Oncolytic virotherapy is a novel treatment for cancer that exerts direct lytic and indirect immune-mediated antitumor effects. A Finnish research team has reported on an advanced therapy access program for oncolytic adenovirus. The strengths and weaknesses of this approach are highlighted with a view to informing future study conduct. Clin Cancer Res; 19(10); 2595–7. ©2013 AACR.

Cancer is not merely a cell-intrinsic genetic disease but also the result of complex cell-extrinsic interactions with host components, including immune cells. For example, effector T lymphocytes and natural killer cells are thought to participate in an immunosurveillance process, which eliminates neoplastic cells, whereas regulatory T lymphocytes and some myeloid cells, including macrophages, can create a milieu that prevents antitumor activity, supports tumor growth, and reduces survival of the host. Increasing evidence supports the notion that carcinoma cells communicate with immune cells directly, both within and away from the tumor stroma, and that this process fosters suppression of immunosurveillance and promotes tumor outgrowth. An important mode of communication between carcinoma cells and immune cells may involve tumor-derived microvesicles (tMV), also known as exosomes, ectosomes, or microparticles. These microvesicles carry lipids, proteins, mRNAs and microRNAs and travel short or long distances to deliver undegraded and undiluted material to other cells. Here, we consider the capacity of tMVs to control tumor-associated immune responses and highlight the known and unknown actions of tMVs in vivo. We also discuss why microvesicles may play a role in cancer diagnostics and prognostics and how they could be harnessed for anticancer therapy. Clin Cancer Res; 19(10); 2598–604. ©2013 AACR.

Progression-free survival (PFS) is increasingly used as an important and even a primary endpoint in randomized cancer clinical trials in the evaluation of patients with solid tumors for both practical and clinical considerations. Although in its simplest form, PFS is the time from randomization to a predefined endpoint, there are many factors that can influence the exact moment of when disease progression is recorded. In this overview, we review the circumstances that can devalue the use of PFS as a primary endpoint and attempt to provide a pathway for a future desired state when PFS will become not just a secondary alternative to overall survival but rather an endpoint of choice. Clin Cancer Res; 19(10); 2607–12. ©2013 AACR.

Progression-free survival (PFS) is frequently used as the primary efficacy endpoint in the evaluation of cancer treatment that is considered for marketing approval. Missing or incomplete data problems become more acute with a PFS endpoint (compared with overall survival). In a given clinical trial, it is common to observe incomplete data due to premature treatment discontinuation, missed or flawed assessments, change of treatment, lack of follow-up, and unevaluable data. When incomplete data issues are substantial, interpretation of the data becomes tenuous. Plans to prevent, minimize, or properly analyze incomplete data are critical for generalizability of results from the clinical trial. Variability in progressive disease measurement between radiologists further contributes to data problems with a PFS endpoint. The repercussions of this on phase III clinical trials are complex and depend on several factors, including the magnitude of the variability and whether there is a systematic reader evaluation bias favoring one treatment arm particularly in open-label trials. Clin Cancer Res; 19(10); 2613–20. ©2013 AACR.

Tumor measurements on computed tomgoraphic or MRI scans and/or the appearance of new lesions on any of a variety of imaging studies including positron emission tomographic scans are key determinants for assessing progression-free survival as an endpoint in many clinical trials of therapies for solid tumors. Test–retest tumor measurement reproducibility may vary considerably across serial scans on the same patient unless rigorous attention is paid to standardization of image acquisition parameters and unless measurements are made by trained, experienced observers using validated objective methods. Target lesion selection also must be done with care to choose lesions that are or will be reproducibly measurable. Likewise, new lesions will be missed or misinterpreted on follow-up imaging studies unless those imaging studies are obtained using techniques suitable for detecting early, small lesions. Reader variability is clearly a major component of the problem. The increasing availability of semiautomatic image processing algorithms will help ameliorate that issue. In addition, an array of internationally accepted guidelines, standards, and accreditation programs now exist to help address these problems. Clin Cancer Res; 19(10); 2621–8. ©2013 AACR.

In selecting an endpoint in clinical trial design, it is important to consider that the endpoint is both reliably measured and clinically meaningful. As such, overall survival (OS) has traditionally been considered the most clinically relevant and convincing endpoint in clinical trial design as long as it is accompanied by preservation in quality of life. However, progression-free survival (PFS) is increasingly more prominent in clinical trial design because of feasibility issues (smaller sample sizes and shorter follow-up). PFS has the advantage of taking into account not only responsive disease, but stable disease as well, an issue of particular importance in the relapsed and refractory setting in which therapies are often associated with a minimal to nil response but may still confer a survival advantage. Finally, PFS has a significant advantage in molecularly selected populations, in whom OS advantages are difficult to detect due to the effects of crossover. With an understanding of the limitations and biases that are introduced with PFS as a primary endpoint, we believe that PFS is not only a viable but also a necessary alternative to OS in assessing the efficacy of selected novel-targeted therapies in molecularly defined cancer populations. Ultimately, the selection of a clinical trial endpoint should not be based on a one-size-fits all approach; rather, it should be based on the specifics of the therapeutic strategy being tested and the population under study. Clin Cancer Res; 19(10); 2629–36. ©2013 AACR.

As progression-free survival (PFS) has become increasingly used as the primary endpoint in oncology phase III trials, the U.S. Food and Drug Administration (FDA) has generally required a complete-case blinded independent central review (BICR) of PFS to assess and reduce potential bias in the investigator or local site evaluation. However, recent publications and FDA analyses have shown a high correlation between local site evaluation and BICR assessments of the PFS treatment effect, which questions whether complete-case BICR is necessary. One potential alternative is to use BICR as an audit tool to detect evaluation bias in the local site evaluation. In this article, the performance characteristics of two audit methods proposed in the literature are evaluated on 26 prospective, randomized phase III registration trials in nonhematologic malignancies. The results support that a BICR audit to assess potential bias in the local site evaluation is a feasible approach. However, implementation and logistical challenges need further consideration and discussion. Clin Cancer Res; 19(10); 2637–45. ©2013 AACR.

The standard phase II trial design has changed dramatically over the past decade. Randomized phase II studies have essentially become the standard phase II design in oncology for a variety of reasons. The use of these designs is motivated by concerns about the use of historical data to determine if a new agent or regimen shows promise of activity. However, randomized phase II designs come with the cost of increased study duration and patient resources. Progression-free survival (PFS) is an important endpoint used in many phase II designs. In many clinical settings, changes in PFS with the introduction of a new treatment may represent true benefit in terms of the gold standard outcome, overall survival (OS). The phase II/III design has been proposed as an approach to shorten the time of discovery of an active regimen. In this article, design considerations for a phase II/III trial are discussed and presented in terms of a model defining the relationship between OS and PFS. The design is also evaluated using 15 phase III trials completed in the Southwest Oncology Group (SWOG) between 1990 and 2005. The model provides a framework to evaluate the validity and properties of using a phase II/III design. In the evaluation of SWOG trials, three of four positive studies would have also proceeded to the final analysis and 10 of 11 negative studies would have stopped at the phase II analysis if a phase II/III design had been used. Through careful consideration and thorough evaluation of design properties, substantial gains could occur using this approach. Clin Cancer Res; 19(10); 2646–56. ©2013 AACR.

Purpose: BAF57, a component of the switching-defective and sucrose nonfermenting (SWI/SNF) chromatin-remodeling complex conglomerate, modulates androgen receptor activity to promote prostate cancer. However, the molecular consequences of tumor-associated BAF57 expression have remained undefined in advanced disease such as castration-resistant prostate cancer and/or metastasis.

Experimental Design: Clinical human specimens of primary and metastatic prostate cancer were immunohistochemically examined for tumor-grade association of BAF57 expression. Global gene expression analyses were conducted in models mimicking tumor-associated BAF57 expression. Aberrant BAF57-dependent gene expression changes, bypass of androgen-mediated signaling, and chromatin-specific SWI/SNF complex alterations with respect to cytoskeletal remodelers such as integrins were validated. Cell migration assays were used to profile the biologic phenotypes conferred under conditions simulating tumor-derived BAF57 expression.

Results: Immunohistochemical quantitation of primary human specimens revealed that BAF57 was significantly and aberrantly elevated as a function of tumor grade. Critically, gene expression analyses showed that BAF57 deregulation circumvented androgen-mediated signaling, elicited α2 integrin upregulation, and altered other SWI/SNF complex components at the α2 integrin locus. BAF57-dependent α2 integrin induction conferred a prometastatic migratory advantage, which was attenuated by anti-α2 integrin antibody blockade. Furthermore, BAF57 was found to be markedly upregulated in human prostate cancer metastases of the lung, lymph node, and dura.

Conclusion: The findings herein, identifying tumor-associated BAF57 perturbation as a means to bypass androgen-signaling events that facilitate novel prometastatic phenotypes, link BAF57 upregulation to tumor dissemination. These data thereby establish BAF57 as a putative marker of metastatic potential that could be leveraged for therapeutic intervention. Clin Cancer Res; 19(10); 2657–67. ©2013 AACR.

Purpose: We queried whether comprehensive genomic profiling using a next-generation sequencing–based assay could identify novel and unanticipated targets of therapy for patients with relapsed invasive lobular carcinoma (ILC).

Experimental Design: DNA sequencing (Illumina HiSeq 2000) was conducted for 3,320 exons of 182 cancer-related genes and 37 introns of 14 genes frequently rearranged in cancer on indexed, adaptor-ligated, hybridization-captured libraries using DNA isolated from formalin-fixed paraffin-embedded sections from 22 histologically verified ILC.

Results: A total of 75 genomic alterations were identified with an average of 3.4 alterations per tumor (range, 1–6), of which 35 were actionable for an average of 1.59 actionable alterations per patient (range, 0–3). Nineteen of 22 (86%) of the ILC samples harbored at least one actionable alteration. Six (27%) cases featured alterations in ERRB2 including 4 (18%) with ERBB2 mutation, 1 (5%) with an ERBB2 gene fusion, and 1 (5%) with an ERBB2 copy number gain (amplification). The enrichment of ERBB2 mutations/fusion in CDH1-mutated ILC (5 of 22, 23%) compared with the 5 ERBB2 mutations in a series of 286 non-CDH1-mutated breast cancers from which the ILC cases were obtained (5 of 286, 2%) was significant (P = 0.0006).

Conclusions: Comprehensive genomic profiling of relapsed CDH1-mutated ILC revealed actionable genomic alterations in 86% of cases, featured a high incidence of ERBB2 alterations, and can reveal actionable alterations that can inform treatment decisions for patients with ILC. Clin Cancer Res; 19(10); 2668–76. ©2013 AACR.

Purpose: To analyze the antimyeloma potential of TG02, an ERK5/CDK inhibitory drug.

Experimental Design: Utilizing different multiple myeloma cell lines we determined the effect of TG02 over viability by MTT assays. The apoptotic effect over multiple myeloma patient samples was studied ex vivo by cytometry. The mechanism of action of TG02 was analyzed in the cell line MM1S, studying its effect on the cell cycle, the induction of apoptosis, and the loss of mitochondrial membrane potential by cytometry and Western blot. Two models of multiple myeloma xenograft were utilized to study the in vivo action of TG02.

Results: TG02 potently inhibited proliferation and survival of multiple myeloma cell lines, even under protective bone marrow niche conditions, and selectively induced apoptosis of primary patient-derived malignant plasma cells. TG02 displayed significant single-agent activity in two multiple myeloma xenograft models, and enhanced the in vivo activity of bortezomib and lenalidomide. Signaling analyses revealed that the drug simultaneously blocked the activity of CDKs 1, 2, and 9 as well as the MAP kinase ERK5 in MM1S cells, leading to cell-cycle arrest and rapid commitment to apoptosis. TG02 induced robust activation of both the intrinsic and extrinsic pathways of apoptosis, and depletion of XIAP and the key multiple myeloma survival protein Mcl-1.

Conclusions: TG02 is a promising new antimyeloma agent that is currently in phase I clinical trials in leukemia and multiple myeloma patients. Clin Cancer Res; 19(10); 2677–87. ©2013 AACR.

Purpose: BRAF^V600E mutations are associated with poor clinical prognosis in colorectal cancer (CRC). Although selective BRAF inhibitors are effective for treatment of melanoma, comparable efforts in CRC have been disappointing. Here, we investigated potential mechanisms underlying this resistance to BRAF inhibitors in BRAF^V600E CRC.

Experimental Design: We examined phosphoinositide 3-kinase (PI3K)/mTOR signaling in BRAF^V600E CRC cell lines after BRAF inhibition and cell viability and apoptosis after combined BRAF and PI3K/mTOR inhibition. We assessed the efficacy of in vivo combination treatment using a novel genetically engineered mouse model (GEMM) for BRAF^V600E CRC.

Results: Western blot analysis revealed sustained PI3K/mTOR signaling upon BRAF inhibition. Our BRAF^V600E GEMM presented with sessile serrated adenomas/polyps, as seen in humans. Combination treatment in vivo resulted in induction of apoptosis and tumor regression.

Conclusions: We have established a novel GEMM to interrogate BRAF^V600E CRC biology and identify more efficacious treatment strategies. Combination BRAF and PI3K/mTOR inhibitor treatment should be explored in clinical trials. Clin Cancer Res; 19(10); 2688–98. ©2013 AACR.

Purpose: An understanding of how hematopoietic cells respond to therapy that causes myelosuppression will help develop approaches to prevent this potentially life-threatening toxicity. The goal of this study was to determine how human myeloid precursor cells respond to temozolomide (TMZ)-induced DNA damage.

Experimental Design: We developed an ex vivo primary human myeloid precursor cells model system to investigate the involvement of cell-death pathways using a known myelosuppressive regimen of O⁶-benzylguanine (6BG) and TMZ.

Results: Exposure to 6BG/TMZ led to increases in p53, p21, -H2AX, and mitochondrial DNA damage. Increases in mitochondrial membrane depolarization correlated with increased caspase-9 and -3 activities following 6BG/TMZ treatment. These events correlated with decreases in activated AKT, downregulation of the DNA repair protein O⁶-methylguanine–DNA methyltransferase (MGMT), and increased cell death. During myeloid precursor cell expansion, FAS/CD95/APO1(FAS) expression increased over time and was present on approximately 100% of the cells following exposure to 6BG/TMZ. Although c-flip_short, an endogenous inhibitor of FAS-mediated signaling, was decreased in 6BG/TMZ–treated versus control, 6BG-, or TMZ alone–treated cells, there were no changes in caspase-8 activity. In addition, there were no changes in the extent of cell death in myeloid precursor cells exposed to 6BG/TMZ in the presence of neutralizing or agonistic anti-FAS antibodies, indicating that FAS-mediated signaling was not operative.

Conclusions: In human myeloid precursor cells, 6BG/TMZ–initiated apoptosis occurred by intrinsic, mitochondrial-mediated and not extrinsic, FAS-mediated apoptosis. Human myeloid precursor cells represent a clinically relevant model system for gaining insight into how hematopoietic cells respond to chemotherapeutics and offer an approach for selecting effective chemotherapeutic regimens with limited hematopoietic toxicity. Clin Cancer Res; 19(10); 2699–709. ©2013 AACR.

Purpose: Effective therapy for malignant melanoma, the leading cause of death from skin cancer, remains an area of significant unmet need in oncology. The elevated expression of PKC in advanced metastatic melanoma results in the increased phosphorylation of the transcription factor ATF2 on threonine 52, which causes its nuclear localization and confers its oncogenic activities. The nuclear-to-mitochondrial translocation of ATF2 following genotoxic stress promotes apoptosis, a function that is largely lost in melanoma cells, due to its confined nuclear localization. Therefore, promoting the nuclear export of ATF2, which sensitizes melanoma cells to apoptosis, represents a novel therapeutic modality.

Experimental Design: We conducted a pilot high-throughput screen of 3,800 compounds to identify small molecules that promote melanoma cell death by inducing the cytoplasmic localization of ATF2. The imaging-based ATF2 translocation assay was conducted using UACC903 melanoma cells that stably express doxycycline-inducible GFP-ATF2.

Results: We identified two compounds (SBI-0089410 and SBI-0087702) that promoted the cytoplasmic localization of ATF2, reduced cell viability, inhibited colony formation, cell motility, and anchorage-free growth, and increased mitochondrial membrane permeability. SBI-0089410 inhibited the 12-O-tetradecanoylphorbol-l3-acetate (TPA)–induced membrane translocation of protein kinase C (PKC) isoforms, whereas both compounds decreased ATF2 phosphorylation by PKC and ATF2 transcriptional activity. Overexpression of either constitutively active PKC or phosphomimic mutant ATF2^T52E attenuated the cellular effects of the compounds.

Conclusion: The imaging-based high-throughput screen provides a proof-of-concept for the identification of small molecules that block the oncogenic addiction to PKC signaling by promoting ATF2 nuclear export, resulting in mitochondrial membrane leakage and melanoma cell death. Clin Cancer Res; 19(10); 2710–22. ©2013 AACR.

Purpose: Patients with triple-negative breast cancer (TNBC) and residual disease after neoadjuvant chemotherapy generally have worse outcome; however, some patients with residual tumor after neoadjuvant chemotherapy do not relapse. We hypothesize that there are subgroups of patients with chemoresistant TNBC with different prognosis.

Experimental Design: Forty-nine chemoresistant cases from 111 patients with TNBC treated with neoadjuvant chemotherapy (M.D. Anderson Cancer Center, Houston, TX) constituted the discovery cohort, and 25 chemoresistant samples from 47 neoadjuvant chemotherapy-treated TNBC (The Methodist Hospital, Houston, TX) were chosen for validation. Extended validation was carried out in 269 operable TNBC predicted to be chemoresistant by expression pattern from published datasets.

Results: We established a seven-gene prognostic signature using dChip and gene set enrichment analyses. In the independent validation cohort, the classifier predicted correctly with positive predictive value of 75.0% and negative predictive value (i.e., relapse-free survival; RFS) of 76.9% at 3 years. Those predicted to relapse had a HR of 4.67 [95% confidence interval (CI): 1.27–17.15] for relapse in 3 years. In extended validation, patients predicted not to relapse exhibited 3-year RFS of 78.9%, whereas the 3-year RFS was 48.5% for patients predicted to relapse, with HR of 2.61 (95% CI: 1.52–4.49). The TNBC subgroup that predicted to have relatively favorable prognosis was characterized by high expression of "luminal-like" genes [androgen-receptor (AR) and GATA3], whereas the subgroup with worse prognosis was characterized by expression of cancer stem-cell markers.

Conclusion: We developed a clinically relevant signature for patients with chemoresistant TNBC. For these women, new therapeutic strategies like targeting AR activation or cancer stem cells may need to be developed. Clin Cancer Res; 19(10); 2723–33. ©2013 AACR.

Purpose: Multiple injections of oncolytic adenovirus could enhance immunologic response. In the first part of this article, the focus was on immunologic aspects. Sixty patients previously naïve to oncolytic virus and who had white blood cells available were treated. Thirty-nine of 60 were assessed after a single virus administration, whereas 21 of 60 received a "serial treatment" consisting of three injections within 10 weeks. In the second part, we focused on 115 patients treated with a granulocyte macrophage colony-stimulating factor (GM–CSF)–coding capsid chimeric adenovirus, CGTG-102.

Results: Following serial treatment, both increase and decrease in antitumor T cells in blood were seen more frequently, findings which are compatible with induction of T-cell immunity and trafficking of T cells to tumors, respectively. Safety was good in both groups. In 115 patients treated with CGTG-102 (Ad5/3-D24-GMCSF), median overall survival was 111 days following single and 277 days after serial treatment in nonrandomized comparison. Switching the virus capsid for avoiding neutralizing antibodies in a serial treatment featuring three different viruses did not impact safety or efficacy. A correlation between antiviral and antitumor T cells was seen (P = 0.001), suggesting that viral oncolysis can result in epitope spreading and breaking of tumor-associated immunologic tolerance. Alternatively, some patients may be more susceptible to induction of T-cell immunity and/or trafficking.

Conclusions: These results provide the first human data linking antiviral immunity with antitumor immunity, implying that oncolytic viruses could have an important role in cancer immunotherapy. Clin Cancer Res; 19(10); 2734–44. ©2013 AACR.

Purpose: We assessed adding the multikinase inhibitor sorafenib to gemcitabine or capecitabine in patients with advanced breast cancer whose disease progressed during/after bevacizumab.

Experimental Design: This double-blind, randomized, placebo-controlled phase IIb study (ClinicalTrials.gov NCT00493636) enrolled patients with locally advanced or metastatic human epidermal growth factor receptor 2 (HER2)–negative breast cancer and prior bevacizumab treatment. Patients were randomized to chemotherapy with sorafenib (400 mg, twice daily) or matching placebo. Initially, chemotherapy was gemcitabine (1,000 mg/m² i.v., days 1, 8/21), but later, capecitabine (1,000 mg/m² orally twice daily, days 1–14/21) was allowed as an alternative. The primary endpoint was progression-free survival (PFS).

Results: One hundred and sixty patients were randomized. More patients received gemcitabine (82.5%) than capecitabine (17.5%). Sorafenib plus gemcitabine/capecitabine was associated with a statistically significant prolongation in PFS versus placebo plus gemcitabine/capecitabine [3.4 vs. 2.7 months; HR = 0.65; 95% confidence interval (CI): 0.45–0.95; P = 0.02], time to progression was increased (median, 3.6 vs. 2.7 months; HR = 0.64; 95% CI: 0.44–0.93; P = 0.02), and overall response rate was 19.8% versus 12.7% (P = 0.23). Median survival was 13.4 versus 11.4 months for sorafenib versus placebo (HR = 1.01; 95% CI: 0.71–1.44; P = 0.95). Addition of sorafenib versus placebo increased grade 3/4 hand–foot skin reaction (39% vs. 5%), stomatitis (10% vs. 0%), fatigue (18% vs. 9%), and dose reductions that were more frequent (51.9% vs. 7.8%).

Conclusion: The addition of sorafenib to gemcitabine/capecitabine provided a clinically small but statistically significant PFS benefit in HER2-negative advanced breast cancer patients whose disease progressed during/after bevacizumab. Combination treatment was associated with manageable toxicities but frequently required dose reductions. Clin Cancer Res; 19(10); 2745–54. ©2013 AACR.

Purpose: To investigate the short-term biologic effects of neoadjuvant chemotherapy +/– zoledronic acid (ZOL) in invasive breast cancer.

Experimental Design: Forty patients were randomized to receive a single 4 mg infusion of ZOL 24 hours after the first cycle of FE₁₀₀C chemotherapy, or chemotherapy alone. Randomization was stratified for tumor stage, ER, HER2, and menopausal status. All patients had repeat breast core biopsy at day 5 (D5) ± day 21 (D21). Effects on apoptotic index, proliferation (Ki67), growth index, surrogate serum markers of angiogenesis (VEGF), and serum reproductive hormones within the TGFβ family (activin-A, TGFβ1, inhibin-A, and follistatin) were evaluated and compared.

Results: Baseline clinicopathologic characteristics were well balanced. Cell growth index (increased apoptosis and reduced proliferation) fell at D5 in both groups but recovered more rapidly with chemotherapy + ZOL compared with chemotherapy alone by D21 (P = 0.006). At D5, a greater reduction in serum VEGF occurred with chemotherapy + ZOL compared with chemotherapy: median percentage change –23.8% [interquartile range (IQR): –32.9 to –15.8] versus –8.4% (IQR: –27.3 to +8.9; P = 0.02), but these effects were lost by D21. Postmenopausal women showed a decrease in follistatin levels from baseline in the chemotherapy + ZOL group at D5 and D21, compared with chemotherapy alone (P_interaction = 0.051).

Conclusions: In this pilot study, short-term changes in biomarkers suggest potentially relevant interactions between tumor biology, chemotherapy, modification of the bone microenvironment, and the endocrine status of the host. Larger studies with more frequent dosing of zoledronic acid are needed to assess these complex interactions more thoroughly. Clin Cancer Res; 19(10); 2755–65. ©2013 AACR.

Purpose: To conduct a first-in-human phase I study to determine the dose-limiting toxicities (DLT), characterize the pharmacokinetic profile, and document the antitumor activity of IPI-926, a new chemical entity that inhibits the Hedgehog pathway (HhP).

Experimental Design: Patients with solid tumors refractory to standard therapy were given IPI-926 once daily (QD) by mouth in 28-day cycles. The starting dose was 20 mg, and an accelerated titration schedule was used until standard 3 + 3 dose-escalation cohorts were implemented. Pharmacokinetics were evaluated on day –7 and day 22 of cycle 1.

Results: Ninety-four patients (32F, 62M; ages, 39–87) received doses ranging from 20 to 210 mg QD. Dose levels up to and including 160 mg administered QD were well tolerated. Toxicities consisted of reversible elevations in aspartate aminotransferase (AST), alanine aminotransferase (ALT) and bilirubin, fatigue, nausea, alopecia, and muscle spasms. IPI-926 was not associated with hematologic toxicity. IPI-926 pharmacokinetics were characterized by a slow absorption (T_max = 2–8 hours) and a terminal half-life (t_1/2) between 20 and 40 hours, supporting QD dosing. Of those HhP inhibitor-naïve patients with basal cell carcinoma (BCC) who received more than one dose of IPI-926 and had a follow-up clinical or Response Evaluation Criteria in Solid Tumors (RECIST) assessment, nearly a third (8 of 28 patients) showed a response to IPI-926 at doses ≥130 mg.

Conclusions: IPI-926 was well tolerated up to 160 mg QD within 28-day cycles, which was established as the recommended phase II dose and schedule for this agent. Single-agent activity of IPI-926 was observed in HhP inhibitor–naïve patients with BCC. Clin Cancer Res; 19(10); 2766–74. ©2013 AACR.

Purpose: Estrogen withdrawal by treatment with aromatase inhibitors is the most effective form of endocrine therapy for postmenopausal estrogen receptor–positive (ER+) breast cancer. However, response to therapy varies markedly and understanding of the precise molecular effects of aromatase inhibitors and causes of resistance is limited. We aimed to identify in clinical breast cancer those genes and pathways most associated with resistance to aromatase inhibitors by examining the global transcriptional effects of AI treatment.

Experimental Design: Baseline and 2-week posttreatment biopsies were obtained from 112 postmenopausal women with ER+ breast cancer receiving neoadjuvant anastrozole. Gene expression data were obtained from 81 baseline and 2-week paired samples. Pathway analysis identified (i) the most prevalent changes in expression and (ii) the pretreatment genes/pathways most related to poor antiproliferative response.

Results: A total of 1,327 genes were differentially expressed after 2-week treatment (false discovery rate < 0.01). Proliferation-associated genes and classical estrogen-dependent genes were strongly downregulated whereas collagens and chemokines were upregulated. Pretreatment expression of an inflammatory signature correlated with antiproliferative response to anastrozole and this observation was validated in an independent study. Higher expression of immune-related genes such as SLAMF8 and TNF as well as lymphocytic infiltration were associated with poorer response (P < 0.001) and validated in an independent cohort.

Conclusions: The molecular response to aromatase inhibitor treatment varies greatly between patients consistent with the variable clinical benefit from aromatase inhibitor treatment. Higher baseline expression of an inflammatory signature is associated with poor antiproliferative response and should be assessed further as a novel biomarker and potential target for aromatase inhibitor-treated patients. Clin Cancer Res; 19(10); 2775–86. ©2013 AACR.