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Background:As human papillomavirus positive (HPV+) oral cavity and pharynx cancer (OCPC) incidence increases significantly, our objective was to determine whether selected sociodemographic and clinical factors were associated with HPV+ OCPCs overall and by oropharyngeal and non-oropharyngeal sites.Methods:Surveillance, Epidemiology and End Results (SEER) Program data were used in this study. Specifically, univariate and logistic regression models were used to examine the relationships between HPV+ and HPV− OCPC cases and age, sex, race, ethnicity, marital status, factors of neighborhood socioeconomic status (i.e., nSES/Yost index) and rurality/urbanity, first malignancy status, histology, reporting source, stage at diagnosis, and OCPC anatomic site. The same approach was used to identify risk factors for HPV positivity for oropharyngeal and non-oropharyngeal OCPCs separately.Results:In all OCPCs, cases that were male, Conclusions:Sociodemographic and clinical differences in HPV+ and HPV− OCPC, overall and for (non)oropharyngeal, cases exist.Impact:Identification of OCPC and (non)oropharyngeal risk factors for HPV positivity may assist in discovering high-risk groups that should receive enhanced public health efforts to reduce the U.S. OCPC burden.

Introduction: Adults age ≥65y constitute the majority of patients (pts) diagnosed with cancer. There is a gap in knowledge about the safest and most effect cancer treatments for older pts. At The Ohio State University, we have a longitudinal multidisciplinary geriatric clinic for adults ≥ 65 years of age diagnosed with breast cancer (BC). The clinic team consists of a physician, nurse practitioner, dietician, physical therapist, social worker nurse, and pharmacist. We evaluate the unique needs of older pts with breast cancer by completing a comprehensive geriatric assessment (CGA). Eligible patients are enrolled into OSU-16153 which is a is prospective cohort study of pts ≥65y with new diagnosis of BC to better understand complex health issues of this population, and to collect data to support future studies. Methods: Forty eight pts have completed the baseline questionnaires including demographics, lifestyle and health history and CGA. Summary statistics were used to describe the baseline characteristics. Results: The median age of patients enrolled in the study was 77 years (range 67-94), the mean BMI was 28, 50% (24/48) were Caucasian and 6% (3/48) were African American. Mobility was assessed mobility with the time get up and go (TGUG), mean 9.8 (SD=6.2) and grip strength, mean of 31. Cognitive limitations were screened with the blessed orientation memory concentration test, mean 3.9 (SD=5.0) and mini-cog, mean 3.6 (SD=1), malnutrition, mean 12.3 (SD=12.2) and depression, mean 1.6 (SD=2.4). Functional limitations were measured with Katz, mean 5.9 (SD=0.2), and Lawson, mean 7.8 (SD=0.8). Disease characteristics included 18% (9/48) Tis, 54% (26/48) T1, 21% (10/48) T2, 2%(1/48) T3, and 4% (2/48) T4 tumors, 65% (31/48) lymph node negative and 81% (39/48) estrogen positive (ER+),17% (8/48) ER negative and 4% (2/48) HER2 positive. Oncotype score was 25 in 4% (2/48). Twelve percent (6/48) received adjuvant chemotherapy for triple negative or ER+ breast cancer with high oncotype with docetaxel/cytoxan and 4% received trastuzumab based therapy and they were able to complete all planned cycles. Two pts received chemotherapy based on results of CGA. Forty-two pts were eligible to receive endocrine therapy (ET); 3 pts with ductal carcinoma in-situ (DCIS) and 2 pts with invasive BC declined, 1 did not follow up after her initial visit. Five pts switched ET due to side effects. The 7 patients with invasive BC who declined or switched ET due to side effects all had an abnormal TGUG, 43% (3/7) had an impaired min-cog and 57% (4/7) had impaired hand grip. Conclusions: The majority of older adults have no functional deficits in ADL/IADL, have adequate mobility and grip strength and did not screen positive for cognitive limitations, depression or, malnutrition. Our data shows that the mobility and cognitive assessment of a CGA may serve as a predictor of toxicity from ET therapy and identify patients who are at risk for side effects and who may benefit from additional interventions. The majority of pts who received adjuvant chemotherapy and ET tolerated well. Our pilot data shows a CGA is feasible and that a CGA helped direct appropriate therapy. Citation Format: Nicole Williams, Julie Stephens, Elizabeth Kress, Erin Frey, Susan Fugett, Paige Erdeljac, Stephanie Yager, Erin Holley, Cari Utendorf, Nikki Ford, Caitln Ubbing, Jeanie Overcash, Bhuvaneswari Ramaswamy, Anne Noonan. Feasibility of comprehensive geriatric assessment in an academic breast oncology clinic [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-16-01.

Background:Invasive lobular carcinoma (ILC) accounts for up to 15% of all breast cancers and is clinically and biologically distinct from invasive ductal carcinoma (IDC). Despite that, women with early stage ILC are often treated similarly to IDC. However, several retrospective studies suggest that patients (pts) with ILC may not derive survival benefit from the addition of chemotherapy to endocrine therapy relative to pts with IDC. The purpose of our study was to compare outcomes of pts with ILC treated with chemotherapy with those who received endocrine monotherapy. Methods: A retrospective review of pts with ILC or pleomorphic lobular carcinoma treated at the Ohio State University James Cancer Center from 2004-2014 was performed. Clinico-pathologic characteristics, treatment summary and clinical outcomes were collected. Distant disease-free survival (DDFS) was defined as time from diagnosis to the first distant metastases or death and overall survival (OS) was the time from diagnosis to death or last known follow up. DDFS and OS curves were created using Kaplan-Meier methods and compared using log-rank tests. Cox proportional hazard models were used to calculate univariate and multi variable hazard ratios (HR) for OS and DDFS. Results: We identified 379 pts with early stage ILC (stage I: 43% (162/379), stage II: 34% (127/379), stage III: 22% (84/379), unknown: 1% (6/379)). The majority of pts were post-menopausal (79%), Caucasian (92%) and ER+/PR+ (87%) and HER2 negative (96%). One hundred seventy six pts (46%) received chemotherapy and 189 (50%) pts received endocrine therapy alone. Pts who received chemotherapy had stage II or III disease, positive lymph nodes and grade 2 or 3 tumors; while pts who received endocrine monotherapy had stage I disease, negative lymph nodes and grade 1 or 2 tumors. We found a 51% decrease in chemotherapy (from 63% to 31%) and an increase in endocrine monotherapy use (from 34% to 65%) between 2004-2010 and 2011-2014. One hundred thirty two pts were evaluated with Oncotype DX, of which 76% (100/132) were node negative with the majority having a low recurrence score (low: 64%; intermediate: 33%; high: 3%). The use of Oncotype DX increased from 21.1% in 2004-2010 to 47.9% in 2011-2014. We found that 112 of 149 pts with at least 5 years follow up (75.2%) successfully completed five or more years of endocrine therapy. Univariate cox models showed worse DDFS HRs for type of therapy and node status (HR: 2.36, p=0.005, HR: 4.16, p Conclusion: We found no difference in DDFS between endocrine monotherapy and chemotherapy after adjusting for age, grade, and nodal involvement in pts with early stage ILC. This supports the hypothesis that ILC may not derive a significant benefit from the addition of chemotherapy. We need more prospective clinical trials considering histology to better understand how best to treat ILC. Citation Format: Williams N, Liu J, Stephens J, Palettas M, Boutrid H, Sardesai S, Reinbolt R, Stover D, VanDeusen J, Noonan A, Wesolowski R, Lustberg M, Ramaswamy B. Outcomes in hormone receptor positive, invasive lobular cancer in the era of endocrine monotherapy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-14-12.

Background: Trastuzumab (T) induced cardiomyopathy remains a significant limitation to adjuvant HER2 directed therapy. Recent studies have aimed to reduce cardiotoxicity through combination with non-anthracycline (non-A) chemotherapy or shorter treatment duration. However there is limited data regarding cardiac outcomes and long-term survival with early discontinuation of adjuvant T. Methods: An IRB-approved single-institution retrospective analysis was performed for 401 consecutive patients with non-metastatic HER2+ breast cancer treated at the Ohio State University Comprehensive Cancer Center from 2005-2015. Medical records were reviewed for clinicopathologic features, systemic treatment and survival information. Disease Free Survival (DFS) was defined as time from diagnosis to first recurrence (loco-regional or distant recurrence) including second primary breast cancer or death. Overall survival (OS) was defined as time from diagnosis to death or last known follow up. OS and DFS estimates were generated using Kaplan Meier methods and compared using Log-rank tests. Cox proportional hazard models were used to calculate univariate and multivariate hazard ratios for OS and DFS. Results: A total of 371/401 (92.5%) patients received adjuvant T (n= 401, mean age: 59.4 years; stage 1: 120, 30%; stage II: 194, 48%; stage III: 87, 22%; ER+: 235, 58%); among whom 106/371 (28.6%) patients held adjuvant T for any reason. Median duration of therapy in patients with any interruption with T was 11.3 (0.5-16.9) months and 23/371 (6.9%) received less than 6 months of adjuvant T. Cardiomyopathy (measured as LVEF decline on 2D echocardiogram or MUGA >= 15 points) was the most common reason for withholding T (66/106, 62.3%). The majority of these patients received a cardiology referral (77/ 106, 72.6%) with a 13 day mean time to evaluation in outpatient clinic. Patients receiving non-A chemotherapy and beta blockers or ACE inhibitors during treatment were significantly less likely to experience cardiomyopathy (A vs non-A: 49/190, 25.8% vs. 16/136, 11.8% p=0.002); (Med vs no Med: 7/148, 4.73% vs 59/184, 32.1%; p Table 1- Discontinuation of adjuvant trastuzumab Number of patients (%)Initial treatment371Completed therapy with no interruption265 (71.4)Interruption of therapy for minimum of 2 weeks64 (17.2)Permanently discontinued42 (11.3) Conclusion: Discontinuation of adjuvant trastuzumab, most often from cardiomyopathy, is an independent prognostic marker for worse DFS in non-metastatic HER2 positive breast cancer. Non-anthracycline chemotherapy and use of cardio-protective medication is associated with significantly reduced incidence of cardiotoxicity in this population. Future prospective studies should consider optimizing cardiovascular function to avoid interruption in adjuvant HER 2 directed therapy. Citation Format: Sardesai S, Liu J, Palettas M, Stephens J, Stover D, Williams N, Reinbolt R, VanDeusen J, Wesolowski R, Lustberg M, Ramaswamy B. Cardiovascular outcomes and long term survival with discontinuation of adjuvant trastuzumab [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-16-03.

Background: The approved dosing schedule of capecitabine monotherapy in metastatic breast cancer (MBC) is 1250 mg/m2/dose administered days 1 through 14 of a 21-day cycle, but many patients (pts) have difficulty with this schedule due to side effects. Use of a lower starting dose such as 1000 mg/m2/dose or use of an alternative 28-day administration schedule (7 day on, 7 day off, repeat) allows for greater tolerability. Given limited data regarding efficacy of the alternative 28-day schedule, the primary objective of this study was to compare the efficacy of different schedules of capecitabine in patients with MBC. Methods: A retrospective chart review of pts with metastatic breast cancer who received capecitabine as monotherapy between 2002 and 2014 at the Ohio State University James Cancer Hospital was performed. We excluded any HER2-positive patients who had received concurrent HER2-targeted therapy. Pts who initiated therapy at a dose of 1000 mg/m2/dose were classified by these dosing schedules: Arm A (21 day), B (28 day), and C (changeover from 21 day to 28 day). Time to treatment failure (TTF) and overall survival (OS) were compared between dosing schedules using Kaplan Meier curves and log-rank tests. Results: A total of 181 MBC patients (Arm A: n = 113, Arm B: n = 25, Arm C: n = 43) with the following patient characteristics met eligibility criteria; 86.2% Caucasians, 13.8% non-Caucasians, 64.64% estrogen receptor (ER)-positive, 3.31% ER positive/HER2-positive, 2.22% ER negative/HER2-positive, and 29.83% triple-negative. The HER2-positive patients were excluded as they received concurrent therapy. A significant difference was seen in TTF (Arm A: 2.7 mo, Arm B: 2.8 mo, Arm C: 7.1 mo, p = 0.001) when comparing all dosing schedules as well as in OS (Arm A: 5.7 yrs, Arm B: 9.6 yrs, Arm C: 7.8 yrs, p = 0.006). After an initial dose reduction, patients on Arm B tolerated capecitabine for a longer period of time than patients on Arm A before needing a second dose reduction (Table 1). The median time on capecitabine for Arm A was 11.9 weeks and 12.6 weeks for Arm B, and the mean time of both Arm A and Arm B on capecitabine was 22.2 weeks. Patients with ER-positive breast cancer had improved TTF (4.45 months vs 2.32 months, p < 0.001) and OS (7.26 years vs 3.99 years, p < 0.001) compared to ER-negative breast cancer. Caucasians had improved TTF compared to African Americans (AA) and other races (3.90 mo vs 2.87 mo, p = 0.004); however, there was no significant difference in OS. Median starting dose (mg/m2): Arm A - 1000; Arm B - 1043; Arm C - 1000 Time to 1st dose reduction (weeks): Arm A - 6; Arm B - 6; Arm C - 6.5 Dose after 1st reduction (mg/m2): Arm A - 808; Arm B - 848.5; Arm C - 802 Time to 2nd dose reduction (weeks): Arm A - 6; Arm B - 20; Arm C - 8 Dose after 2nd reduction (mg/m2): Arm A - 599.5; Arm B - 690; Arm C - 697 Time to 3rd dose reduction (weeks): Arm A - 6; Arm B - 0; Arm C - 24 Dose after 3rd reduction (mg/m2): Arm A - 575; Arm B - 0; Arm C - 557 Table 1: Median dose (mg/m2) and median time to reductions (in weeks) Conclusions: Our study shows that patients who received the 28-day cycle initially or who were switched to the 28-day cycle appeared to have improved TTF and OS compared to patients on the 21-day cycle. It also shows that AA women had worse TTF on capecitabine when compared to Caucasians. One hypothesis for the improved TTF and OS is that this could be due to a higher total dose of capecitabine received in Arm B and C as shown in Table 1. We acknowledge that the limitations of our study include the sample size and the retrospective nature, and that further work needs to be done. However, the 28-day dosing schedule for capecitabine could be an alternative for elderly patients or patients with poor performance status who are at higher risk for drug toxicities. Citation Format: Nicole Olivia Williams, Anupama Suresh, Julie Stephens, Marilly Palettas, Michael J. Berger, Akaansha Ganju, Raquel Reinbolt, Robert Wesolowski, Anne M. Noonan, Jeffrey Bryan VanDeusen, Sagar Sardesai, Maryam Lustberg, Maryam B. Lustberg, Bhuvaneswari Ramaswamy. Efficacy of alternative 28-day capecitabine dosing schedule in metastatic breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A69.

Background: Adults over age 65 are the fastes- growing segment of the US population. However, clinicians have less evidence of how to treat older adults, because they are underrepresented in clinical trials, and studies designed specifically for older adults are rare. Therefore, clinicians have to extrapolate from trials conducted in younger, healthier populations when developing treatment plans for older adults. Over 40% of new breast cancer diagnoses in the US occur in women aged over 65 years. In general, breast cancer in the older woman has distinct biologic features, including less aggressive characteristics and greater expression of estrogen receptor and progesterone receptor. Increasing age is associated with higher rates of comorbidity and frailty, which has been shown to potentially reduce the survival advantage of more aggressive breast cancer therapies. We are conducting a prospective cohort study of adults > or = 65 years with a new diagnosis of breast cancer (OSU-16153) in order to better understand the complex health issues faced by this population, and to collect data with which to support future studies designed to improve the management of these patients. Specific Aims: 1) To assess overall and progression-free survival of breast cancer patients ages 65 and older seen in the Breast Medical Oncology clinics at the Stefanie Spielman Comprehensive Breast Center at The Ohio State University; 2) to examine the association of demographic, diagnostic, and treatment data with patient outcomes, such as progression-free and overall survival, within this patient population; 3) to evaluate the unique needs of breast cancer patients ages 65 and older by implementing a Comprehensive Geriatric Assessment (CGA) within the Breast Medical Oncology clinics at The Ohio State University. Methods: The study will enroll patients > or = 65 years with a new diagnosis of breast cancer. Participants will complete a brief baseline questionnaire, including items addressing demographics, lifestyle, and health history. Patients will then be asked to complete a Comprehensive Geriatric Assessment (CGA) at the time of enrollment, and approximately every six months while on follow-up. The CGA contains both performance-based assessments of patients’ function, completed by study staff, as well as the patients’ self-reports of symptoms and quality of life. The CGA contains a multifaceted battery of clinical instruments including the PROMIS Global Short Form, Functional Assessment of Cancer Therapy-Breast (FACT-B), Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale, The Pittsburgh Sleep Quality Index, Geriatric Depression Scale, The James Supportive Care Screening Tool, Timed Up & Go Test, Grip Strength, Blessed Orientation-Memory-Concentration Test, Mini-Cog Test, Charlson Comorbidity Index, Mini Nutritional Assessment, Katz Index of Independence in Activities of Daily Living, and Instrumental Activities of Daily Living. Participant medical records will be reviewed every three months to assess survival, disease progression, and treatment changes. All questionnaire data will be completed using iPads, and will be directly recorded into the REDCap database. Electronic medical records will be reviewed by research staff, and relevant data will be manually entered into the REDCap database. The aim is to enroll 1,000 participants, and the recruitment period will be five years from study initiation. Participants will be followed for five years from the time of enrollment, resulting in a total study length of ten years. The study opened to accrual on 18 April 2017. To date 3 patients have been enrolled and have completed baseline assessments. Citation Format: Anne M. Noonan, Janine A. Overcash, Anupama Suresh, Laura K. Flora, Julie Stephens, Geetika Bhatt, Raquel Reinbolt, Nicole O. Williams, Robert Wesolowski, Jeffrey B. VanDeusen, Sagar D. Sardesai, Maryam B. Lustberg, Bhuvaneswari Ramaswamy. A prospective geriatric breast cancer cohort study to define unique features and outcomes in older breast cancer patients [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A55.

Background: Increasing evidence suggests that higher parity and lack of breastfeeding associates strongly with the risk of developing the aggressive triple-negative breast cancer (TNBC). There is a 25-50% reduction in risk of developing TNBC in women who have breastfed >4-6 months when compared to parous women who have never breastfed. Higher rates of breastfeeding and lower incidence of BC observed in native African women support this postulate. Observational studies and recent national statistics indicate that the prevalence of breastfeeding is markedly low among African-American women (AAW) (58.9%) compared to Caucasian women (CW) (75.2%). Due to the remarkable health and economic benefit of breastfeeding, we investigated whether patients received information about breast cancer risk reduction as part of breastfeeding counseling and whether this knowledge affected participants' decision to initiate and sustain breastfeeding. Methods: A cross-sectional survey study was conducted from September 2016 to June 2017 at The Ohio State University Comprehensive Cancer Center (OSUCCC) on women aged 18-50 who had at least one live-born child. Participants completed an electronic survey that included demographic information and details of breastfeeding history. Recruitment occurred via primary care secure patient portal electronic messaging (MyChart) and an online national clinical research registry (Research Match). Summary statistics were used to describe responses. Wilcoxon Rank Sum test was used to compare length of breastfeeding. Results: A total of 724 women (496 CW and 152 AAW and 76 unknown) completed the online survey; 503 responses through Research Match, 197 through MyChart, and 24 unknown. 92% of those who responded had breastfed. 56% (60.7% Caucasians and 46.1% AA) of women said they were aware breastfeeding reduced the risk of cancer. Of those who were aware of the risk, 36.4% said that this knowledge affected their decision to breastfeed. Of the 39 who did not breastfeed, 23 (59.0%) said being aware of this risk would have influenced their decision. Only 16.6% of women reported they received this information from health care providers; others were informed through magazines and Internet. The mean length of breastfeeding among women who were aware of this benefit was significantly longer than the women who were not aware (13.2 months vs 9.3 months, respectively, p Conclusions: Our study showed that there are disparities between AAW and CW in the knowledge that breastfeeding reduces the risk of breast cancer and in the duration of breast feeding. In addition, we showed that increased knowledge impacts decision-making regarding breastfeeding. Hence, development of culturally relevant communication strategies, especially in AAW, can impact initiation and maintenance of breastfeeding, and ultimately result in aggressive breast cancer reduction. Citation Format: Akaansha Ganju, Anupama Suresh, Julie Stephens, Marilly Palettas, Diana Burke, Laura Miles, Maryam Lustberg, Seuli Brill, Bhuvaneswari Ramaswamy. Knowledge of breastfeeding to reduce breast cancer risk [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr C57.

Background: Heat shock protein 90 (HSP90) is a molecular chaperone that is required for proper folding and stabilization of proteins. Client proteins of HSP90 include many mediators of signal transduction known to be over-activated in triple negative breast cancer such as AKT, EGFR, members of RAS/MAPK signaling pathways and androgen receptor. Expression of HSP90 has been found to be upregulated in multiple triple negative breast cancer cell lines and associated with poor outcome of breast cancer patients. In addition, over-expression of HSP90 client proteins such as AKT and c-RAF has been implicated in paclitaxel resistance. Onalespib (AT13387) is a synthetic non-ansamycin small molecule that acts as an inhibitor of HSP90 by binding to the amino terminal of the protein and has dissociation constant (Kd) of 0.71 nM. Materials and Methods: Patients with inoperable or metastatic triple negative or weakly hormone receptor positive breast cancer are treated with onalespib and paclitaxel on days 1, 8, 15 every 28 days. Paclitaxel is given at a standard dose of 80 mg/m2 while the dose of onalespib is gradually increased using standard 3+3 design (see table). In order to assess the effect of each drug on pharmacokinetics of the other drug, onalespib is given on day -7 prior to cycle 1 and skipped on day 1 of cycle 1 during which paclitaxel in administered alone. The primary objective of the study is to determine recommended phase 2 dose and assess the toxicity profile of the combination. The secondary objectives include effect of onalespib on pharmacokinetics of paclitaxel and effect of paclitaxel on pharmacokinetics of onalespib. Overall response rate, response duration and progression-free survival will also be assessed. Dose Escalation ScheduleDose LevelDoseOnalespib (mg/m2 IV on days 1, 8, 15)Paclitaxel (mg/m2 IV on days 1, 8, 15)Level -110080Level 112080Level 215080Level 320080Level 426080 Conclusion: The study opened to accrual on January 15, 2016 and is currently enrolling the first 3 patients to dose level 1. Citation Format: Robert Wesolowski, Maryam B. Lustberg, Ewa Mrozek, Rachel Layman, Raquel Reinbolt, Ming Poi, Nadia Osman, Andrea Lively, Julie Stephens, Michael Grever, Bhuvaneswari Ramaswamy. Phase 1b study of heat shock protein 90 inhibitor onalespib in combination with paclitaxel in patients with advanced, triple-negative breast cancer (NCT02474173). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT033.

Germline mutations in the PTEN tumor suppressor cause Cowden and Bannayan-Riley-Ruvalcaba syndromes, two dominantly inherited disorders characterized by mental retardation, multiple hamartomas and variable cancer risk. Here we modeled three sentinel mutant alleles of PTEN identified in Cowden patients and show that the nonsense PtenΔ4–5 and missense PtenC124R and PtenG129E alleles lacking lipid phosphatase activity cause similar developmental abnormalities but distinct tumor spectra with varying severity and age-of-onset. Allele-specific differences may be accounted by loss-of-function for Pten Δ4-5, hypomorphic function for PtenC124R and gain-of-function for PtenG129E. These data demonstrate that the variable tumor phenotypes observed in Cowden and Bannayan-Riley-Ruvalcaba syndrome patients can be attributed to specific mutations in PTEN that alter protein function through distinct mechanisms. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3260.