Search

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.

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