Genomic instability is a key hallmark of cancer that arises owing to defects in the DNA damage response (DDR) and/or increased replication stress. These alterations promote the clonal evolution of cancer cells via the accumulation of driver aberrations, including gene copy-number changes, rearrangements and mutations; however, these same defects also create vulnerabilities that are relatively specific to cancer cells, which could potentially be exploited to increase the therapeutic index of anticancer treatments and thereby improve patient outcomes. The discovery that BRCA-mutant cancer cells are exquisitely sensitive to inhibition of poly(ADP-ribose) polymerase has ushered in a new era of research on biomarker-driven synthetic lethal treatment strategies for different cancers. The therapeutic landscape of antitumour agents targeting the DDR has rapidly expanded to include inhibitors of other key mediators of DNA repair and replication, such as ATM, ATR, CHK1 and CHK2, DNA-PK and WEE1. Efforts to optimize these therapies are ongoing across a range of cancers, involving the development of predictive biomarker assays of responsiveness (beyond BRCA mutations), assessment of the mechanisms underlying intrinsic and acquired resistance, and evaluation of rational, tolerable combinations with standard-of-care treatments (such as chemotherapeutics and radiation), novel molecularly targeted agents and immune-checkpoint inhibitors. In this Review, we discuss the current status of anticancer therapies targeting the DDR.

State-of-the-art strategies for targeting the DNA damage response in cancer

Tumors evolve in close interaction with their microenvironment, which encompasses a continual tension between the developing tumor and the host immune system. Clinical trials have shown that appropriate enhancement of a tumor immune response can lead to long-lasting clinical responses and patient benefit. Understanding the contribution of the immune contexture, in addition to the molecular subtype across different tumor indications, is a significant knowledge gap with limited sagacity to drive rational immunotherapy combinations. To better inform clinical studies, we must first strive to understand the multifaceted elements of the tumor-immune interaction, the spatiotemporal interplay of numerous different immune cell types, in conjunction with an understanding of the oncogenic drivers and mutations that may lead to presentation of neoepitopes and could drive changes within the tumor microenvironment. In this review, we discuss the Immunoscore and its probable universal characteristic. The overlay of immune quantification with the molecular segments of disease and how this may benefit identification of patients at high risk of tumor recurrence will be discussed. The Immunoscore may translate to provide a tumor agnostic method to define immune fitness of a given tumor and predict and stratify patients who will benefit from certain therapies (in particular immune therapies) and, ultimately, help save the lives of patients with cancer.

/pdf/the-immunoscore-colon-cancer-and-beyond-55vo116716.pdf

The Immunoscore: Colon Cancer and Beyond

Importance There is tremendous interest in using immunotherapy to treat breast cancer, as evidenced by the more than 290 clinical trials ongoing at the time of this narrative review. The objective of this review is to describe the current status of immunotherapy in breast cancer, highlighting its potential in both early-stage and metastatic disease. Observations After searching ClinicalTrials.gov on April 24, 2018, and PubMed up to June 30, 2018, to identify breast cancer immunotherapy trials, we found that immune checkpoint blockade (ICB) is the most investigated form of immunotherapy in breast cancer. Use of ICB as monotherapy has achieved objective responses in patients with breast cancer, with higher rates seen when administered in earlier lines of therapy. For responding patients, those responses are durable. More recent data suggest clinical efficacy when ICB is given in combination with chemotherapy. Ongoing studies are evaluating combination strategies pairing ICB with additional chemotherapeutic agents, targeted therapy, vaccines, and local ablative therapies to enhance response. To date, robust predictive biomarkers for response to ICB have not been established. Conclusions and Relevance It is anticipated that combination therapy strategies will be the way forward for immunotherapy in breast cancer, with an improved understanding of tumor, microenvironment, and host factors informing treatment combination decisions. Thoughtful study design incorporating appropriate end points and correlative studies will be critical in identifying optimal strategies for enhancing the immune response against breast tumors.

Current Landscape of Immunotherapy in Breast Cancer: A Review

Summary Background Poly (ADP-ribose) polymerase inhibitors combined with immunotherapy have shown antitumour activity in preclinical studies. We aimed to assess the safety and activity of olaparib in combination with the PD-L1-inhibitor, durvalumab, in patients with germline BRCA1-mutated or BRCA2-mutated metastatic breast cancer. Methods The MEDIOLA trial is a multicentre, open-label, phase 1/2, basket trial of durvalumab and olaparib in solid tumours. Patients were enrolled into four initial cohorts: germline BRCA-mutated, metastatic breast cancer; germline BRCA-mutated, metastatic ovarian cancer; metastatic gastric cancer; and relapsed small-cell lung cancer. Here, we report on the cohort of patients with breast cancer. Patients who were aged 18 years or older (or aged 19 years or older in South Korea) with germline BRCA1-mutated or BRCA2-mutated or both and histologically confirmed, progressive, HER2-negative, metastatic breast cancer were enrolled from 14 health centres in the UK, the USA, Israel, France, Switzerland, and South Korea. Patients should not have received more than two previous lines of chemotherapy for metastatic breast cancer. Patients received 300 mg olaparib in tablet form orally twice daily for 4 weeks and thereafter a combination of olaparib 300 mg twice daily and durvalumab 1·5 g via intravenous infusion every 4 weeks until disease progression. Primary endpoints were safety and tolerability, and 12-week disease control rate. Safety was analysed in patients who received at least one dose of study treatment, and activity analyses were done in the full-analysis set (patients who received at least one dose of study treatment and were not excluded from the study). Recruitment has completed and the study is ongoing. This trial is registered with ClinicalTrials.gov, NCT02734004. Findings Between June 14, 2016, and May 2, 2017, 34 patients were enrolled and received both study drugs and were included in the safety analysis. 11 (32%) patients experienced grade 3 or worse adverse events, of which the most common were anaemia (four [12%]), neutropenia (three [9%]), and pancreatitis (two [6%]). Three (9%) patients discontinued due to adverse events and four (12%) patients experienced a total of six serious adverse events. There were no treatment-related deaths. 24 (80%; 90% CI 64·3–90·9) of 30 patients eligible for activity analysis had disease control at 12 weeks. Interpretation Combination of olaparib and durvalumab showed promising antitumour activity and safety similar to that previously observed in olaparib and durvalumab monotherapy studies. Further research in a randomised setting is needed to determine predictors of therapeutic benefit and whether addition of durvalumab improves long-term clinical outcomes compared with olaparib monotherapy. Funding AstraZeneca.

Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): an open-label, multicentre, phase 1/2, basket study.

Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer. TNBC is a heterogenous subtype of breast cancer that is beginning to be refined by its molecular characteristics and clinical response to a targeted therapeutic approach. Until recently the backbone of therapy against TNBC has been cytotoxic chemotherapy. However, the breast oncology community is now seeing encouraging clinical activity from molecularly targeted approaches to TNBC. Recently, we have seen 3 newly approved targeted therapies for TNBC, including the PARP inhibitors olaparib and talazoparib for germline BRCA mutation associated breast cancer (gBRCAm-BC) and most recently the checkpoint inhibitor, atezolizumab in combination with nab-paclitaxel for programmed death-ligand 1 (PD-L1+) advanced TNBC. Improved biomarkers are needed to inform better patient selection for treatment with checkpoint inhibition. Higher response rates are seen when checkpoint inhibitors are combined with chemotherapy in the first-line setting and the use of these agents at an earlier stage of the disease does show promise. Antibody-drug conjugates are generating much excitement and may allow re-examination of prior cytotoxics that failed in development due to toxicity. Tumor sequencing is identifying potential molecular targets and ongoing studies are evaluating novel small molecule agents in this field such as AKT inhibition and many others. The treatment paradigm of chemotherapy as “one size fits all” approach for management of TNBC is changing based on molecular subtyping. Soon, the term TNBC may no longer be appropriate, as this heterogenous subtype of breast cancer is further refined by its molecular characteristics and clinical response to a targeted therapeutic approach.

Targeted Therapies for Triple-Negative Breast Cancer

Background Olaparib is a potent poly(ADP-ribose) polymerase (PARP) inhibitor, with first-in-class approval (400 mg capsules BID) for BRCA-mutated advanced ovarian cancer. Olaparib was recently found to be superior compared with chemotherapy in HER2-negative gBRCAm MBC in the Phase III OlympiAD trial. Olaparib induces DNA damage and genomic instability in gBRCAm tumors, which is hypothesized to result in enhanced immunogenicity. Here, we assess if a combination of olaparib and an anti-programmed cell death ligand-1 (PD-L1) agent, durvalumab, leads to enhanced antitumor activity in one of the four cohorts (NCT02734004). Methods Individuals with deleterious gBRCA1 or BRCA2 mutations and HER2-negative MBC were eligible. Patients with prior platinum therapy were allowed to enter if they had not experienced disease progression on platinum. No more than two prior lines of chemotherapy were allowed for metastatic disease, and patients with hormone receptor (HR) positive disease had to have at least one line of prior endocrine therapy. Concomitant use of endocrine therapy was not allowed. All patients received olaparib tablets 300 mg PO BID for a 4-week run-in, followed by a combination of olaparib 300 mg PO BID and durvalumab 1.5 g IV q 4 weeks. The combination was continued until progressive disease (PD) by RECIST 1.1 criteria. Tumor assessments were done at baseline, 4 weeks and every 8 weeks thereafter. The primary endpoint was disease control rate (DCR) at 12 weeks, and safety and tolerability of the combination. The secondary endpoints included DCR at 28 weeks, objective response rate, duration of response, progression-free survival (PFS) and overall survival. Biomarker endpoints included PD-L1 expression and evaluation of tumor infiltrating lymphocytes. Olaparib monotherapy has previously demonstrated a median PFS (mPFS) of 6 months in this patient population, and addition of durvalumab was predicted to increase the mPFS to 7.5 months, corresponding to a target DCR of 75% at 12 weeks. This was achievable by enrolling 30 patients using a Bayesian predictive probability design. Results of the first 25 patients are presented. Results Median age was 46 years (range 29−66); 11 and 14 patients had BRCA1 and BRCA2 mutations, respectively; 13 patients had HR positive disease, and nine had previously received platinum therapy. Median number of prior chemotherapy lines was 1 (range 0-4). Grade 3 or higher adverse events (AEs) were anemia (8%), neutropenia (8%), hemolysis (4%), dyspnea (4%), pancreatitis (4%), fatigue (4%), lymphopenia (4%) and leukopenia (4%). There was one grade 5 AE (dyspnea), which was attributed to disease progression. Observed DCR at 12 weeks was 80%. Eight confirmed responses and five unconfirmed responses were seen. The updated results from primary and secondary endpoints, including DCR at 28 weeks, as well as biomarker and PK data, will be presented. Conclusions The combination of olaparib and durvalumab was well tolerated, with no apparent overlapping toxicities. The efficacy of the combination at an early time point reached the target DCR in gBRCAm HER2-negative MBC, and warrants further investigation. Citation Format: Domchek SM, Postel-Vinay S, Bang Y-J, Park YH, Alexandre J, Delord J-P, Italiano A, You B, Bastian S, Krebs M, Wang D, Waqar S, Angell H, Learoyd M, Chang S-C, Gresty C, Herbolsheimer P, Kaufman B. An open-label, multitumor, phase II basket study of olaparib and durvalumab (MEDIOLA): Results in germline BRCA-mutated (gBRCAm) HER2-negative metastatic breast cancer (MBC) [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 PD6-11.

Abstract PD6-11: An open-label, multitumor, phase II basket study of olaparib and durvalumab (MEDIOLA): Results in germline BRCA-mutated (gBRCAm) HER2-negative metastatic breast cancer (MBC)

P1.15-004 An Open-Label, Multitumor Phase II Basket Study of Olaparib and Durvalumab (MEDIOLA): Results in Patients with Relapsed SCLC

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Abstract PD6-11: An open-label, multitumor, phase II basket study of olaparib and durvalumab (MEDIOLA): Results in germline BRCA-mutated (gBRCAm) HER2-negative metastatic breast cancer (MBC)

P1.15-004 An Open-Label, Multitumor Phase II Basket Study of Olaparib and Durvalumab (MEDIOLA): Results in Patients with Relapsed SCLC