Anne C Armstrong

Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial

BACKGROUND Disease progression in patients with HER2-positive breast cancer receiving trastuzumab might be associated with activation of the PI3K/Akt/mTOR intracellular signalling pathway. We aimed to assess whether the addition of the mTOR inhibitor everolimus to trastuzumab might restore sensitivity to trastuzumab. METHODS In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited women with HER2-positive, trastuzumab-resistant, advanced breast carcinoma who had previously received taxane therapy. Eligible patients were randomly assigned (1:1) using a central patient screening and randomisation system to daily everolimus (5 mg/day) plus weekly trastuzumab (2 mg/kg) and vinorelbine (25 mg/m(2)) or to placebo plus trastuzumab plus vinorelbine, in 3-week cycles, stratified by previous lapatinib use. The primary endpoint was progression-free survival (PFS) by local assessment in the intention-to-treat population. We report the final analysis for PFS; overall survival follow-up is still in progress. This trial is registered with ClinicalTrials.gov, number NCT01007942. FINDINGS Between Oct 26, 2009, and May 23, 2012, 569 patients were randomly assigned to everolimus (n=284) or placebo (n=285). Median follow-up at the time of analysis was 20.2 months (IQR 15.0-27.1). Median PFS was 7.00 months (95% CI 6.74-8.18) with everolimus and 5.78 months (5.49-6.90) with placebo (hazard ratio 0.78 [95% CI 0.65-0.95]; p=0.0067). The most common grade 3-4 adverse events were neutropenia (204 [73%] of 280 patients in the everolimus group vs 175 [62%] of 282 patients in the placebo group), leucopenia (106 [38%] vs 82 [29%]), anaemia (53 [19%] vs 17 [6%]), febrile neutropenia (44 [16%] vs ten [4%]), stomatitis (37 [13%] vs four [1%]), and fatigue (34 [12%] vs 11 [4%]). Serious adverse events were reported in 117 (42%) patients in the everolimus group and 55 (20%) in the placebo group; two on-treatment deaths due to adverse events occurred in each group. INTERPRETATION The addition of everolimus to trastuzumab plus vinorelbine significantly prolongs PFS in patients with trastuzumab-resistant and taxane-pretreated, HER2-positive, advanced breast cancer. The clinical benefit should be considered in the context of the adverse event profile in this population.

Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation

BACKGROUND Olaparib is an oral poly(adenosine diphosphate–ribose) polymerase inhibitor that has promising antitumor activity in patients with metastatic breast cancer and a germline BRCA mutation. METHODS We conducted a randomized, open‐label, phase 3 trial in which olaparib monotherapy was compared with standard therapy in patients with a germline BRCA mutation and human epidermal growth factor receptor type 2 (HER2)–negative metastatic breast cancer who had received no more than two previous chemotherapy regimens for metastatic disease. Patients were randomly assigned, in a 2:1 ratio, to receive olaparib tablets (300 mg twice daily) or standard therapy with single‐agent chemotherapy of the physicians choice (capecitabine, eribulin, or vinorelbine in 21‐day cycles). The primary end point was progression‐free survival, which was assessed by blinded independent central review and was analyzed on an intention‐to‐treat basis. RESULTS Of the 302 patients who underwent randomization, 205 were assigned to receive olaparib and 97 were assigned to receive standard therapy. Median progression‐free survival was significantly longer in the olaparib group than in the standard‐therapy group (7.0 months vs. 4.2 months; hazard ratio for disease progression or death, 0.58; 95% confidence interval, 0.43 to 0.80; P<0.001). The response rate was 59.9% in the olaparib group and 28.8% in the standard‐therapy group. The rate of grade 3 or higher adverse events was 36.6% in the olaparib group and 50.5% in the standard‐therapy group, and the rate of treatment discontinuation due to toxic effects was 4.9% and 7.7%, respectively. CONCLUSIONS Among patients with HER2‐negative metastatic breast cancer and a germline BRCA mutation, olaparib monotherapy provided a significant benefit over standard therapy; median progression‐free survival was 2.8 months longer and the risk of disease progression or death was 42% lower with olaparib monotherapy than with standard therapy. (Funded by AstraZeneca; OlympiAD ClinicalTrials.gov number, NCT02000622.)

Detection of PIK3CA mutations in circulating free DNA in patients with breast cancer.

Somatic mutations in PIK3CA (encoding a class I phosphoinositide 3 kinase (PI3K) subunit) modulate PI3K signalling to influence tumour behaviour and occur in up to 40% of breast cancers. Inhibitors of PI3K signalling are entering clinical trials, but the impact of PIKC3A mutation on tumour response has yet to be clarified. This study investigated the potential utility of circulating free DNA (cfDNA) as a source for PIK3CA mutation detection in patients with breast cancer. cfDNA extracted (QIAamp Virus spin kit) from blood and matched archival tumour from 46 patients with metastatic breast cancer and 30 patients with localised, operable breast cancer was assessed for hotspot PIK3CA mutations using Amplification Refractory Mutation System (ARMS™) allele-specific PCR and Scorpion probes. PIK3CA mutations were detected in 13/46 (28%) plasma-derived and 10/46 (21%) serum-derived cfDNA samples from metastatic breast cancer patients. In 41 cases with matched tumour and plasma-derived cfDNA data, concordance (same mutation status in plasma and tumour) was 95%. Where a PIK3CA mutation was present in tumour, the ‘pick up’ in plasma-derived cfDNA was 80%. PIK3CA mutations were present in tumours from 14/30 (47%) localised breast cancers, but no PIK3CA mutations were detected in matched cfDNA. These data demonstrate feasibility and potential utility of cfDNA for PIK3CA mutation detection in patients with metastatic breast cancer. Studies are underway to qualify PIK3CA mutation in cfDNA as a predictive biomarker allowing patient stratification in clinical trials of mechanism-based therapeutics that target PI3K signalling pathways.

Immunization with a Recombinant Adenovirus Encoding a Lymphoma Idiotype: Induction of Tumor-Protective Immunity and Identification of an Idiotype-Specific T Cell Epitope

The Ig Id of a B cell lymphoma is a tumor-specific Ag, although as a self-Ag it is likely to be a weak immunogen. Provision of a foreign gene may enhance the immunogenicity of the idiotype. Viral vectors allow highly efficient transfer of genetic material and are themselves innately immunogenic. We have investigated the ability of recombinant adenoviral vectors, encoding the idiotypic gene with or without fusion to the human Fc region, to produce anti-idiotypic Ab- and T cell-mediated responses in a syngeneic BALB/c A20 murine lymphoma model. The idiotypic VH and VL sequences were assembled as a single chain variable fragment (scFv) and adenoviral vectors encoding the A20 scFv (Ad.A20) and A20 scFv linked to the Fc fragment of human IgG1 (Ad.A20hFc) were constructed. A single immunization of BALB/c mice with Ad.A20hFc but not Ad.A20 induced a specific anti-idiotypic Ab response. T cell lines generated from mice vaccinated with either vector displayed specific cytotoxicity, proliferation, and IFN-γ release against a syngeneic dendritic cell line transduced using a retroviral vector to express the A20 scFv idiotype (XS52.A1.A20). Importantly, both T cell lines lysed the A20 lymphoma cells. An immunodominant H-2Kd-restricted CD8+ T cell peptide, DYWGQGTEL (A20[106–114]), was identified as a naturally occurring A20 scFv epitope. A single immunization with Ad.A20hFc but not Ad.A20 provided protection in >40% of animals challenged with a lethal dose of the A20 tumor line and was more effective, in this model, than a previously optimized plasmid vaccine.

Facilitating reproductive choices: the impact of health services on the experiences of young women with breast cancer

Objective: Chemotherapy and hormone treatments carry significant implications on the fertility of young women with breast cancer. Increasingly, nulliparous women experience fertility dilemmas due to rising survival rates and pregnancy delay. This qualitative study investigated womens responses to being told that treatments affected their fertility and how their interactions with health services impacted on their experiences.

Use of adenoviruses encoding CD40L or IL-2 against B cell lymphoma

Some B cell lymphomas lack important costimulatory properties that could prevent them from being used as cell based vaccines. Infection of A20 B lymphoma cells with a replication‐defective adenovirus encoding murine (m) CD40L, but not mIL‐2, produces an antigen presentation phenotype with upregulation of MHC Class I/II, induction of B7‐1/2 molecules and production of MIL‐12 and MIP‐1α. Subcutaneous vaccination with irradiated Ad‐mCD40L‐infected‐ or Ad‐mIL‐2‐infected‐A20 cells generated A20‐specific CD8+ T cell responses and cross reactive A20 Ig antibodies. Only vaccination with Ad‐mCD40L‐infected A20 cells produced a significant delay in tumor growth and long‐term survival (p = 0.0039). Stronger protective immunity to A20 challenge was generated by intravenous priming with A20 cells infected with Ad‐mCD40L, Ad‐mIL‐2 or their combination followed by a boost immunization with A20 cells activated with syngeneic fibroblasts expressing CD40L. Compared to Ad‐LacZ‐infected A20 priming, the combination priming was most effective followed by Ad‐mCD40L and Ad‐mIL‐2 (p = 0.0027, p = 0.0027, p = 0.0163 respectively). Significant A20‐specific CD8+ T cell‐mediated cytotoxicity was only demonstrated in splenocytes from these groups of vaccinated animals. By contrast, ELISPOT assay of splenocytes from all A20 prime/boosted vaccinated groups demonstrated increases in γ‐interferon release by T cells elicited by in vitro stimulation either with A20 cells or another syngeneic 2PK‐3 lymphoma, indicating the presence of cross reactive immunity. Similarly anti‐A20 immunoglobulin antibodies generated after vaccination were not necessarily A20 idiotype‐specific. Direct therapy of pre‐established tumors was achieved with the combination of Ad‐mCD40L and Ad‐mIL‐2 given at Days 4 and 8 at the tumor site with a significant long‐term survival of 85% of tumor‐bearing mice (p = 0.0001). Our study strongly supports the use of Ad‐CD40L and Ad‐IL‐2 combination therapy for the treatment of patients with B cell lymphoma.

Adoptive transfer of anti-idiotypic T cells cure mice of disseminated B cell lymphoma.

Abstract: There is extensive interest in idiotypic vaccination as a treatment of lymphoma. An alternative approach is the adoptive transfer of in vitro generated T cells. This strategy has been used to treat posttransplantation EBV-related diseases. 1 The ability to generate in vitro T cells to peptides derived from immunoglobulin idiotypes raises the possibility of directly using such cells as a treatment of lymphoma. 2 Investigating the adoptive transfer of specific T cells to idiotype derived peptides in a murine lymphoma model is therefore an important part of the clinical translation of this alternative approach. We have generated an idiotype-specific T cell line, able to recognise a defined, naturally processed idiotype-derived epitope. This line has been used to successfully treat mice with disseminated lymphoma supporting the clinical use of idiotype specific T cells.

Developing effective cancer vaccines: design and monitoring are critical

Published in this edition of the BJC are the results of a randomized phase II vaccine trial for patients with colorectal cancer. The trial, one of the largest to date, investigated the use of an anti-idiotypic antibody mimicking a tumour-associated antigen, in patients with advanced colorectal cancer. No survival advantage was demonstrated with the use of the vaccine. In an age where there is increased interest in the use of cancer vaccines it is important to assess the justification for their continued development. Vaccine immunology Central to the renewed interest in cancer vaccine therapy is the increased understanding of mechanisms involved in an antigenspecific T-cell response, with animal studies demonstrating that although the humoral immune system may be relevant, it is cellmediated immunity that is of critical importance in tumour protection (Golumbek et al, 1991; Dranoff et al, 1993). T cells recognize antigen only when displayed on the surface of the target cell or antigen-presenting cell as peptide fragments bound to the class I and II molecules of the major histocompatibility complex (MHC). MHC antigens are highly polymorphic, with different alleles binding different peptide epitopes derived from the tumour antigen. Class I MHC molecules, recognized by cytotoxic CD8 + T

Phase 1B/2 study of the HSP90 inhibitor AUY922 plus trastuzumab in metastatic HER2-positive breast cancer patients who have progressed on trastuzumab-based regimen.

This open-label, multicenter, phase 1B/2 trial assessed AUY922 plus trastuzumab in patients with locally advanced or metastatic HER2-positive breast cancer previously treated with chemotherapy and anti-HER2 therapy. This study was composed of a dose-escalation part with AUY922 administered weekly at escalating doses with trastuzumab 2 mg/kg/week (phase 1B), followed by a phase 2 part using the same regimen at recommended phase 2 dose (RP2D). The primary objectives were to determine the maximum tolerated dose (MTD) and/or RP2D (phase 1B), and to evaluate preliminary antitumor activity (phase 2) of AUY922 plus trastuzumab at MTD/RP2D. Forty-five patients were treated with AUY922 plus trastuzumab (4 in phase 1B with AUY922 at 55 mg/m2 and 41 in phase 1B/2 with AUY922 at 70 mg/m2 [7 in phase 1B and 34 in phase 2]). One patient in phase 1B (70 mg/m2) experienced a dose-limiting toxicity (grade 3 diarrhea); the RP2D was weekly AUY922 70 mg/m2 plus trastuzumab. Of the 41 patients in the 70 mg/m2 cohort, the overall response rate (complete or partial responses) was 22.0% and 48.8% patients had stable disease. Study treatment-related adverse events occurred in 97.8% of patients; of these, 31.1% were grade 3 or 4. Forty-one patients (91.1%) reported ocular events (82.3% had grade 1 or 2 events). Two patients (4.4%) had ocular events leading to the permanent discontinuation of study treatment. AUY922 at 70 mg/m2 plus trastuzumab standard therapy is well tolerated and active in patients with HER2-positive metastatic breast cancer who progressed on trastuzumab-based therapy.

Abstract B109: AZD5363, a catalytic pan-Akt inhibitor, in Akt1 E17K mutation positive advanced solid tumors

This abstract has been withheld from publication due to its inclusion in the AACR-NCI-EORTC Molecular Targets Conference 2015 Official Press Program. It will be posted online at the time of its presentation in a press conference or in a session: 10:00 AM ET Saturday, November 7. Citation Format: David M. Hyman, Lillian Smyth, Philippe L. Bedard, Amit Oza, Emma Dean, Anne Armstrong, Joao Lima, Hideaki Bando, Peter Kabos, J. Alejandro Perez-Fidalgo, Kathleen Moore, Shannon N. Westin, Benoit You, Sarat Chandarlapaty, Leila Alland, Helen Ambrose, Andrew Foxley, Justin Lindemann, Martin Pass, Paul Rugman, Shaista Salim, Gaia Schiavon, Kenji Tamura, Jose Baselga, Udai Banerji. AZD5363, a catalytic pan-Akt inhibitor, in Akt1 E17K mutation positive advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B109.