P1 Trials Research Articles

Inhibition of p38α MAPK-MK2 axis alleviate inflammatory response in various inflammation-related disease models

Abstract Mitogen-activated protein kinase (MAPK)-activated protein kinase-2 (MK2) is activated by p38 MAPK and regulates stability of mRNAs encoding inflammatory cytokines. Preclinical studies indicate that targeting MK2 may be a much safer approach than blocking p38a MAPK activation because that dissect the pathway downstream of p38α MAPK without affecting additional cellular functions. 141-A was identified as a highly potent and selective p38α MAPK-MK2 allosteric inhibitor that exhibited nanomolar-level inhibition on p38α MAPK activation of MK2 while sparing the p38α MAPK activation of ATF2 and PRAK. 141-A potently reduced various cytokine production (TNFα, IL-1β, IL-6, IL-8 and IL-17) in human peripheral blood mononuclear cells (PBMC) and displayed excellent efficacy in adjuvant-induced arthritis (AIA), psoriasis and MSU-induced air pouch rat models with 1/6 of the systematic exposure of CDD450. The compound exhibits favorable physicochemical and pharmacokinetic properties, along with an excellent preclinical toxicity profile, which may enhance therapeutic efficacy without causing side effects. 141-A is currently under IND-enabling studies and P1 trial is planned in early 2025.

Association of CYP2D6 genotype and tamoxifen metabolites with breast cancer recurrence in a low-dose trial

Low-dose tamoxifen halves recurrence in non-invasive breast cancer without significant adverse events. Some adjuvant trials with tamoxifen 20 mg/day had shown an association between low endoxifen levels (9–16 nM) and recurrence, but no association with CYP2D6 was shown in the NSABP P1 and P2 prevention trials. We studied the association of CYP2D6 genotype and tamoxifen metabolites with tumor biomarkers and recurrence in a randomized phase III trial of low-dose tamoxifen. Median (IQR) endoxifen levels at year 1 were 8.4 (5.3–11.4) in patients who recurred vs 7.5 (5.1–10.2) in those who did not recur (p = 0.60). Tamoxifen and metabolites significantly decreased C-reactive protein (CRP, p < 0.05), and a CRP increase after 3 years was associated with higher risk of recurrence (HR = 4.37, 95% CI, 1.14–16.73, P = 0.03). In conclusion, endoxifen is below 9 nM in most subjects treated with 5 mg/day despite strong efficacy and there is no association with recurrence, suggesting that the reason for tamoxifen failure is not poor drug metabolism. Trial registration: ClinicalTrials.gov, Identifier: NCT01357772.

Phase II study of lamivudine in p53 mutant metastatic colorectal cancer (mCRC).

149 Background: Non-coding repeat RNAs in cancers are pervasive and “mimic” viruses with activation of pattern recognition receptors and the innate immune response. Many repeat RNAs replicate in cancer genomes through a reverse transcriptional intermediate analogous to retroviruses. Nucleoside reverse transcriptase inhibitors (NRTIs) block this retroviral life cycle to increases repeat RNAs in p53 mutant colon cancer cell cancer lines. We initiated a Phase 2 study of lamivudine (3TC) in TP53 mutant mCRC. Methods: Two-stage design with target accrual of 20 patients (pts) in stage 1 and total of 32. Eligibility: pts with p53 mutant refractory mCRC with progression on or intolerance to 5FU, oxaliplatin and irinotecan and anti-EGFR if RAS WT. RNA sequencing was performed on pre-treatment (tx) and on tx biopsy to evaluate for repeat RNA expression and expression of other genes linked to 3TC response/resistance. Radiation was allowed. 9 pts were treated with 3TC 150 mg po bid for 28-day cycles, the maximum FDA approved dose of 3TC in HIV. Subsequent pts were treated at 600 mg po bid, previously tested in P1 trials. Tumor assessments were performed every 8 weeks until documented disease progression by RECIST 1.1 criteria or drug intolerance. Results: 29/32 pts have been treated. Median age: 60 yrs. (27-82) 18 males, 11 females. 2/ 9 (22%) pts on standard 3TC dosing had stable disease (SD) on single agent 3TC with a duration of tx of 169 and 167 days, respectively. Both pts had an initial drop in CEA upon initiation of 3TC. Of the next 20 pts on high dose 3TC, 19 were evaluable. 4 had SD, for 110, 159, 130 and 228+ days. 14 pts had tx-related adverse events (TRAE). 1 pt with a definite Grade 1 TRAE (fatigue). No pts with Grade ≥3 TRAEs. We obtained pre-tx fresh frozen biopsies on 24/29 pts. Of those with SD, 4 had biopsies and differential expression identified significantly higher HSATII repeat RNA in pts with SD compared to PD. There was an association of decreased epigenetic gene expression in HSATII repeat RNA high tumors. Conclusions: This proof-of-concept study demonstrates the safety and activity of single-agent 3TC. Repeat RNA levels appear to correlate with clinical benefit and can be measured in biopsies. Further combination studies and correlatives are planned. Clinical trial information: NCT03144804.

1055P - Clinical impact of molecular profiling of cervical cancer (CC) patients (pts) in a dedicated phase I (P1) unit

BackgroundMetastatic CC prognosis remains poor. Molecular characterisation (MC) allows better understanding of the mutations (mut) driving carcinogenesis or treatment resistance. We report the cervical tumour MC of pts in a P1 unit and its clinical implications. MethodsCC pts referred to the P1 unit of The Royal Marsden Hospital from 2011-18 underwent tumour molecular profiling using OncoCartaTM (Sequenom), TruSeq® Cancer Amplicon (Illumina), GeneReadTM custom DNA damage (Qiagen) or FoundationOne® panel. Retrospective data was extracted from electronic medical records. ResultsOf the 37 pts (median age: 34.7 years) analysed, 45.9% had squamous histology, and 37.8% were FIGO stage 2 at diagnosis; 34 different pathogenic mut were identified with 70.3% of pts having mut. PIK3CA mut were the most common (32.4%), followed by KRAS (13.5%), APC (8.1%), TP53 (8.1%), PTEN (5.4%), KDR (5.4%), ATM (5.4%), STK11 (5.4%) and BRCA1 (5.4%). 40.5% (15/37) patients had a potentially actionable mutation. Median overall survival (mOS) was 36 months (mo) in study population, 33mo in KRAS mut, 40mo in PIK3CA mut, 52mo in APC mut and 40mo in the mut-negative group; however, this difference was not statistically significant. In the KRAS mut group, 60% were adenocarcinoma and 40% adenosquamous. All KRAS mut pts had FIGO stage 2/3 at diagnosis. 80% had visceral metastasis when referred to the P1 unit; whereas in the PIK3CA mut group, tumour histologies were 33.3% squamous, 25% adenocarcinoma, 25% adenosquamous, 8.3% mucinous, 8.3% uncommon histologies. In the PIK3CA mut group, 75% were stage 1/2 at diagnosis, and 41.6% had visceral metastasis when referred. 5.4% (2/37) of pts were allocated to a P1 trial based on the finding of a PIK3CA mut with a mOS of 40mo compared to 36mo for the total population (p=0.6). One pt received an AKT inhibitor (i) but developed progressive disease (PD) after 3 cycles; the other received a PI3K i with PD after 4 cycles. ConclusionsOur study corroborates existing knowledge of the association between KRAS mut and adenocarcinoma histology in CC which confers worse prognosis. The high rate of potentially actionable mut indicates the increasing scope for targeted treatment trials in CC, thus prompting early MC which may improve pt allocation to P1 trials. Legal entity responsible for the studyThe Institute of Cancer Research and The Royal Marsden Foundation Trust. FundingThe Institute of Cancer Research and The Royal Marsden Foundation Trust. DisclosureS. Banerjee: Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Honoraria/reimbursement: Tesaro; Honoraria (self), Honoraria/reimbursement: Clovis; Honoraria (self), Honoraria/reimbursement: Merck Serono; Honoraria (self), Honoraria/reimbursement: Nucana; Honoraria (self), Honoraria/reimbursement: Immunogen; Honoraria (self), Honoraria/reimbursement: Seattle Genetics; Honoraria (self), Honoraria/reimbursement: Roche; Honoraria (self), Honoraria/reimbursement: Gamamabs. J.S. de Bono: Honoraria (self), Non-remunerated activity/ies: Astellas Pharma; Honoraria (self), Research grant / Funding (institution), Non-remunerated activity/ies: AstraZeneca; Honoraria (self): Genentech/Roche; Honoraria (self): Pfizer; Honoraria (self), Non-remunerated activity/ies: Sanofi; Honoraria (self): Bayer; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Merck Serono; Honoraria (self): Merck Sharp & Dohme; Non-remunerated activity/ies: Genmab; Non-remunerated activity/ies: GlaxoSmithKline; Non-remunerated activity/ies: Orion Pharma GmbH; Non-remunerated activity/ies: Qiagen; Non-remunerated activity/ies: Taiho Pharmaceutical; Non-remunerated activity/ies: Vertex; Licensing / Royalties, Royalties paid to Institution, no personal income: Abiraterone Rewards to Inventors; Licensing / Royalties, Royalties paid to Institution, no personal income: PARP inhibitors and DNA repair defects. U. Banerji: Honoraria (self), Precision Medicine - Advanced Prostate Cancer Meeting, London UK -30/11/2018: Astellas; Honoraria (self), Advisory / Consultancy, Translational Clinical Oncology Advisory Board, London, 24/07/2018; FIH Precision Oncology SAB, Frankfurt, 10-11/11/2015: Novartis; Advisory / Consultancy, Clinical Advisory Board, London, 19/03/2018 and 12/02/2015: Karus Therapeutics; Advisory / Consultancy, GI Advisory Board, London, 2/12/2017: Phoenix ACT; Honoraria (self), European Digestive Oncology Research Forum, London, 27-28/11/2017: Eli Lilly; Honoraria (self), KOL ERK Workshop, New Orleans, 17/04/2016; HSP90 Workshop, Washington DC,8/03/2014: Astex; Honoraria (self), AUY922 meeting, New Jersey, USA,12/02/2015: Vernalis; Research grant / Funding (institution), ONX-0801:Funding for investigator-initiated Phase I trial: Onyx Pharmaceuticals; Research grant / Funding (institution), ONX-0801:top-up funding for investigator-initiated phase I trial: BTG International; Research grant / Funding (institution), RAF/MEK: funding for investigator-initiated phase I trial: Chugai; Research grant / Funding (institution), TAX-TORC: funding for investigator-initiated phase I trial: AstraZeneca; Research grant / Funding (institution), FRAME: funding for investigator-initiated phase I trial: Verastem. A. Minchom: Travel / Accommodation / Expenses: Loxo; Advisory / Consultancy: Janssen; Honoraria (self): Faron; Speaker Bureau / Expert testimony: Bayer Media Event. J. Lopez: Advisory / Consultancy: Genmab; Advisory / Consultancy: Novartis; Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche/Genentech; Research grant / Funding (institution), Travel / Accommodation / Expenses: Basilea. All other authors have declared no conflicts of interest.

ACCURACY: phase (P) 2 trial of AL101, a pan-Notch inhibitor, in patients (pts) with recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC) with Notch activating mutations (Notchact mut).

TPS6098 Background: Notch signaling plays a key role in tumorigenesis. Notch cleavage by γ-secretase frees the Notch intracellular domain, which promotes the expression of target genes involved in cancer. AL101, a small molecule, is a γ-secretase inhibitor that potently inhibits Notch1-4, resulting in robust antitumor activity in vivo (PMID 26005526), including ACC xenograft models with Notchact mut (Ferrarotto, AACR 2019, Abstr 4885). Three P1 trials tested AL101 as monotherapy or in combination regimens in &gt; 200 solid/hematologic cancer pts. In the P1 trial of AL101 monotherapy, conducted in 94 pts with advanced/metastatic solid tumors refractory to standard therapies (Tx), AL101 was generally well tolerated, with manageable AEs, and the recommended P2 dose was 4 mg IV once weekly (QW; El-Khoueiry, ASCO 2018, Abstr 2515). 4 pts had objective responses, 2 of those had Notchmut (1 of which had ACC). ACC, a rare cancer that most commonly develops in the major salivary glands, but can also arise in minor salivary glands in the trachea, lacrimal gland, and other sites, is refractory to chemotherapy, with a high recurrence rate. Notchact mut are found in a subset of ACC pts (11%–22%), with particularly aggressive disease and poor prognosis. There is no proven active treatment for R/M ACC pts (PMID 27870570). Methods: ACCURACY (NCT03691207) is an open-label, single-arm, multicenter study of AL101 (4 mg IV QW) in pts with R/M ACC (bone-exclusive disease included) with known Notch1-4act mut. Pts with disease progression within 6 months of enrollment or newly diagnosed metastatic pts are allowed; pts who received &gt; 3 prior systemic Tx are excluded. Primary endpoint: ORR by RECIST v1.1 (or modified MDA bone criteria), by independent review committee (IRC). Secondary endpoints: ORR by investigator review (IR), duration of response by IRC and IR, PFS by IRC, OS, and safety. Per the Simon optimal design, 12 pts are enrolled in stage 1; if ≥2 pts respond, 24 additional pts are enrolled in stage 2. If ≥4 pts in stage 2 respond, the trial is deemed positive. This design yields 5% type I error rate and 80% power, if ORR is 25%. 4 of planned 36 pts have been enrolled as of 2/12/19. Clinical trial information: NCT03691207.

Prevalence and correlates of critical malnutrition (CMN) among gastrointestinal (GI) and non-GI participants in phase I/II (P1/2) clinical trials.

770 Background: Patients (pts) with cancer, in particular GI malignancies, are vulnerable to CMN from both tumor-related digestive symptoms and treatment-related toxicity (TRT). CMN is associated with poor cancer outcomes, including reduced quality of life, poor treatment tolerance and decreased survival. P1/2 trial participants are not routinely screened for CMN or potentially associated psychological and physical activity impairments. Methods: Baseline assessments of nutrition (PG-SGA), distress (NCCN-DT), anxiety (HADS-A), depression (HADS-D), and sedentary lifestyle (SL, Godin-LTQ) were conducted in pts beginning a P1/2 trial. CMN was defined as a PG-SGA score of ≥9. Statistical significance was determined by Fisher’s exact test. A regression model was used to identify a composite predictor of CMN. Results: 100 pts (87% P1, 13% P2) were enrolled. Results of assessments are shown in Table 1. 39% of pts had CMN and 52% had a SL. CMN was more common in non-whites (p = 0.05) and those on P1 trials (p = 0.073). No differences were noted by age, gender, or prior lines of therapy. CMN was strongly associated with depression (p &lt; 0.001) and SL (p &lt; 0.001). 31 pts had GI malignancies [CRC (15), pancreas (8), and other (8)]. CMN was more prevalent in GI pts than non-GI (61% vs 29%, p = 0.004). When evaluating the predictive value of commonly used clinical indicators for CMN such as BMI ( &lt; 25), weight loss (WL) past 2 weeks, or WL past month, having 2/3 of these indicators was the optimal cut-point predictor of CMN (76% sensitivity, 85% specificity). TRT data collection is ongoing. Conclusions: CMN and SL are highly prevalent in P1/2 trial pts, particularly in those with GI cancers and minorities. CMN is strongly associated with depression and SL. A composite clinical indicator (BMI + WL) may be most useful in screening for CMN. Urgent nutritional interventions in these participants may be warranted in light of magnified mortality and toxicity risks. [Table: see text]

Development of the Princess Margaret Immune Oncology Prognostic Index (PM-IPI): A novel prognostic score for patients (pts) treated in immune oncology (IO) phase I (P1) trials.

3058Background: Several previously published scores prognosticate survival for pts treated in cytotoxic and molecularly targeted P1 trials. IO is rapidly evolving in early drug development with uni...

Impact of preventive therapy on the risk of breast cancer among women with benign breast disease

There are three main ways in which women can be identified as being at high risk of breast cancer i) family history of breast and/or ovarian cancer, which includes genetic factors ii) mammographically identified high breast density, and iii) certain types of benign breast disease. The last category is the least common, but in some ways the easiest one for which treatment can be offered, because these women have already entered into the treatment system. The highest risk is seen in women with lobular carcinoma in situ (LCIS), but this is very rare. More common is atypical hyperplasia (AH), which carries a 4–5-fold risk of breast cancer as compared to general population. Even more common is hyperplasia of the usual type and carries a roughly two-fold increased risk. Women with aspirated cysts are also at increased risk of subsequent breast cancer.Tamoxifen has been shown to be particularly effective in preventing subsequent breast cancer in women with AH, with a more than 70% reduction in the P1 trial and a 60% reduction in IBIS-I. The aromatase inhibitors (AIs) also are highly effective for AH and LCIS. There are no published data on the effectiveness of tamoxifen or the AIs for breast cancer prevention in women with hyperplasia of the usual type, or for women with aspirated cysts.Improving diagnostic consistency, breast cancer risk prediction and education of physicians and patients regarding therapeutic prevention in women with benign breast disease may strengthen breast cancer prevention efforts.

Correction: Evaluation of CYP2D6 and Efficacy of Tamoxifen and Raloxifene in Women Treated for Breast Cancer Chemoprevention: Results from the NSABP P1 and P2 Clinical Trials

Correction: Evaluation of CYP2D6 and Efficacy of Tamoxifen and Raloxifene in Women Treated for Breast Cancer Chemoprevention: Results from the NSABP P1 and P2 Clinical Trials

Evaluation of CYP2D6 and Efficacy of Tamoxifen and Raloxifene in Women Treated for Breast Cancer Chemoprevention: Results from the NSABP P1 and P2 Clinical Trials

Controversy exists regarding the association between CYP2D6 enzyme activity and tamoxifen effectiveness in the adjuvant treatment of invasive breast cancer; however, this association in the primary prevention of breast cancer is unknown. We conducted a nested case-control study in the context of the NSABP P1 and P2 prevention trials to determine the impact of CYP2D6 genotype, CYP2D6 inhibitor use, and metabolizer status (CYP2D6 genotype combined with CYP2D6 inhibitor use), on breast cancer events. Women who developed breast cancer (both noninvasive and invasive) while on 5 years of selective estrogen receptor modulators therapy (cases) were matched to controls free of breast cancer. Comprehensive CYP2D6 genotyping was conducted for alleles associated with absent (*3, *4, *5, and *6), reduced (*10, *17, and *41), and increased (*1XN and *2XN) enzyme activity. Information regarding the use of CYP2D6 inhibitors was recorded. A total of 591 cases were matched to 1,126 controls and DNA was genotyped in more than 97%. In patients treated with tamoxifen, there was no association of CYP2D6 genotype [OR (extensive/poor metabolizer): 0.90; 95% CI: 0.46-1.74, P = 0.74), use of a potent CYP2D6 inhibitor (OR 0.92; 95% CI: 0.575-1.486), or CYP2D6 metabolizer status (OR 1.03; 95% CI: 0.669-1.607) with breast cancer occurrence. Likewise, there was no association between any CYP2D6 metabolism parameter with breast cancer events in raloxifene-treated patients. In the NSABP P1 and P2 clinical trials, alterations in CYP2D6 metabolism are not associated with either tamoxifen or raloxifene efficacy.

Abstract PD05-02: Genome-Wide Associations of Breast Events and Functional Genomic Studies in High-Risk Women Receiving Tamoxifen or Raloxifene on NSABP P1 and P2 Prevention Trials. A Pharmacogenomics Research Network-RIKEN-NSABP Collaboration

Abstract Background: NSABP P1 and P2 are the largest prevention trials of tamoxifen and raloxifene in women at high risk of developing breast cancer. Both agents have been shown to decrease, but not eliminate breast cancer risk in these women. The goal of our study was to identify single nucleotide polymorphisms (SNPs) associated with development of breast cancer in high-risk women treated with tamoxifen or raloxifene. Methods: We performed a nested matched case-control genome-wide association study (GWAS) in subjects entered on the P2, which included only postmenopausal women, and subjects at least 50 years old entered on the P1 phase III prevention trials who were treated with tamoxifen or raloxifene. Cases were defined as subjects who developed invasive breast cancer or ductal carcinoma in situ and each was matched to two controls based on trial (P1, P2), age at trial entry, Gail risk score, history of lobular carcinoma in situ, and time on study. The study was restricted to the 94% of subjects self-identified as Caucasian. Genotyping was performed with the Illumina Human610-Quad chip. Eigenstrat analyses were performed to control for population stratification. SNPs were imputed within 200 Kb on either side of regions containing SNPs with p ≤ 3E-05. CYP2D6 genotyping was performed on all subjects. Results: The GWAS included 592 cases and 1171 controls. 547,356 SNPs were used in the analyses after removing 14,019 for call rates less than 98%, 30,560 for minor allele frequencies &amp;lt;1%, and 301 with Hardy-Weinberg equilibrium p-value &amp;lt;1E-06. Eigenvectors did not alter the results when used as covariates. Eleven genotyped SNPs with p-values ranging from 2.12E-06 to 9.98E-06 (conditional logistic regression with eigenvector adjustment) were identified; and 22 SNPs with p &amp;lt; 4E-05 were identified by imputation around these SNPs on chromosomes (Chr) 4, 8, 9, 13, 16 and 22, which were then genotyped with the Invader platform. Following imputation and genotyping, initial functional genomic studies have focused on 8 SNPs on Chr 16 (p-values 1.81E-06 to 9.55E-06, with the lowest p-value for an imputed and fine mapped SNP), all of which were in ZNF423, a gene known to encode a protein that associates with SMAD family members. In lymphoblastoid cell lines genotyped for the 2 top SNPs in ZNF423 (rs8060157 and rs11076499) and stably transfected with estrogen receptor-α, the variant and wild type SNPs displayed striking differences in estradiol-induced expression of ZNF423, SMAD3, BRCA1, and BRCA2. Conclusions: This GWAS revealed SNPs associated with the development of breast cancer in high-risk women treated with tamoxifen or raloxifene. Genome-wide significance was not achieved, but SNPs in ZNF423 identified on Chr 16 were associated with differential expression of ZNF423, SMAD3, BRCA1, and BRCA2 in response to estradiol in vitro, providing direction for future research. (Supported in part by NIH grants U01GM61388, U01GM63173, P50CA116201, U10CA77202, U10CA37377, U10CA69974, U24CA114732, and the Biobank Japan Project funded by the Ministry of Education, Culture, Sports, Science and Technology, Japan) Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD05-02.

Cost-Benefit Analysis of Post-Lumpectomy Treatment in Elderly Women.

Abstract Introduction In this era of rising cost of medical care, it is difficult to decide how to treat patients (pts). Specifically, with elderly pts who have small breast cancers (BC), there are many options. The NSABP B21 study looked at the need for breast radiotherapy (RT) after lumpectomy in node - pts with invasive BC &amp;lt;=1 cm, by speculation that tamoxifen (tam) might be as effective as radiotherapy (RT) in reducing in breast tumor recurrence (IBTR). Pts were randomly assigned to tam, RT/placebo or RT/tam. IBTR rates were similar in the 2 groups of pts aged &amp;gt;=70 who received tam or RT alone. The CALGB also looked at this question in pts &amp;gt;= 70 with stage 1, node -, ER+ BC by randomly assigning them to tam or tam/RT. The only difference between the 2 groups was the rate of IBTR, which was 1% in the tam/RT group and 4% in the tam group. There was no differences in mastectomy for local recurrences, distant metastases, or 5 year OS. With the addition of aromatase inhibitors (AI), the IBTR rate in this cohort would be smaller. Based on these studies, we undertook a cost-benefit analysis of RT vs tam vs AI in pts &amp;gt;=70 with node -, ER+, stage 1 BC.MethodsThe 3 adjuvant treatment (tx) methods considered were conventional whole breast RT (28 fractions) alone, anastrozole (1mg Qday x 5 years), &amp; tam (20mg Qday x 5 yrs). Rates of IBTRs were extrapolated from the CALGB 5 year data as a basis, the NSABP B21 trial relative risks (9.3% RT alone vs 16.5% Tam alone), &amp; the ATAC trial relative risks (1.5% RT+Tam vs 1.0% RT+AI). Rates of contralateral breast cancers (CBC) were similarly estimated. Costs of outpatient tx was estimated using Medicare Part B reimbursements as a surrogate. Drug costs were taken from prices from Drugstore.com. All breast failures (CBC + IBTRs) were assumed treated with mastectomy alone. Costs associated with mastectomy were estimated using Medicare Part B reimbursements for surgical costs and associated Part A inpatient prospective payments. Total cost for each tx was calculated by the formula C = FC + TC, where C= total cost, FC= failure associated cost (failure rate x mastectomy cost), and TC = tx cost.ResultsThe results for estimation of failure rates at 5 years is shown in Table 1.Table 1 IBTRCBCTotal Breast FailuresRT alone2.25%3.07%5.32%AI alone2.67%0.74%3.41%Tam Alone4.00%1.25%5.25% The cost of mastectomy was $10,037.08.The results for total cost are shown in Table 2.Table 2 Treatment CostFailure Associated CostTotal CostRT alone$11,717.70$533.97$12,251.67AI alone$18,645.14$342.26$18,987.40Tam alone$1,013.28$526.95$1,540.23 DiscussionWe consider costs of initial tx and tx of local failure. Tam alone would be the tx of choice if simply considering this total cost. However, if side effects associated with each tx is considered, then the cost for each would need to be increased accordingly. For example, in NSABP P1 trial, 3 pts died from PE on tam. If a cost were estimated for these deaths (beyond the scope of this abstract), the total cost for tam would be much higher.ConclusionsThe results from adjuvant tx after breast conserving surgery in older women with early stage BC have been excellent. In an era of steadily increasing health care costs, the cost-to-benefit ratio should be one of the factors taken into consideration when deciding tx options. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1074.

Phase I and Pharmacokinetic (PK) Study of Everolimus (RAD001) in Patients with Relapsed or Refractory Non-Hodgkin's Lymphoma (NHL).

Abstract 1712Poster Board I-738[Background and Purpose] Everolimus (RAD001), an oral derivative of rapamycin, inhibits the mammalian target of rapamycin (mTOR) serine-threonine kinase, which plays a key role in regulating cell growth and proliferation. Although anti-lymphoma effects of RAD001 have been shown in preclinical studies and one phase II clinical study in NHL, there is no PK data in NHL patients (pts). A phase I (P1) study was conducted to evaluate safety, PK profile, and efficacy of RAD001 in Japanese pts with relapsed and/or refractory NHL.[Patients and Methods] Pts with relapsed or refractory NHL, age ≥20, and PS 0-2 (ECOG) were enrolled and treated with RAD001, administered orally once daily at either 5 or 10 mg. Dose escalation was based on the clinical assessment of safety, incidence of dose-limiting toxicity (DLT), and probability of incidence of DLT. The latter probability distribution was estimated by a Bayesian logistic model, using prior information from other P1 trials with this agent in solid tumors. DLTs were evaluated in 6 pts at each dose level during the initial 28 days of study treatment (cycle 1). PK parameters were evaluated on days 1 and 15 of cycle 1. Response was assessed according to the International Workshop Criteria for NHL (1999).[Results] A total of 13 pts were enrolled into 2 cohorts as follows; 5 mg (7 pts, DLBCL: 2; MCL: 1; FL: 1; PTCL: 1; CTCL: 1; ALCL: 1) and 10 mg (6 pts, FL: 4; MCL: 1; ALCL: 1). 12 pts were evaluable for DLTs. 1 pt in the 5 mg cohort was inevaluable for DLTs due to early disease progression. No DLTs were observed at either dose level. Frequently encountered potentially drug-related adverse events (AEs) (≥40%) include leukopenia (8/13, 62%), thrombocytopenia (8/13, 62%), elevated AST (9/13, 69%), stomatitis (7/13, 54%), anemia (6/13, 46%), nasopharyngitis (6/13, 46%), and elevated ALT (6/13, 46%). Potentially drug-related Gr 3 or 4 toxicities include anemia (Gr 4 : 1), thrombocytopenia (Gr 4 : 1; Gr 3: 1), lymphopenia (Gr 4 : 1; Gr 3: 3), elevated LDH (Gr 3: 1), anorexia (Gr 3: 1), hyperglycemia (Gr 3: 1), fatigue (Gr 3: 1), hepatic function abnormal (Gr 3: 1), P. jiroveci pneumonia (Gr 3: 1), hyperkalemia (Gr 3: 1), and hypokalemia (Gr 3: 1). All toxicities cited above were transient and reversible. Non-infectious pneumonitis (Gr 1) was observed in 1 pt but resolved following discontinuation of RAD001 without additional therapy. Tmax was achieved within 4 hours, and Cmax and AUCtau both showed dose-proportional increases. The accumulation ratio after daily administration was approximately 2-fold. These data are consistent with those from a previous P1 study in solid tumors. A total of 4 objective responses (OR) were observed (summarized below):[Conclusions] RAD001 is well tolerated in this pt population at doses up to 10 mg/day and shows preliminary evidence of activity in relapsed or refractory NHL. The PK profile in pts with NHL is similar to that in pts with solid tumors. A global randomized phase III study to determine efficacy of RAD001 as adjuvant therapy following front-line R-CHOP induction in poor-risk DLBCL is currently ongoing. The data from this P1 study led directly to Japan's decision to participate in the global phase III study. DisclosuresShimada:Novartis Pharma K.K. Japan: Employment. Kobayashi:Novartis Pharma K.K. Japan: Employment.Dose (mg)ORHistologyDuration of response (mo)Status*5CRDLBCL12+Ongoing5PRDLBCL10+Ongoing10CRFL10+Ongoing10PRFL1.5d/c**As of 31 July 2009, 5/13 pts are still on active treatment.*as of 31 July 2009**treatment stopped due to Non-infectious pneumonitis

LCIS and tamoxifen use: A single institution review

1527 Background: Results of the NSABP-P1 trial were published in 1998 showing a 50% reduction in breast cancer in the high- risk population with the use of tamoxifen. The use of tamoxifen is individualized, and depends on both patient and physician factors. We looked at the recommendations for and the use of tamoxifen in women with LCIS. Methods: A retrospective chart review at a single institution was performed from March 27, 1980 through September 19, 2005 for patients diagnosed with LCIS. Pathology and operative reports, as well as patient notes were reviewed for discussions about tamoxifen. Data was collected on whether a discussion took place, whether tamoxifen was or was not advised, whether the patient declined to take tamoxifen, whether they took it in the past or were currently on tamoxifen. We also examined the rate of DCIS and invasive cancer in this population. Results: There were 321 patients diagnosed with LCIS. Of those patients 193 were diagnosed after the publication of the P1 trial. Of these 193 patients we identified 104(54%) patients whose charts contained notes indicating a discussion about tamoxifen. The results of the discussion about tamoxifen are as follows: 21(20%) patients were currently taking tamoxifen, 16(15%) had taken it in the past, 37(36%) patients declined to take tamoxifen, and 17(16%) had not made a decision about taking tamoxifen. There were 13(13%) patients for whom tamoxifen was advised against. In the entire cohort of 321 patients, 15% went on to develop DCIS or invasive cancer in the first 12 years of follow up. We did not look at cancer rate Vs tamoxifen use due to the small numbers with available information. Conclusions: While the P1 trial recommends tamoxifen for breast cancer prevention in high-risk patients, in our experience, almost half of the patients did not have a documented discussion about the medication, and the majority of those who did decided not to take tamoxifen. This will likely have a large impact on the rate of DCIS and invasive breast cancer in this group. No significant financial relationships to disclose.

Barriers to minority participation in breast carcinoma prevention trials

Breast carcinoma prevention trials must recruit large cohorts of women who have an above-average risk of developing breast carcinoma. Recruitment for the Study of Tamoxifen and Raloxifene (STAR) trial required volunteers to complete a risk assessment questionnaire form (RAF). Women whose estimated risk of developing breast carcinoma in the next 5 years was > or = 1.67% based on the Gail model were invited to participate in STAR. Less than 4% of participants in the previously conducted P1 (tamoxifen vs. placebo) trial were minority women. We, therefore, studied barriers to minority participation in STAR among black, white, and Hispanic women who completed an RAF. The authors analyzed the association of Gail model risk factors, education, and insurance with race/ethnicity using chi-square tests and two-sided P values. They developed logistic regression models of trial eligibility, controlling for the Gail model risk factors, education, and insurance status. Among 823 women who completed an RAF, white women were 10 times as likely as Hispanic women and 45 times as likely as black women to be eligible for STAR. Age at first birth (P = 0.04), having an affected first-degree relative (P < 0.0001), having had a biopsy (P < 0.0001), education (P < 0.0001), and insurance status (P < 0.0001) varied by race/ethnicity. All variables except insurance status were associated with eligibility when race was excluded from the model. In a model that included race/ethnicity, the same factors remained statistically significant. These findings suggested that both the race/ethnicity adjustment and socioeconomic factors were barriers to eligibility for and contribute to low minority participation in breast cancer prevention trials.

A working model for the time sequence of genetic changes in breast tumorigenesis.

INTRODUCTION Although steady gains have been made in the early diagnosis and treatment of breast cancer, 30%–50% of affected women still die from the disease. Attention has turned to the major potential of chemoprevention for decreasing breast cancer incidence and mortality. Chemoprevention refers to the administration of drugs to block or reverse carcinogenesis before the development of invasive cancer. The promise of chemoprevention in breast cancer was raised by the results of clinical trials of tamoxifen in women with clinically detectable breast cancers. These studies showed a benefit from tamoxifen in reducing tumor recurrence, prolonging survival, and reducing the incidence of contralateral breast cancer, as compared with placebo. The National Surgical Adjuvant Breast and Bowel Project P1 trials demonstrated that tamoxifen was also useful as a breast cancer preventive agent in many women at increased risk for the disease but without a prior history of invasive breast carcinoma. Chemoprevention trials typically use the occurrence of cancer as an endpoint, and thus require large sample sizes and long durations of study. To circumvent these problems, several researchers have explored the use of surrogate endpoint biomarkers (SEBs) that could be used in lieu of the occurrence of cancer as an indicator of efficacy. Neoplastic transformation is accompanied by a number of measurable phenotypic changes at both the cellular and molecular level, and it is expected that an effective chemopreventive agent would affect these changes through alterations in the expression of specific markers. SEB studies have typically used one of two models. The short-term ductal carcinoma in situ (DCIS) model uses women with DCIS with or without small invasive tumors who are randomized to receive drug or placebo in the interval between biopsy and definitive surgery. The directed core biopsy hyperplasia model randomizes women with core biopsy-detected hyperplasia to receive drug or placebo for a more extended period of time. An important issue in the conduct of an SEB trial is the selection of appropriate biomarkers. Clearly, they should be biologically relevant to the process of breast tumorigenesis. Equally important, they should be characteristic of the premalignant lesion that is being examined. Molecular changes that characterize the development of a metastatic phenotype, for example, may not be appropriate in a model system looking at DCIS or atypical hyperplasia, but changes associated with immortalization might be very useful in these models. The purpose of this review was to use published data to develop a working model of the time sequence of genetic changes in human breast tumorigenesis. Clearly, many of the genetic loci that have been associated with breast tumorigenesis have not yet been examined in sufficient detail to determine where they might fit in such a time sequence. This review is restricted to those relatively few markers where this question has been addressed, and should be considered as a work in progress. As background, Vogelsteins’s model system for colorectal tumorigenesis was reviewed. Two types of human breast cancer studies were included: (1) studies using normal and neoplastic breast tissue, which provide information about the occurrence of specific genetic changes (mutation, deletion, amplification) in different types of breast lesions, ranging from typical hyperplasia to metastatic carcinoma; and (2) studies using human mammary epithelial cell lines, which provide in-depth information about the effects of adding or deleting specific genes or chromosome segments on the processes of immortalization and transformation in normal mammary epithelial cells. No competing interests declared.