitivity to TRAIL. Furthermore, combining obatoclax with TRAIL improved response in SKBR3-L cells but not in HCC1954-L cells. CONCLUSIONS: Our findings highlight the possibility of targeting altered apoptotic signalling to overcome acquired lapatinib resistance, and identify potential novel treatment strategies, with potential biomarkers, for HER2-positive breast cancer that is resistant to HER2 targeted therapies.