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Despite improvements in care of patients with breast cancer, up to half develop refractory or resistant disease. There is therefore a need for new, modified anticancer therapies with greater effectiveness, tolerability to patients, and tumour specificity. Trastuzumab (Herceptin) is the first clinically available oncogene-targeted therapeutic agent for treatment of solid tumours. Clinical trials in patients positive for HER2 (human epidermal-growth-factor receptor 2) show that trastuzumab is effective and well tolerated; as a single-agent second-line or third-line treatment, the drug produced durable tumour responses. First-line trastuzumab in combination with chemotherapy, particularly paclitaxel, significantly improved time to disease progression, duration of response, and time to treatment failure. Combination therapy resulted in a 25% improvement in overall survival compared with chemotherapy alone. Patients with HER2 gene amplification, high overexpression of HER2 (3+ on immunohisto-chemistry), or both features, obtained the greatest clinical benefit. Trastuzumab is the first monoclonal antibody with efficacy in breast cancer and the first gene-product-targeted therapy to produce a significant survival advantage in this disease. Trastuzumab is likely to find its ultimate role in the adjuvant setting. Its development provides a model for the integration of other gene-targeted therapies into breast-cancer management to improve survival and quality of life. [ABSTRACT FROM AUTHOR]

The pharmacokinetics of the R and S enantiomers of ifosfamide (IFF) and of its 2- and 3-N-dechloroethylated metabolites (2-DCE-IFF and 3-DCE-IFF) were investigated in 14 cancer patients treated with a 3-h infusion of (R,S)-IFF (3 g/m2) with mesna uroprotection. An enantioselective gas chromatographic-mass spectrometric (GC-MS) assay was used to determine the concentrations in plasma and urine. The AUCs of (R)-IFF were significantly larger than those of (S)-IFF (2480 +/- 200 vs 1960 +/- 150 microM.h). The terminal half-lives (7.57 +/- 0.99 h) and mean residence times (11.17 +/- 1.10 h) of (R)-IFF were significantly longer than those of (S)-IFF, 6.03 +/- 0.82 h and 9.37 +/- 0.88 h, respectively. The mean volume of distribution at steady rate of (R)-IFF (25.68 +/- 0.80 l/m2) was slightly smaller than that of (S)-IFF (27.35 +/- 0.89 l/m2). While the renal clearances of (R)-IFF and (S)-IFF were similar, the nonrenal clearance was significantly lower for (R)-IFF (30.20 +/- 2.70 vs 41.40 +/- 3.55 ml/m2 per min) as was total clearance (41.52 +/- 2.90 vs 52.37 +/- 3.75 ml/m(2) per min). The AUC values for all of the DCE metabolites from (S)-IFF were significantly greater than those from (R)-IFF with 47% of the measured AUC accounted for by DCE from (S)-IFF compared to only 20% for (R)-IFF. Therefore, the enantioselective difference in IFF elimination can be partially explained by differences in N-dechloroethylation. [ABSTRACT FROM AUTHOR]

The antitumor agent cisplatin has a broad antitumor spectrum and has been incorporated into regimens that are curative for some malignant diseases. However, one of the major limitations to its clinical usefulness is the incidence of severe toxicities involving several major organ systems. Therefore, much enthusiasm has been generated for the development of cisplatin analogs that demonstrate an improved therapeutic index in some preclinical models. The two most promising analogs are CBDCA (carboplatin) and CHIP (iproplatin). The preclinical and early clinical trial results have demonstrated that these two compounds show activity in cisplatin-responsive tumors. The preclinical background providing the rationale for the clinical development of these two analogs is described. We suggest a means of screening for each analog's clinical antitumor activity and determining the analogs' utility against specific malignant diseases compared with that of the parent compound or standard treatment. [ABSTRACT FROM AUTHOR]

Background: Personalized healthcare tailors treatments to patients and their disease characteristics through the use of genetics and other biomarkers. Genetic differences among individuals may explain variations in drug treatment response, including side effects. With such information physicians could make more informed decisions about drugs and dosing for a given individual, thereby improving patient care. Although there has been some success, to a large extent genetic variation related to drug response remains unexplained. Bevacizumab, a humanized monoclonal antibody against the angiogenic factor VEGF, has demonstrated activity in patients with metastatic breast cancer (MBC). The InVite study will evaluate the feasibility of performing genomewide association studies using self-reported information collected via an online platform from patients with MBC who have been treated with bevacizumab. Using novel methodology in a convenient, user-friendly, and scientifically rigorous format, InVite ultimately aims to identify potential pharmacogenetic associations in this patient population. Trial design: InVite is a pilot, non-interventional, observational, web-based, prospective cohort study designed to collect patient-reported safety, efficacy, and genetic data from patients with MBC treated with bevacizumab. Data on demographics, breast cancer disease status, cancer treatment history, bevacizumab-related outcomes, and certain safety events will be collected directly from patients entirely via online surveys. Patients will be asked to complete surveys at the time of enrollment and then every 3 months for 1 year after enrollment. A saliva sample for DNA collection will be gathered using an at-home kit. Evaluations of data quality and collection feasibility will be conducted intermittently. There will be an optional substudy to allow for blood sample collection for DNA analysis. Eligibility criteria: ≥18 years of age, residing in the US, locally recurrent breast cancer or MBC, currently being or having been treated with bevacizumab starting on or before Dec 31, 2011, fluent in English, and access to a computer with an internet connection. Specific aims: The primary objective is to assess the feasibility of recruiting subjects and collecting biospecimens and self-reported data online. The secondary objective is to characterize the patient population. Exploratory objectives include analyzing potential associations between genetic polymorphisms and 1) bevacizumab-induced hypertension, the most common bevacizumab-related adverse event, and 2) patient-reported time-to-progression. Statistical methods: Baseline demographics, clinical and treatment characteristics of enrolled patients will be summarized. Each polymorphism genotyped will be tested for association with the defined endpoint using appropriate statistical modeling. Present and target accrual: Accrual as of May 23, 2012 is 82 patients. Target accrual is 1000 patients. [ABSTRACT FROM AUTHOR]

Abstract During the past decade, genomic microarrays have been applied with some success to the molecular profiling of breast tumours, which has resulted in a much more detailed classification scheme as well as in the identification of potential gene signature sets. These gene sets have been applied to both the prognosis and prediction of outcome to treatment and have performed better than the current clinical criteria. One of the main limitations of microarray analysis, however, is that frozen tumour samples are required for the assay. This imposes severe limitations on access to samples and precludes large scale validation studies from being conducted. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), on the other hand, can be used with degraded RNAs derived from formalin-fixed paraffin-embedded (FFPE) tumour samples, the most important and abundant source of clinical material available. More recently, the novel DASL (cDNA-mediated Annealing, Selection, extension and Ligation) assay has been developed as a high throughput gene expression profiling system specifically designed for use with FFPE tumour tissue samples. However, we do not believe that genomics is adequate as a sole prognostic and predictive platform in breast cancer. The key proteins driving oncogenesis, for example, can undergo post-translational modifications; moreover, if we are ever to move individualization of therapy into the practical world of blood-based assays, serum proteomics becomes critical. Proteomic platforms, including tissue micro-arrays (TMA) and protein chip arrays, in conjunction with surface-enhanced laser desorption ionization time-of-flight mass spectrometry (SELDI-TOF/MS), have been the technologies most widely applied to the characterization of tumours and serum from breast cancer patients, with still limited but encouraging results. This review will focus on these genomic and proteomic platforms, with an emphasis placed on the utilization of FFPE tumour tissue samples and serum, as they have been applied to the study of breast cancer for the discovery of gene signatures and biomarkers for the early diagnosis, prognosis and prediction of treatment outcome. The ultimate goal is to be able to apply a systems biology approach to the information gleaned from the combination of these techniques in order to select the best treatment strategy, monitor its effectiveness and make changes as rapidly as possible where needed to achieve the optimal therapeutic results for the patient.

The anticipated approval of the first specific PIK3CA inhibitor, apelisib, has increased interest in the frequency and range of PIK3CA genomic alterations (GA) in the major subtypes of mBC. DNA was extracted from 3,871 mBC: 1,259 ER+/HER2-, 1,969 HER2 amplified (amp) and 643 TNBC. GA, tumor mutational burden (TMB) and microsatellite instability (MSI) were identified by hybrid-capture. PD-L1 was determined by IHC. PIK3CA GA were significantly higher in ER + (39%) and HER2amp (37%) and lower in TNBC (21%) groups and dominated by point mutations and indels (mut) (Table). The H1047R was the most frequent PIK3CA GA in all groups. ESR1 GA were highest in ER+ and BRCA1 GA were most frequent in PIK3CAmut- TNBC and BRCA2 GA were most frequent in PIK3CAmut- ER+. FGFR1 GA were significantly more frequent in PIK3CAmut- ER+ and EGFR and BRAF GA were most frequent in PIK3CAmut+ TNBC. Biomarkers of potential immunotherapy benefit including CD274amp and PD-L1 expression in immunocytes were most frequent in the TNBC patients, while TMB was highest in the PIK3CAmut+ cohort, regardless of subtype. Table 306PD Table ER+/HER2- (1,249) HER2 Amp (1,922) TNBC (925) PIK3CAmut+ PIK3CAmut- PIK3CAmut+ PIK3CAmut- PIK3CAmut+ PIK3CAmut- 481 (39%) CN 4% Mut 96% H1047R 30% E545K 17% E542K 15% N345K 5% 768 (61%) 715 (37%) CN 8% Mut 92% H1047R 34% E545K 15% E542K 10% N345K 3% 1,207 (63%) 192 (21%) CN 17% Mut 83% H1047R 30% E545K 8% E542K 7% N345K 3% 733 (79%) Age (range in years) 57 (23-89+) 53 (22-89) 55 (25-88) 53 (20-89+) 56.5 (30-89+) 53 (20-89+) PIK3CA GA 100% 0% 100% 0% 100% 0% TP53 GA 39% 47% 75% 68% 74% 88% PTEN GA 9% 12% 3% 6% 15% 15% CDH1 GA 11% 5% 5% 3% 9% 3% ESR1 GA 16% 16% 7% 6% 2% <1% BRCA1/2 GA 1%/3% 4%/7% 1%/2% 3%/3% 3%/3% 8%/4% HER2 amp 0% 0% 100% 100% 0% 0% HER2 mut 2% 3% 7% 6% 5% 2% Other Kinase GA FGFR1 14% EGFR 1% BRAF 1% FGFR1 21% EGFR 2% BRAF 2% FGFR1 11% EGFR 3% BRAF 1% FGFR1 11% EGFR 3% BRAF 1% FGFR1 9% EGFR 11% BRAF 3% FGFR1 8% EGFR 3% BRAF 3% AR amp <1% <1% 2% 1% 3% <1% MSI High <1% <1% <1% <1% 0% <1% CD274 (PD-L1) amp <1% 1% 1% 1% 3% 3% TMB > 10/20 mut/Mb 11%/5% 5%/1% 11%/3% 8%/1% 11%/3% 6%/1% PD-L1 TILs low/high 9%/0% n = 33 11%/0% n = 57 11%/0% n = 45 9%/0% n = 79 20%/0% n = 15 17%/1% n = 75 A wide variety of PIK3CA GA are identified in mBC and appear to influence other important biomarkers such as BRCA1/2 GA and TMB status. The PIK3CA GA distribute differently among the ER+, HER2+ and TNBC cohorts and may impact the initial and future use of PIK3CA inhibitors in the treatment of the disease. Foundation Medicine. Foundation Medicine. E.S. Sokol: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. L.A. Albacker: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. J.A. Elvin: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. J. Vergilio: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. J..K. Killian: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. N. Ngo: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. D. Lin: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. S. Ramkissoon: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. E. Severson: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. S.M. Ali: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. A.B. Schrock: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. J. Chung: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. P. Reddy: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. V.A. Miller: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. B.M. Alexander: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: Foundation Medicine. K. McGregor: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. J.S. Ross: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background: While representing the largest fraction of women diagnosed with primary breast cancer, older postmenopausal women with ER+, HER2-- tumors are less responsive to chemoendocrine therapy than younger women and have been underrepresented in molecular profiling of randomized trials. IBCSG Trial IX, a randomized controlled trial in postmenopausal women, median age 61y, with node negative disease, failed to demonstrate the benefit of preceding tamoxifen (T) by 3 cycles of CMF for ER+ tumors. We sought to determine if MS, a proliferation score, could identify a subset of women who differentially benefit from addition of chemotherapy to T in this trial. Methods: From 1988-1999, 1669 eligible patients (1040 with ER+, HER2-- tumors) were randomized to CMF ->T vs T. Disease-free survival (DFS) was the primary trial endpoint; breast cancer-free interval (BCFI) which excludes second (non-breast) malignancies and censors deaths without prior cancer event was also evaluated. Analysis was limited to the first 7 years of follow-up. From 671 (ER+, HER2--) available subjects, 568 were successfully profiled by RT-PCR. The mRNA expression levels of 14 equally-weighted proliferation genes and 3 normalization genes were used to generate MS; predetermined binary categorization of MS was used. Analysis of this post hoc, pre-specified study used results from centralized laboratory IHC and Cox models to assess the predictive value of MS on DFS and BCFI, adjusting for traditional risk factors of local treatment, age, ER, PR, Ki67, tumor size and grade. Results: Subgroups of MS (low, 169 samples (30%) and high, 399 samples (70%)) were identified. MS by treatment interaction was significant for DFS and BCFI (each p ≤ 0.004). Among patients with low MS, CMF -> T improved DFS (HR 0.19, 95% CI 0.06-0.59) and BCFI (HR 0.19, 95% CI 0.05-0.72) vs T; 7y DFS was 95% vs 83% with CMF -> T vs T. Among patients with high MS, CMF T did not improve DFS (HR 1.27, 95% CI 0.79-2.05) or BCFI (HR 1.37, 95% CI 0.80-2.33) and 7y DFS of 81% for CMF T and T. Continuous MS was moderately correlated with log Ki67 (r = 0.47) but not correlated with ER or PR. The MS by treatment interaction remained significant with Ki67 in the model. Conclusions: Low MS was associated with differential benefit favoring those women receiving CMF -> T vs T alone for both DFS and BCFI in the first 7 years. The effect was independent of traditional risk factors including Ki67. Hence this study, which is unconfounded by chemotherapy-induced ovarian ablation in younger women, identifies a subset of postmenopausal women with ER+, HER2- tumors that benefit from CMF chemotherapy. This seemingly incongruous observation is consistent with a) the prior observation that only the lowproliferation subgroup by PAM50 11-gene signature benefits from the addition of weekly paclitaxel to adjuvant FEC (GEICAM/9906), b) the ability of MS to identify a subset of women with tumors with disseminated luminal progenitor cells activated through the agonistic activity of tamoxifen, and c) the repetitive dosing of cyclophosphamide and taxol being hypothesized to act via tumor stroma/anti-angiogenesis. The relative contribution of these factors is under investigation. [ABSTRACT FROM AUTHOR]

Introduction: PARP inhibition has emerged as one of the most exciting and promising 'targeted' therapeutic strategies in the treatment of advanced triple negative breast cancer (TNBC) - the intended 'target,' being DNA repair (Anders CK, 2010). Although olaparib is known to have antitumor activity in BRCA-related TNBC cells, a limited number of preclinical and clinical studies have shown antitumor efficacy of olaparib in non-BRCA-related BC (Shimo T, 2012). Understanding the biology of TNBC cells has identified molecular targets including RTK(s), such as EGFR. Purpose: Here we tested the combination of a PARP inhibitor, olaparib (O) (AstraZeneca) plus carboplatin (C) with the EGFR/VEGFR inhibitor, vandetanib (V) (AstraZeneca) in a BRCA-wt TNBC model. Methods: Athymic mice bearing TNBC (BRCA-wt VEGFR expressing MDA-MB231& MDA-MB468 [EGFR amplified/overexpressed]) xenograft tumors (200 mm3) were treated with O plus C in combination with V (Arms: vehicle control 1, vehicle control 2, C+O, V, C+O+V). In vitro effects of V in combination with O plus C (or temozolomide) on clonogenic growth (3D on-TOP assay), proliferation (MTT and CelltiterGLO), apoptosis (Apoptosis Array), cell signaling marker(s) (Western Blot), and tumor cell phenotypes (fibronectin-directed migration, matrigel-invasion, and vascular mimicry) were investigated in a panel of five BRCA-wt and BRCA-mutated TNBC cell lines. The effects of V were tested on (a) cell signaling marker(s), (b) angiogenesis marker (HIF-1 alpha), and (c) angiogenesis related phenotypes (vitronectin-directed migration, and cord formation) in HUVEC. Results: (1) O plus C in combination with V caused a regression of the in vivo growth of established tumors by 50% which was evident in both the BRCA-wt TNBC models tested. Interestingly, a marked suppression of the progression of tumor-growth was observed in the O plus C arm. (2) In vitro, V alone (10 µM) inhibited baseline as well as EGF-induced phosphorylation of AKT (S473/T308), S6RP, 4EBP1 and ERK. (3) TNBC cells exhibited higher sensitivity to V in clonogenic assays when combined with a 10 µM fixed dose of O and C/temozolomide. (4) A combination of V with O plus C increased cleaved caspase-3, PARP cleavage, and pro-apoptotic signals, while inhibiting vascular mimicry, migration, and invasion in MDA-MB231, MDA-MB468, and SUM149 cells. (5) Treatment with V blocked cord formation, migration, EGF-induced HIF-1α accumulation, and phosphorylation of AKT, 4EBP1, and ERK in HUVEC. Conclusion: A profound anti-tumor efficacy of O plus C in combination with V in BRCA-wt TNBC model can be explained by a significant anti-proliferative/pro-apoptotic and anti-migratory/anti-invasive actions of the drugs (alone or in combination), as observed both in tumor cells as well as in endothelial compartments. The combination of O plus C plus V merits further investigation in TNBC. [ABSTRACT FROM AUTHOR]

Background: We have reported that a 97-gene signature, the Genomic Grade Index (GGI) can separate histological grade (HG) 2 breast tumors into low vs high GGI tumors with different outcomes. We have also developed a quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) tool including 6 reporter and 3 control genes that can reliably evaluate Genomic Grade (GG) in paraffin embedded tumors. Methods: We evaluated the qRT-PCR GG in women treated with either tamoxifen or letrozole monotherapy in the Breast International Group (BIG) 1-98 study with 8.1 year median follow-up. The association between continuous GG and distant recurrence-free interval (DRFI) was evaluated in Cox regression models stratified for the 2 vs 4 arm randomization option, chemotherapy and hormonotherapy use, with and without adjustment for clinicopathological characteristics. Estrogen, progesterone receptor (ER, PR), Ki67 and HG were centrally reviewed. The clinicopathological model included age and log2 tumor size, ER and PR as continuous variables, nodal status (N0 vs 1-3 vs >3), HG (1 vs 2 vs 3) and HER2 (negative vs positive). Similar analyses were performed for log2 Ki67 as continuous variable. Added prognostic value was assessed using the likelihood ratio statistic. Results: We obtained GG in 883 (62%) of 1428 samples. Non evaluable results were due to pre-analytical issues or technical failure. Among the 883 patients, 521 (59%) had N0 disease, 435 (49%) were treated with tamoxifen and 84 (10%) had distant recurrences. The GG classified 502 patients with HG2 tumors as either GG1 (N = 202, 40%), equivocal (N = 220, 44%) or GG3 (N = 80, 16%). In univariate analysis, increasing GG and Ki67 were significantly associated with lower DRFI (Table). When the 773 N0/1-3 patients were analyzed based on HG, the Kaplan-Meier estimate for 10-year DRFI was 98% (95% confidence intervals 96-100%) for the 123 HG1, 92% (88-95%) for the 456 HG2 and 84% (78-90%) for the 194 HG3 patients. In the N0/1-3 population, 10 year DRFI based on GG was 95% (96-100%) for the 290 GG1, 92% (89-95%) for the 309 GG equivocal and 84% (77-90%) for the 178 GG3 patients. Interestingly, when the 456 HG2 and N0/1-3 patients were analyzed based on GG, the 10-year DRFI was 95% (92-100%) for the 185 HG2/GG1 patients, 92% (88-96%) for the 202 HG2/GG equivocal patients, 86% (76-96%) for the 69 HG2/GG3 patients. In all patients either GG or Ki67 as continuous variable significantly improved the clinicopathological model in predicting distant recurrence (Table). Conclusion: Either Genomic Grade or centrally reviewed Ki67 provides independent prognostic information for risk of distant recurrence beyond clinicopathological characteristics in patients treated with endocrine therapy. [ABSTRACT FROM AUTHOR]

Background: Approximately 60-70% of breast cancers (BC) express estrogen receptor (ERa) and/or progesterone receptor (PR), the most common malignancy in women in the US and Europe. Many though not all patients with ER+ BC respond to hormonal therapy (e.g. tamoxifen and aromatase-inhibitor) but a large number will eventually develop resistance to long term therapy. Purpose: Development of resistance to endocrine therapy is a clinical issue in ER+ BC. Studies with human cell lines have shown that upregulation of PI3K-AKT-mTOR and MEK-ERK pathways contributes to resistance to endocrine therapy (Miller TWet al JCO 2011; Sanchez CG et al Breast Cancer Res 2011). Using leterozole-resistant ER+ BC model, we investigated the effects of PI3K-AKT-mTOR pathway inhibitor alone and in combination with MEK1/2 inhibitor. Methodology: The anti-proliferative, anti-migratory, and intracellular signaling (pAKT, pS6RP, p4EBP1 and pERK) effects of GDC-0941 (Class I PI3K inhibitor) or GDC-0980 (dual PI3K/mTOR inhibitor) alone and in combination with GDC-0973 (MEK1/2 inhibitor) were evaluated in aromatase overexpressed (MCF-7aro), letrozole-resistant (MCF-7aro/LetR) and long-term-estrogen-deprived (LTEDaro) BC cell lines by MTT assays, integrin-mediated migration assay and Western blots. Results: 1) Both GDC-0980 and GDC-0941 exhibited excellent in vitro cell killing activity in MTT assay in all cell lines with IC50's 10-30 nM & 0.2-1.5 µM respectively. PI3K pathway inhibitors were more potent when combined with GDC-0973; 2) Integrin-mediated migration was significantly higher in both MCF-7aro/LetR andLTEDaro cells than MCF-7 and MCF-7aro cells; 3) Both MCF-7aro/LetR and LTEDaro cells movement were significantly abrogated following the treatment of GDC-0980, and the combination of GDC-0980 plus GDC-0973 more effectively blocked integrin-mediated migration; 4) Inhibition of phosphorylation of AKT (S473/T308), S6RP and 4EBP1 (T37/46) was observed following PI3K pathway inhibitors; 5) pERK was upregulated following the treatment of GDC-0941 (PI3K inhibitor); 6) Basal level of pERK was significantly high in MCF7/LetR and MCF7/LTED cells, and GDC-0980 failed to change the level of pERK in those cell lines; and 7) Combination of PI3K pathway inhibitor plus MEK1/2 inhibitor significantly blocked activation of both pathways. Conclusion: Our/n vitro data suggest that therapeutic targeting of the PI3K-AKT-mTOR and the MEK-ERK signaling pathways should be effective in abrogating aromatase-inhibitor -resistance in ER+ BC. [ABSTRACT FROM AUTHOR]

Background: The Worldwide Innovative Network (WIN) Consortium has developed the Simplified Interventional Mapping System (SIMS) to better define the cancer molecular milieu based on genomics/transcriptomics from tumor and analogous normal tissue biopsies. SPRING is the first trial to assess a SIMS-based tri-therapy regimen in advanced non-small cell lung cancer (NSCLC)., Methods: Patients with advanced NSCLC (no EGFR, ALK, or ROS1 alterations; PD-L1 unrestricted; ≤2 prior therapy lines) received avelumab, axitinib, and palbociclib (3 + 3 dose escalation design)., Results: Fifteen patients were treated (five centers, four countries): six at each of dose levels 1 (DL1) and DL2; three at DL3. The most common ≥Grade 3 adverse events were neutropenia, hypertension, and fatigue. The recommended Phase II dose (RP2D) was DL1: avelumab 10 mg/kg IV q2weeks, axitinib 3 mg po bid, and palbociclib 75 mg po daily (7 days off/21 days on). Four patients (27%) achieved a partial response (PR) (progression-free survival [PFS]: 14, 24, 25 and 144+ weeks), including two after progression on pembrolizumab. Four patients attained stable disease (SD) that lasted ≥24 weeks: 24, 27, 29, and 64 weeks. At DL1 (RP2D), four of six patients (66%) achieved stable disease (SD) ≥6 months/PR (2 each). Responders included patients with no detectable PD-L1 expression and low tumor mutational burden., Conclusions: Overall, eight of 15 patients (53%) achieved clinical benefit (SD ≥ 24 weeks/PR) on the avelumab, axitinib, and palbociclib combination. This triplet showed antitumor activity in NSCLC, including in tumors post-pembrolizumab progression, and was active at the RP2D, which was well tolerated. NCT03386929 clinicaltrial.gov., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Importance: Residual cancer burden (RCB) distributions may improve the interpretation of efficacy in neoadjuvant breast cancer trials., Objective: To compare RCB distributions between randomized control and investigational treatments within subtypes of breast cancer and explore the relationship with survival., Design, Setting, and Participants: The I-SPY2 is a multicenter, platform adaptive, randomized clinical trial in the US that compares, by subtype, investigational agents in combination with chemotherapy vs chemotherapy alone in adult women with stage 2/3 breast cancer at high risk of early recurrence. Investigational treatments graduated in a prespecified subtype if there was 85% or greater predicted probability of higher rate of pathologic complete response (pCR) in a confirmatory, 300-patient, 1:1 randomized, neoadjuvant trial in that subtype. Evaluation of a secondary end point was reported from the 10 investigational agents tested in the I-SPY2 trial from March 200 through 2016, and analyzed as of September 9, 2020. The analysis plan included modeling of RCB within subtypes defined by hormone receptor (HR) and ERBB2 status and compared control treatments with investigational treatments that graduated and those that did not graduate., Interventions: Neoadjuvant paclitaxel plus/minus 1 of several investigational agents for 12 weeks, then 12 weeks of cyclophosphamide/doxorubicin chemotherapy followed by surgery., Main Outcomes and Measures: Residual cancer burden (pathological measure of residual disease) and event-free survival (EFS)., Results: A total of 938 women (mean [SD] age, 49 [11] years; 66 [7%] Asian, 103 [11%] Black, and 750 [80%] White individuals) from the first 10 investigational agents were included, with a median follow-up of 52 months (IQR, 29 months). Event-free survival worsened significantly per unit of RCB in every subtype of breast cancer (HR-positive/ERBB2-negative: hazard ratio [HZR], 1.75; 95% CI, 1.45-2.16; HR-positive/ERBB2-positive: HZR, 1.55; 95% CI, 1.18-2.05; HR-negative/ERBB2-positive: HZR, 2.39; 95% CI, 1.64-3.49; HR-negative/ERBB2-negative: HZR, 1.99; 95% CI, 1.71-2.31). Prognostic information from RCB was similar from treatments that graduated (HZR, 2.00; 95% CI, 1.57-2.55; 254 [27%]), did not graduate (HZR, 1.87; 95% CI, 1.61-2.17; 486 [52%]), or were control (HZR, 1.79; 95% CI, 1.42-2.26; 198 [21%]). Investigational treatments significantly lowered RCB in HR-negative/ERBB2-negative (graduated and nongraduated treatments) and ERBB2-positive subtypes (graduated treatments), with improved EFS (HZR, 0.61; 95% CI, 0.41-0.93) in the exploratory analysis., Conclusions and Relevance: In this randomized clinical trial, the prognostic significance of RCB was consistent regardless of subtype and treatment. Effective neoadjuvant treatments shifted the distribution of RCB in addition to increasing pCR rate and appeared to improve EFS. Using a standardized quantitative method to measure response advances the interpretation of efficacy., Trial Registration: ClinicalTrials.gov Identifier: NCT01042379.

Background: Malignancies are molecularly complex and become more resistant with each line of therapy. We hypothesized that offering matched, individualized combination therapies to patients with treatment-naïve, advanced cancers would be feasible and efficacious. Patients with newly diagnosed unresectable/metastatic, poor-prognosis cancers were enrolled in a cross-institutional prospective study., Methods: A total of 145 patients were included in the study. Genomic profiling (tissue and/or circulating tumor DNA) was performed in all patients, and PD-L1 immunohistochemistry, tumor mutational burden, and microsatellite status assessment were performed in a subset of patients. We evaluated safety and outcomes: disease-control rate (stable disease for ≥ 6 months or partial or complete response), progression-free survival (PFS), and overall survival (OS)., Results: Seventy-six of 145 patients (52%) were treated, most commonly for non-colorectal gastrointestinal cancers, carcinomas of unknown primary, and hepatobiliary malignancies (53% women; median age, 63 years). The median number of deleterious genomic alterations per patient was 5 (range, 0-15). Fifty-four treated patients (71%) received ≥ 1 molecularly matched therapy, demonstrating the feasibility of administering molecularly matched therapy. The Matching Score, which reflects the percentage of targeted alterations, correlated linearly with progression-free survival (R 2 = 0.92; P = 0.01), and high (≥ 60%) Matching Score was an independent predictor of improved disease control rate [OR 3.31 (95% CI 1.01-10.83), P = 0.048], PFS [HR 0.55 (0.28-1.07), P = 0.08], and OS [HR 0.42 (0.21-0.85), P = 0.02]. Serious adverse event rates were similar in the unmatched and matched groups., Conclusions: Personalized combination therapies targeting a majority of a patient's molecular alterations have antitumor activity as first-line treatment. These findings underscore the feasibility and importance of using tailored N-of-1 combination therapies early in the course of lethal malignancies., Trial Registration: I-PREDICT ( NCT02534675 ) was registered on August 25, 2015., (© 2021. The Author(s).)

Background: The sensitivity to endocrine therapy assay (SET2,3) predicts treatment outcomes in Stage II-III breast cancer. SET2,3 measures transcription related to estrogen and progesterone receptors (SETER/PR index) and the molecular subtype (RNA4: ESR1, PGR, ERBB2, AURKA) from formalin-fixed paraffin-embedded (FFPE) tissue sections., Methods: We designed a nested study across 3 pathology laboratories, each testing 60 breast cancers twice in controlled batches. Laboratories macrodissected and directly homogenized the unstained FFPE tumor sections, then performed the QuantiGene Plex bead-based hybridization assay. SET2,3 was calculated centrally using predefined statistical R-scripts and applying pre-defined cutpoints. Concordance correlation coefficient (CCC) was calculated from continuous measurements and Kappa statistic from categorical results. A mixed-effects model estimated contributions to bias (fixed effects) and variance (random effects) from the replicated design., Results: Intralaboratory (CCC 0.96-0.99) and interlaboratory (CCC 0.98-0.99) SET2,3 results were concordant, with rates of agreement for high/low categorization within (Kappa 0.83-0.93) and between laboratories (Kappa 0.87-0.88). The relative contributions to overall variance of SET2,3 measurements were 96.90% from biological differences between cancers, 0.67% from interlaboratory variability, and 2.44% from residual causes including intralaboratory replicates. Similar results were obtained with SETER/PR, the baseline prognostic index calculated using pathological or clinical tumor and nodal staging information, and the 4 individual genes (ESR1, PGR, ERBB2, and AURKA)., Conclusion: Intra- and interpathology laboratory measurements of SET2,3 and its components were highly reproducible when tested from FFPE tumor sections., (© American Association for Clinical Chemistry 2021.)

HER2 signaling network and its complex relationship with the PI3K-AKT-mTOR pathway explain the acquired resistance to anti-HER2 therapy observed in clinics. Such complexity has been clinically evident from the limited efficacy of data in the BOLERO-1 and BOLERO-3 trials, which tested combinations of trastuzumab (T), everolimus, and chemotherapy in women with HER2+ advanced BC. In the following MARIANNE trial also, a combination of T-DM1 plus pertuzumab delivered a non-inferior but yet not superior PFS compared to trastuzumab plus a taxane. Algorithmic inhibition of PI3K/mTOR along with T or T-DM1 is, therefore, an attractive drug combination, and we tested the combination(s) in HER2+ BC, especially in T-resistant and PIK3CA mutated conditions. GDC-0980, a dual pan-PI3K/mTOR inhibitor alone or in combination with T or T-DM1, was examined in a panel of HER2+ T-sensitive (BT474, SKBR3), HER2+ T-resistant (BT474HerR), HER2+/ PIK3CA mutant (HCC1954, MDA-MB453), and HER2+/ PTEN mutant (HCC1569) BC cell lines. GDC-0980 re-sensitized trastuzumab-resistant, PIK3CA mutant, or PTEN mutant cells to T and acted additively with T. Importantly, this activity was more when GDC-0980 is combined with T-DM1. The combination (with T or with T-DM1) was then tested in the HER2+/T-sensitive, HER2+/T-resistant, and HER2+/ PIK3CA mutated BC xenograft models for the anti-tumor effect. Along with its anti-tumor effect, GDC-0980 effectively decreased tumor angiogenesis (CD31 staining). Maximum anti-tumor (from tumor growth inhibition to tumor regression) efficiency was observed in all three xenograft models when T-DM1 was combined with GDC-0980. The anti-proliferative effects of GDC-0980 as evidenced by a decreased p-AKT (Ser473, The308), p-P70S6K, p-S6RP, and p-4EBP1, along with blockade of clonogenic 3D growth was accompanied by the initiation of apoptotic activity (annexin V, CASPASE3, cleaved PARP1 and mitochondrial depolarization); and was significantly superior when GDC-0980 combined with T-DM1. Interestingly, both trastuzumab and T-DM1 induce PD-L1 expression in HER2 amplified BC cells. Our data provide evidence that an oncogenic mutation of PIK3CA and HER2 -amplification may represent biomarkers to identify patients who may benefit most from the use of GDC-0980 and an opportunity to include immunotherapy in the combination of anti-HER2 therapy., Competing Interests: None., (AJCR Copyright © 2021.)