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PURPOSE Effective therapies are needed for the treatment of patients with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer (MBC) with brain metastases. A trastuzumab radioisotope has been shown to localize in brain metastases of patients with HER2-positive MBC, and intracranial xenograft models have demonstrated a dose-dependent response to trastuzumab. METHODS In the phase II PATRICIA study (ClinicalTrials.gov identifier: NCT02536339 ), patients with HER2-positive MBC with CNS metastases and CNS progression despite prior radiotherapy received pertuzumab plus high-dose trastuzumab (6 mg/kg weekly) until CNS or systemic disease progression or unacceptable toxicity. The primary end point was confirmed objective response rate (ORR) in the CNS per Response Assessment in Neuro-Oncology Brain Metastases criteria. Secondary end points included duration of response, clinical benefit rate (complete response plus partial response plus stable disease ≥ 4 or ≥ 6 months) in the CNS, and safety. RESULTS Thirty-nine patients were treated for a median (range) of 4.5 (0.3-37.3) months at clinical cutoff. Thirty-seven patients discontinued treatment, most commonly because of CNS progression (n = 27); two remained on treatment. CNS ORR was 11% (95% CI, 3 to 25), with four partial responses (median duration of response, 4.6 months). Clinical benefit rate at 4 months and 6 months was 68% and 51%, respectively. Two patients permanently discontinued study treatment because of adverse events (left ventricular dysfunction [treatment-related] and seizure, both grade 3). No grade 5 adverse events were reported. No new safety signals emerged with either agent. CONCLUSION Although the CNS ORR was modest, 68% of patients experienced clinical benefit, and two patients had ongoing stable intracranial and extracranial disease for > 2 years. High-dose trastuzumab for HER2-positive CNS metastases may warrant further study.

OBJECTIVES Over the last decade, new treatment options have transformed the standard of care for patients (pts) with HER2-positive EBC and the treatment landscape continues to evolve. The primary objectives of our study were (1) to describe and compare the demographic and clinical characteristics of pts with HER2-positive EBC who received neoadj or adj treatment, (2) to describe the common neoadj and adj regimens according to hormone receptor (HR) status, and (3) to describe trends in neoadj treatment use from 2011 to 2019 in a US real-world setting. METHODS Unstructured and structured electronic health record-derived data were analyzed from the US Flatiron Health de-identified database (2011-2020), a longitudinal database of >2.4 million pts with cancer in >280 clinics, largely from community-based practices. Eligible pts had HER2-positive EBC (diagnosis: Jan 1, 2011-Jul 31, 2019; follow-up: until Feb 29, 2020). Systemic or oral anti-neoplastic treatments with initiation either prior to (neoadj) or within 6 months (adj) of the first primary surgery date were included. Adj treatment also required at least 6 months of follow-up and was captured for up to 1 year after initiation of adj therapy. RESULTS Pts with HER2-positive EBC treated in the neoadj setting, versus those in the adj setting alone, were more likely to be younger, pre-menopausal, have HR-negative disease, clinical stage II or III stage disease (refer to footnote in Table 1), have received treatment at an academic center, and were ~2 times as likely to have bilateral mastectomies (Table 1). Conversely, race/ethnicity as well as tumor grade, histology and laterality did not differ by neoadj versus adj treatment. The most common therapies are presented in Table 1. There was an upward trend in the annual percentage of pts diagnosed with HER2-positive EBC who initiated neoadj treatment starting in 2011 ( CONCLUSIONS Neoadj therapy use has increased, which is in line with changes in the standard anti-HER2 therapies that have occurred since 2013. Despite considerable variation, neoadj pts are mostly treated with dual HER2 blockade and chemotherapy, with a preference for taxane-based regimens. Table 1. Summary of key demographics and clinical characteristicsCharacteristic*Neoadj (n = 394)Adj (n = 696)Age at diagnosis, mean (IQR)55 (46, 64)61 (51, 69)Race / ethnicity- Non-Hispanic white237 (60)433 (62)- Other134 (34)218 (31)- Unknown23 (6)45 (7)Menopausal status- Postmenopausal219 (56)495 (71)ECOG PS- 0203 (52)277 (40)- 152 (13)86 (12)- 2+7 (2)13 (2)- Unknown132 (34)320 (46)Combined clinical stage†- Clinical stage I30 (8)364 (52)- Clinical stage II167 (42)216 (31)- Clinical stage III104 (26)57 (8)- Unknown93 (24)59 (9)Type of surgery- Lumpectomy155 (41)435 (63)- Mastectomy225 (59)261 (37)- Unknown14 (4)0Year of Diagnosis- 2011-1245 (11)180 (26)- 2013-14109 (28)209 (30)- 2015-1698 (25)170 (24)- 2017-19142 (36)137 (20)Practice type (EHR format)- Community348 (88)659 (95)- Academic46 (12)37 (5)ER-positive and/or PR-positive280 (71)557 (80)Most common treatment regimens, n (%)‡Pts with HER2-positive EBC, with available treatment dataNeoadjn = 280- TCH / TCHP43 (15) / 176 (63)- ACT + H/HP§14 (5) / 18 (6)- Any hormonal therapy25 (9)Adj continuationn = 266- H / HP only171 (64) / 38 (14)- Any hormonal therapy163 (61)- T (H / HP) + other¶35 (13)Adj-onlyn = 642- Any hormonal therapy500 (78)- TCH / TCHP223 (35) / 43 (7)- T (H / HP) + other¶106 (17)*P Citation Format: Preet K. Dhillon, Carlos Flores, Thibaut Sanglier, Vincent Antao, David Tesarowski, Anita Fung, Devin Incerti, Eleonora Restuccia, Patricia Luhn. Neoadjuvant (neoadj) and adjuvant (adj) treatment patterns in HER2-positive early breast cancer (EBC): Analysis of US real-world oncology data [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-20.

Background: There is an unmet need for evidence-based systemic therapies for pts with HER2-positive MBC and progressive brain metastases. Despite assumptions that monoclonal antibodies do not cross the blood-brain barrier, molecular imaging in pts shows localization of 89Zr-trastuzumab to brain metastases. Furthermore, preclinical data support dose-dependent activity of H in intracranial tumor models. The PATRICIA study (NCT02536339) evaluated safety and efficacy of P plus high-dose H in pts with HER2-positive MBC with CNS metastases and CNS progression after RT. Herein, we present results from the primary efficacy analysis of PATRICIA. Methods: PATRICIA was a US-based, phase II, open-label, single arm study. Eligible pts had measurable (≥10 mm) CNS disease that had progressed after CNS-directed RT, in the setting of stable extracranial disease. CNS-directed RT included whole-brain RT (WBRT) or stereotactic radiosurgery (SRS) and must have been completed ≥60 days before study entry. Pts received P (840 mg loading dose, then 420 mg every 3 weeks) and high-dose H (6 mg/kg weekly), which continued until progression (CNS or systemic) or unacceptable toxicity. Pts could continue their existing systemic anti-cancer therapy during the study, with the exception of trastuzumab emtansine (T-DM1) or lapatinib. Switch of other anti-cancer therapy was not permitted during the study. Restaging evaluations including brain MRI were completed every 2 cycles. The primary efficacy endpoint was confirmed objective response rate (ORR) in the CNS per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. Secondary endpoints included duration of response (DOR), clinical benefit rate (CBR) in the CNS, and safety. Samples were collected for exploratory pharmacokinetic analyses on Day 1 of weeks 1, 4, 10, and 16. Results: From 15 Dec 2015 to 18 May 2017, 40 pts were enrolled across 16 sites. Median age was 48 (range 34–69) years, with 33% and 67% of pts having an Eastern Cooperative Oncology Group Performance Status score of 0 or 1, respectively. 41% of pts had received prior WBRT only, 28% had received prior SRS only, and 31% had received both. At the data cut off (1 May 2019), of 39 treated pts, 2 remained on study treatment and 37 discontinued treatment, most commonly due to CNS progression (n=27). Median treatment duration was 4.5 (range 0.3–37.3) months. Four pts in the efficacy population (N=37) experienced a confirmed partial response (Table), leading to an ORR of 11% (95% confidence interval [CI], 3–25%). Response durations were 3.2, 3.3, 4.6, and 5.6 months (median DOR 4.6 months). The CBR (complete response + partial response + stable disease [SD] of ≥4 or ≥6 months) was 68% (SD ≥4 months) and 51% (SD ≥6 months). Results from exploratory pharmacokinetic analyses confirmed greater H exposure with the high-dose schedule. The adverse event profile was similar to that previously reported for P and H, with no new safety signals. One pt discontinued treatment due to an adverse event (grade 3 left ventricular dysfunction, considered related to study treatment). No Grade 5 adverse events were reported. Conclusions: The CNS ORR of 11%, ≥6-month CBR of 51%, and lack of any new safety signals suggest that P plus high-dose H may have clinical utility in some pts with HER2-positive MBC with progressive CNS metastases. Table. Efficacy within the CNS per RANO-BM criteriaEfficacy population (N=37)n (%)95% CIORR*4 (11)3, 25CBR (CR + PR + stable disease [SD] ≥4 months)25 (68)50, 82CBR (CR + PR + SD ≥6 months)19 (51)34, 68Confirmed best response (SD ≥4 months)CR0—PR4 (11)—SD ≥4 months21 (57)—Pts without clinical benefit12 (32)—Confirmed best response (SD ≥6 months)CR0—PR4 (11)—SD ≥6 months15 (41)—Pts without clinical benefit18 (49)—*Confirmed complete response (CR) or confirmed partial response (PR). Citation Format: Nancy U Lin, Priya Kumthekar, Solmaz Sahebjam, Nuhad Ibrahim, Anita Fung, Anna Cheng, Alan Nicholas, Bei Wang, Mark Pegram. Pertuzumab (P) plus high-dose trastuzumab (H) for the treatment of central nervous system (CNS) progression after radiotherapy (RT) in patients (pts) with HER2-positive metastatic breast cancer (MBC): Primary efficacy analysis results from the phase II PATRICIA study [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 P1-18-03.

This study aims to assess differences in costs and benefits of treatment strategies for high-risk human epidermal growth factor receptor 2 positive (HER2+) early-stage breast cancer (ESBC).We used a hybrid decision-tree/Markov model to simulate costs and outcomes across six health states: Invasive disease-free, non-metastatic recurrence, remission, first-line and second-line metastatic cancer, and death. We considered several strategies, defined by four attributes: (1) Neoadjuvant targeted therapy (infused pertuzumab and trastuzumab (PH) versus subcutaneous fixed-dose combination (FDC) of pertuzumab and trastuzumab versus trastuzumab alone (H)); (2) adjuvant targeted therapy if pathological complete response (pCR) is achieved (PH, FDC, or H); (3) adjuvant targeted therapy (T-DM1 or H) in the case of residual disease (RD); and (4) use of branded or biosimilar H. Transition probabilities were derived from relevant clinical trials. We included drug costs and costs associated with adverse events and administration. Health state utilities were obtained from clinical trials and the literature.Strategies not containing T-DM1 were dominated (worse outcomes and greater costs) by strategies containing T-DM1. Among strategies with pertuzumab continuation in the case of pCR and T-DM1 in the case of RD, use of FDC was dominant (equivalent outcomes and lower costs), relative to strategies using infused therapies, regardless of biosimilar versus branded trastuzumab. Adjuvant continuation of FDC was also cost-effective (better outcomes at reasonable cost increases) relative to strategies which discontinued pertuzumab following pCR.Dual targeted therapy via FDC (with transition to T-DM1 in the case of RD) is a cost-effective treatment strategy in high-risk HER2+ ESBC.

Bone, 125, ISSN:8756-3282

Pertuzumab plus trastuzumab, administered intravenously (IV) with chemotherapy, is standard treatment for HER2-positive metastatic or high-risk early breast cancer. Pertuzumab and trastuzumab are administered over 1–2.5 h traditionally; however, the need for IV infusions places a strain on medical centers with respect to scheduling, preparation, and administration. A novel fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection (PHESGO®, PH FDC SC) can be administered in approximately 5–8 min. PH FDC SC was non-inferior to IV pertuzumab plus trastuzumab in terms of pertuzumab and trastuzumab serum levels in the phase III FeDeriCa study, which enrolled 500 patients with HER2-positive early breast cancer. Total pathologic complete response rates were comparable after PH FDC SC (59.7%) or IV pertuzumab plus trastuzumab (59.5%), as was the incidence of grade ≥3 (48.8% vs 52.8%) and serious adverse events (16.1% vs 17.9%). The results of a phase II clinical trial (PHranceSCa) showed that a majority of patients (85%) preferred PH FDC SC treatment over IV pertuzumab plus trastuzumab. A US multicenter expanded access study (NCT04395508) is evaluating the safety of PH FDC SC administered at home by nurse providers in patients receiving maintenance HER2-targeted therapy every 3 weeks. This product takes much less time to administer than IV pertuzumab–trastuzumab and has the potential to alleviate time constraints for patients and busy clinics. In this review we provide an overview of PH FDC SC, and discuss our experience in preparing and administering this product to patients with HER2-positive breast cancer during clinical trials.

Effective therapies are needed for the treatment of patients with HER2-positive MBC who develop brain metastases. In the open-label, phase II PATRICIA study (NCT02536339), 40 patients with HER2-positive MBC with CNS metastases and CNS progression post-radiotherapy (median age 48 years [range, 34–69]; prior CNS treatment [whole brain radiotherapy 71%, stereotactic radiosurgery 59%, both 31%]) were enrolled to receive pertuzumab plus high-dose trastuzumab (6-mg/kg weekly) until CNS or systemic disease progression or unacceptable toxicity. Following a median (range) treatment duration of 4.5 (0.3–37.3) months, the CNS-confirmed objective response rate per Response Assessment in Neuro-Oncology Brain Metastases criteria (primary endpoint) was 11% (95% confidence interval: 3.03, 25.42), and the clinical benefit rate at 4 months was 68%, indicating sustained clinical stability. Patient-reported outcomes (PROs) were evaluated using the MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT), which includes sub-scales for symptom severity (average of 13 core symptom and 9 brain-tumor specific items) and symptom interference (average of 6 interference-with-life items representing overall symptom distress). Among 36 patients included in the PRO analyses, mean (standard deviation [SD]) symptom severity scores at baseline and weeks 12 and 28 were 1.65 (1.62), 2.24 (2.14), and 1.94 (2.55), respectively. Mean (SD) symptom interference scores at baseline and weeks 12 and 28 were 2.51 (2.63), 2.81 (3.39), and 1.76 (2.43), respectively. Mean (SD) changes in symptom severity and interferences scores from baseline to week 12 were 0.34 (1.54) and 0.33 (3.08), respectively. On average, patients who did not achieve stable disease or better in the CNS following treatment had worsened symptom severity and symptom interference scores over 12 weeks, while those with stable disease or better in the CNS exhibited stable or improving scores. Pertuzumab plus high-dose trastuzumab provided clinical benefit to the majority (68%) of patients in PATRICIA, without a decrement in quality of life.

This study assessed real-world risk of invasive disease recurrence (IDR) and associated factors in patients with human epidermal growth factor receptor-2 positive (HER2+) early breast cancer (BC) with pathological complete responses (pCR) after neoadjuvant pertuzumab plus trastuzumab (nPT) plus chemotherapy, followed by adjuvant trastuzumab (aT). Patients with HER2+ BC with pCR after nPT from 2013 to 2015 who received aT were identified in the US Oncology Network and followed until IDR or censoring. Kaplan–Meier and Cox regression methods were used to assess invasive disease-free survival (iDFS) and correlation between iDFS and patient characteristics. A total of 217 pCR patients’ charts were reviewed; median age was 52 years. Most had stage IIA or IIB disease (62%), Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 1 (84%), tumor size > 2 cm (75%), positive nodes (N+, 62%) and negative estrogen and progesterone receptor (ER− and PR−) expression (52%). Four-year iDFS rates were 90.0% overall (95% CI 84.6%, 93.6%), 86.2% for the N+ cohort and 96.0% for the N− cohort. Cox regression suggested that age, body mass index, ECOG PS, N+ status, stage T3 or T4, and ER+ or PR+ status were risk factors for IDR but were not statistically significant. Consistent with previous studies, this real-world study observed that patients with HER2+ BC showing pCR with nPT remain at risk for IDR, especially with node-positive disease at diagnosis. Alternatives to adjuvant trastuzumab alone, including combined trastuzumab and pertuzumab, should be considered to improve outcomes for initially N+ patients showing pCR with nPT.

Femoral fractures from sideways falls in the elderly are associated with significant rates of morbidity and mortality. Approaches to prevent these catastrophic injuries include pharmacological treatments, which have limited efficacy. Prophylactic femoral augmentation systems are a promising alternative that are gaining prominence by addressing the most debilitating osteoporosis-related fracture. We have developed finite element models (FEMs) of a novel experimental sideways fall simulator for cadavers. By virtue of the range of specimens and injury outcomes, these FEMs are well-suited to the evaluation of such implants. The purpose of this study was to use the FEMs to evaluate the mechanical effectiveness of three different prophylactic femoral augmentation systems. Models of the Y-Strut® (Hyprevention®, Pessac, France), Gamma Nail® (Stryker, Kalamazoo, USA), and a simple lag screw femoral fracture implant systems were placed into FEMs of five cadaveric pelvis-femur constructs embedded in a soft tissue surrogate, which were then subject to simulated sideways falls at seven impact velocities. Femur-only FEMs were also evaluated. Peak impact forces and peak acetabular forces were examined, and failure was evaluated using a strain-based criterion. We found that the femoral augmentation systems increased the peak forces prior to fracture, but were unable to prevent fracture for severe impacts. The Gamma Nail® system consistently produced the largest strength increases relative to the unaugmented femur for all five specimens in both the pendulum-drop FEMs and the femur-only simulations. In some cases, the same implant appeared to cause fractures in the acetabulum. The femur-only FEMs showed larger force increases than the pendulum-drop simulations, which suggests that the results of the femur-only simulations may not represent sideways falls as accurately as the soft tissue-embedded pendulum-drop simulations. The results from this study demonstrate the ability to simulate a high energy phenomenon and the effect of implants in an in silico environment. The results also suggest that implants could increase the force applied to the proximal femur during impact. Fracture outcomes from the tested implants can be used to inform the design of future devices, which reaffirms the value of modelling with biofidelic considerations in the implant design process. To the authors’ knowledge, this is the first paper to use more complex biofidelic FEMs to assess prophylactic femoral augmentation methods., Journal of the Mechanical Behavior of Biomedical Materials, 126, ISSN:1751-6161, ISSN:1878-0180

Metatarsal stress fracture is a common injury observed in athletes and military personnel. Mechanical fatigue is believed to play an important role in the etiology of stress fracture, which is highly dependent on the resulting bone strain from the applied load. The purpose of this study was to validate a subject-specific finite element (FE) modeling routine for bone strain prediction in the human metatarsal. Strain gauge measurements were performed on 33 metatarsals from seven human cadaveric feet subject to cantilever bending, and subject-specific FE models were generated from computed tomography images. Material properties for the FE models were assigned using a published density-modulus relationship as well as density-modulus relationships developed from optimization techniques. The optimized relationships were developed with a 'training set' of metatarsals (n=17) and cross-validated with a 'test set' (n=16). The published and optimized density elasticity equations provided FE-predicted strains that were highly correlated with experimental measurements for both the training (r2≥0.95) and test (r2≥0.94) sets; however, the optimized equations reduced the maximum error by 10% to 20% relative to the published equation, and resulted in an X=Y type of relationship between experimental measurements and FE predictions. Using a separate optimized density-modulus equation for trabecular and cortical bone did not improve strain predictions when compared to a single equation that spanned the entire bone density range. We believe that the FE models with optimized material property assignment have a level of accuracy necessary to investigate potential interventions to minimize metatarsal strain in an effort to prevent the occurrence of stress fracture.

e12648 Background: The real-world risk of disease recurrence in patients with HER2+ early breast cancer who achieved pCR after receipt of nPT-based regimens and aT is unclear. Methods: Women with HER2+ breast cancer who achieved pCR after nPT-based regimens and received aT were identified in the US Oncology Network (USON). Patients initiated nPT between 2013 –2015 and were followed until recurrence of invasive disease or censoring. Data was sourced from structured fields and review of USON patient charts. Recurrence of invasive disease was defined as any of: recurrence of ipsilateral locoregional invasive breast cancer, contralateral breast cancer, distant disease recurrence, or death. Descriptive analyses were used to assess baseline demographic and clinical characteristics and the Kaplan-Meier method was used to assess invasive disease-free survival (iDFS), with stratification by nodal status. Results: A total of 238 pCR patients’ charts were reviewed. Median patient age was 52 (range: 23-88) years and a majority were White (77%). Most patients had stage IIA (39%) or IIB (24%) disease at diagnosis, ECOG score < 1 (85%), and tumor size > 2 cm (68%). At diagnosis, the majority of patients (57%) were node positive (N+) and negative for estrogen or progesterone receptor expression (51%). Median durations of therapy for nPT and aT were 4 (range: 1-8) and 7 (range: 0.03-53) months, respectively. The median duration of follow up was 47 (range: 1-70) months. Four-year iDFS probabilities are shown in the Table. Conclusions: Consistent with previously reported clinical trial data and several pooled analyses, results from this real-world study indicate that despite achieving pCR after nPT-based regimens, patients with HER2+ BC remain at risk for disease recurrence; in addition, node+ status appears to increase that risk. Therefore, patients should receive standard pertuzumab, trastuzumab adjuvant therapy to optimize treatment outcomes. [Table: see text]

The metatarsal bones of the foot are particularly susceptible to stress fracture owing to the high strains they experience during the stance phase of running. Shoe cushioning and stride length reduction represent two potential interventions to decrease metatarsal strain and thus stress fracture risk.Fourteen male recreational runners ran overground at a 5-km pace while motion capture and plantar pressure data were collected during four experimental conditions: traditional shoe at preferred and 90% preferred stride length, and minimalist shoe at preferred and 90% preferred stride length. Combined musculoskeletal - finite element modeling based on motion analysis and computed tomography data were used to quantify metatarsal strains and the probability of failure was determined using stress-life predictions.No significant interactions between footwear and stride length were observed. Running in minimalist shoes increased strains for all metatarsals by 28.7% (SD 6.4%; p0.001) and probability of failure for metatarsals 2-4 by 17.3% (SD 14.3%; p≤0.005). Running at 90% preferred stride length decreased strains for metatarsal 4 by 4.2% (SD 2.0%; p≤0.007), and no differences in probability of failure were observed.Significant increases in metatarsal strains and the probability of failure were observed for recreational runners acutely transitioning to minimalist shoes. Running with a 10% reduction in stride length did not appear to be a beneficial technique for reducing the risk of metatarsal stress fracture, however the increased number of loading cycles for a given distance was not detrimental either.

Colorectal cancer is one of the most common cancers affecting men and women in the United States. In 2005, 10% of all new cancer cases in men will be colorectal; for women, 11% of new cases will be colorectal. The disease is the third most frequent cancer occurring in both sexes. Colorectal cancer also is the third most frequent cause of death for men and women, and more than 56,000 cancer deaths in 2005 will be attributed to colorectal cancer. Chemotherapy options for treatment of the disease remained relatively stagnant until the approval of irinotecan in 1996 followed by capecitabine, oxaliplatin, and the new targeted agents. The new agents have improved efficacy of treatment for colorectal cancer and the lives of patients with advanced disease. With the new options for treatment come increased nursing and patient-teaching responsibilities, as well as increased costs associated with the newer drugs in the armamentarium of chemotherapy agents. Formulary budgets are seeing dramatic rises in expenditures for the new, targeted therapy treatments; discussion of the most appropriate therapies may be considered. This article will discuss epidemiology of colorectal cancer, treatment options in advanced colorectal cancer, and nursing care crucial to patients undergoing chemotherapy. Discussion of economic impact also will be presented.

TPS633Background: CNS metastases are observed in up to half of pts with HER2-positive MBC, with incidence likely to rise due to improved systemic treatments and longer overall survival (OS). While ...

Introduction: Ovarian Clear Cell Carcinoma (OCCC) is generally aggressive and chemoresistant, with five year survival rate of approximately 40%. Recent mutation analysis has indicated a high frequency of PIK3CA mutations, the gene encoding for the p110α subunit in PI3K, in OCCC. Aberrant signaling of the PI3K/AKT pathway might be linked to the aggressiveness of OCCC. In this study, we investigated the sensitivity of ovarian clear cell carcinoma cells with different PIK3CA mutations to inhibitors targeting the PI3K signaling pathway. Experimental design: To elucidate the functional roles of PIK3CA mutations in OCCC, 12 OCCC cell lines carrying PIK3CA wildtype or different PIK3CA mutations were used. By performing WST-1 assay, the IC50 values for cisplatin of the cell lines were compared. Eight stable OCCC cell lines expressing a luciferase reporter fused with a FOXO3a promoter were constructed. FOXO3a is a transcription factor that is exported out of the nucleus by AKT. The difference in the PI3K/AKT pathway activation in these cell lines was then correlated with luciferase activity. PI3K inhibitor LY294002 and dual PI3K/mTOR inhibitor NVP-BEZ235 were used to elucidate the dependency of OCCC cell lines on the PI3K/AKT pathway. Results: When compared with PIK3CA wildtype cell lines, cell lines with PIK3CA mutations K111N, E545K and H1047R had higher IC50 values for cisplatin and PI3K inhibitor LY294002. These 3 cell lines also have lower luciferase activity, indicating increased activation of the PI3K/AKT pathway. The IC50 values for NVP-BEZ235 are similar in PIK3CA wildtype or mutated cell lines. Conclusion: The constitutive activation of the PI3K/AKT pathway in ovarian clear cell carcinoma appears to lead to increased resistance to chemotherapy, possibly by promoting cell survival and inhibiting apoptosis. Inhibition of PI3K/AKT pathway may overcome this resistance. NVP-BEZ235 was shown to be a potent drug in OCCC, it was effective in the nano molar range (IC90 value was reached in all cells lines at drug concentration of 100nM) and was active against PIK3CA mutants. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5037. doi:10.1158/1538-7445.AM2011-5037