Citations

9508 Background: Chemotherapy-related amenorrhea (CRA) is associated with infertility and may impact treatment decision-making. We investigated whether anti-mullerian hormone (AMH) levels before chemotherapy predict likelihood of CRA. Methods: 591 patients enrolled on the quality of life substudy of ECOG5103, which randomized breast cancer patients to doxorubicin-cyclophosphamide followed by paclitaxel: 1) alone; 2) with concurrent bevacizumab; or 3) with prolonged bevacizumab. 144 of the 195 women who reported a period <12 months before enrollment consented to serum collection prior to chemotherapy. AMH was measured in 143 with available serum. Participants self-reported menstrual frequency at 12 and 18 months after enrollment. 12-month CRA was defined as no menses for 6 months before the 12-month survey, and 18-month CRA as no menses for 6 months before the 18-month survey. Fisher’s exact test was used to identify associations with CRA. Results: Of the 143, 16 were excluded due to bilateral oophorectomy or initiation of ovarian function suppression within 12 months, and 2 due to missing data at 12 months. In the remaining 125, median age at enrollment was 45 (range 25-55). 103 (82%) had CRA at 12 months, including 68% of patients </= 45 (43/63) and 97% of patients >45 (60/62). Median pre-chemotherapy AMH was 0.11 (range 0.01-8.63). 12-month CRA was more likely in women who received bevacizumab (p<0.01), were >45 (p<0.01), and had AMH </=0.11 (p<0.01) pre-treatment. Hormonal tx was not associated with 12-month CRA (p=0.63). 100 patients were eligible for 18-month CRA analysis: 81 (81%) had CRA, including 63% of patients </= 45 (33/52) and 100% (48/48) of patients >45. 18-month CRA was more likely in women >45 (p<0.01) and with AMH </=0.11 (p<0.01) pre-treatment. Bevacizumab (p=0.15) and hormonal tx (p=0.07) were not statistically significant predictors of 18-month CRA. Conclusions: Pre-chemotherapy AMH predicts risk of CRA at 12 and 18 months, and is a promising biomarker of ovarian reserve in young breast cancer survivors. Longer studies will be needed to ascertain whether lower pre-treatment AMH is associated with increased risk of later infertility. Clinical trial information: NCT00433511.

TPS10099 Background: PDGFRα is a receptor commonly overexpressed in STS. Olaratumab is a fully human IgG1 MAb which specifically binds to human PDGFRα and blocks PDGFR-mediated signaling pathways. Olaratumab demonstrated significant tumor inhibition as a monotherapy and in combination with standard chemotherapy in preclinical human sarcoma xenograft models. A Phase 1b/2 clinical trial for patients with advanced or metastatic STS is currently enrolling patients in 9 sites across the United States; approximately 45 patients have been randomized. Methods: In Phase 1b, patients received olaratumab (15 mg/kg) via intravenous infusion on Days 1 and 8 of each 21-day cycle and D (75 mg/m²) 1 hour after olaratumab on Day 1. Phase 1b was completed without encountering dose-limiting toxicities; enrollment into Phase 2 has begun. The primary endpoint of the Phase 2 portion is to compare progression-free survival in patients with advanced STS when treated with D plus olaratumab versus D alone. Planned enrollment goal for Phase 2 is 130 patients. Patients are required to be ≥ 18 years old with ECOG 0-2, have appropriate organ function and histologically confirmed, measurable, and advanced STS. There is no restriction on the number of prior therapies. Patients are randomized 1:1 to either D plus olaratumab (Arm A) at same dose/schedule as in Phase 1b or D alone (Arm B). All patients can receive dexrazoxane. Upon completion of 8 cycles, patients in Arm A continue with olaratumab monotherapy. Patients in Arm B who develop disease progression during or after treatment can subsequently receive olaratumab monotherapy. Patients are stratified to treatment arms according to PDGFRα expression (positive vs. negative), number of previous lines of treatment, sarcoma subtype, and ECOG performance status. Response assessment occurs every 6 weeks. Exploratory analyses include biomarkers of olaratumab pharmacodynamic activity including PDGF ligands, PDGFR downstream molecules, VEGF, and changes in vascularity of tumor specimens.

6025 Background: Blinding patients to treatment regimen is an important component of high quality randomized clinical trials although concern exists about how receipt of a placebo will impact participants’ views. In ECOG5103, patients were randomized to receive adjuvant chemotherapy for breast cancer with either placebo (arm A) or bevacizumab (arms B and C) and treatment assignment was unblinded by 24 weeks. We sought to determine if unblinding was associated with differential changes in participants’ views. Methods: The Decision-Making/Quality of Life component (DM-QOL) included all patients enrolling on E5103 between 1/5- 6/8/10. Women were surveyed pretreatment and after unblinding. Wilcoxon rank sum testing was used to examine differences. Results: 572 patients on DM-QOL started protocol therapy; 118 on arm A, 454 on arm B/C; the two groups (arm A vs. B/C) were well balanced. 516 patients participated in pretreatment, 514 in unblinding survey. Pretreatment, 32% reported >moderate chance of recurrence in 5 years, 27% >moderate chance of serious problem from treatment, 99% feeling at least somewhat informed, 98% at least somewhat confident in study participation, most “extremely” confident. Overall, median response scores did not change over time, with no statistically significant differences between the groups in changes in perceptions of: recurrence risk (p=0.45); chances of a serious problem (p=0.12), feeling informed (p=0.99). However, they differed in confidence about study participation (p=0.04): after unblinding, a higher % of placebo-treated patients had increased confidence (38% vs. 25%), and a higher % of bevacizumab-treated patients had decreased confidence (29% vs. 22%), although 44% across all arms had no change. Conclusions: In a placebo-controlled, double-blinded RCT, unblinding did not significantly affect most participants’ views, regardless of receipt of placebo or experimental drug. However, confidence in study participation may have been affected by knowledge of receipt of bevacizumab; publicity surrounding this experimental therapy may have affected results.

6527 Background: Biomarker information can risk stratify patients based on potential for benefits/toxicity from therapy. Ideally, a biomarker will identify those who benefit with limited toxicity. However, the impact of biomarkers is unclear when indicting individuals with greatest benefit are also at increased risk for toxicity. Methods: We surveyed participants at 18 month follow-up in the Decision-Making/Quality of Life (DM-QOL) component of ECOG5103, a RCT where patients were randomized to receive adjuvant chemotherapy for breast cancer with either placebo or bevacizumab (in 2 schedules). We asked patients for the preferred treatment in two hypothetical scenarios: 1) preference for chemo A or chemo A + B without biomarker information; 2) preference for chemo A or chemo A+B when participants tested positive for a “B-receptor” which increased both the benefit and toxicity of chemo A+B. McNemar’s test was used to examine changes in preferences. Results: 439 patients completed both scenarios on 18-month survey. The Table shows the treatment preferences in each scenario. The positive biomarker information in scenario 2 led 60/439 (14%) participants to switch their preference. The main reason for treatment preference in scenario 2 was greater benefits of chemo A+B (64%), the lower risks with chemo A (20%) and positive biomarker (10%). Among participants who changed preference, those randomized to receive bevacizumab were more likely to switch to chemo A in scenario 2. Conclusions: Information about a positive biomarker, indicating increased benefit and increased risk from additional chemo, did not significantly change participants’ preferred treatment. All participants were involved in a large placebo controlled double blind trial and the majority (70%) preferred the most aggressive course of treatment in both scenarios. Whether patients not enrolled in the trial would be more sensitive to the increased risk information is unclear. [Table: see text]

This study uses genetic and pharmacologic approaches to demonstrate novel roles of eosinophils in the progression of atherosclerosis and arterial thrombosis.

Objectives: To assess the etiologies and outcomes of patients with secondary hemophagocytic lymphohistiocytosis in the PICU. Design: Prospective observational cohort study. Setting: A single PICU at a pediatric tertiary hospital in Hanoi, Vietnam. Patients: Pediatric patients meeting the criteria for secondary hemophagocytic lymphohistiocytosis. Interventions: None. Measurements and Main Results: Between June 2017 and May 2018, 25 consecutive patients with a mean (sd) age of 23.3 months (21.6 mo) were included. Collected variables included etiologies of hemophagocytic lymphohistiocytosis and clinical and laboratory findings at admission. The Pediatric Index of Mortality 2 score at admission was calculated. Outcomes were death and multiple organ dysfunction. The severity of multiple organ dysfunction was assessed by the Pediatric Logistic Organ Dysfunction 2 score. The mean (sd) Pediatric Index of Mortality 2 predicted mortality rate was 5.6% (7.6%). Cytomegalovirus and Epstein-Barr virus coinfections (60%) were the most common suspected etiology of hemophagocytic lymphohistiocytosis. Other etiologies included Epstein-Barr virus sole infections (20%), cytomegalovirus sole infections (16%), and one unknown cause (4%). Multiple organ dysfunction (excluding hematologic failure) was found in 22 patients (88%) with death occurring in 14 patients (56%). The mean (sd) Pediatric Logistic Organ Dysfunction 2 predicted mortality rate among patients with multiple organ dysfunction was 11.9% (11.2%). Despite having lower Pediatric Index of Mortality 2 predicted mortality rates at admission, Epstein-Barr virus-cytomegalovirus coinfection cases with multiple organ dysfunction had slightly greater Pediatric Logistic Organ Dysfunction 2 predicted mortality rates than Epstein-Barr virus sole infection cases with multiple organ dysfunction: 12.2% (10.5%) versus 11.3% (11.0%). However, these rates were lower than cytomegalovirus sole infection cases with multiple organ dysfunction (14.4% [16.3%]). Area under the curve values for Pediatric Index of Mortality 2 and Pediatric Logistic Organ Dysfunction 2 were 0.74 (95% CI, 0.52–0.95) and 0.78 (95% CI, 0.52–1.00), respectively, suggesting that both scales were fair to good at predicting mortality. Conclusions: Viral infections, particularly Epstein-Barr virus-cytomegalovirus coinfections, were a common cause of secondary hemophagocytic lymphohistiocytosis. The implication of these coinfections on the clinical course of hemophagocytic lymphohistiocytosis needs to be delineated.

Abstract Background: In CALGB 40601 (Alliance, NCT00770809), a neoadjuvant phase III trial of paclitaxel and trastuzumab with or without lapatinib for 12 weeks for patients with HER2-positive breast cancer, 33% of pretreatment tumors were Luminal A subtype, however, 69% of post-treatment samples with residual disease were Luminal A subtype. In addition, 71% of Luminal B (12/17) and 67% of HER2-Enriched (6/9) tumors changed into Luminal A, while 80% of Luminal A (20/24) remained Luminal A (Carey et al. J Clin Oncol. 2016). It is not known whether this shift to Luminal A was transient or permanent. Methods: We selected matched pairs of pre- and post-treatment 40601 samples with tumor purity &gt;10% based upon DNA analyses to ensure all samples contained tumor. PAM50 intrinsic subtyping was applied to the 40601 samples gene expression data using a two-step normalization process based on The Genome Cancer Atlas, and PAM50 training set. In addition, a HER2-enriched expression subtype patient-derived xenograft (PDX) tumor called WHIM35, was studied and was either untreated (n=10), or treated with lapatinib at 220 mg/kg for 1 week (wk) (n=5), for 2 wks (n=8), or for 3 wks (n=4). We also treated WHIM35 tumors with lapatinib for 2 wks (on) and then removed laptinib for 1 wk (off) (n=6), or for 2 wks on and 2-4 wk off (n=6), and finally for 3 wks on, and 1 wk off (n=3). PAM50 intrinsic subtyping was applied to the PDX gene expression data and subtype assessed as well as a genomic-based proliferation score. ANOVA p-values were calculated by comparing median values across all gene signature or correlation scores. Results: We found 10 pairs of 40601 samples that kept their tumor purity values, however, their subtype changed to Luminal A after treatment (i.e., in the residual disease), and in these cases no minor tumor subclone became a dominant clone in the post treatment sample. Pretreatment subtypes were 6 Luminal B, 3 Luminal A, and 1 HER2-enriched. The tumor purity values did not change after the treatments, but correlation to Luminal A was significantly higher (p=0.01), while correlation to HER2-enriched (p=0.004) and proliferation signature scores (p=0.003) were significantly lower in the post-treatment samples. Among the WHIM35 PDX tumors, one sample changed its subtype from HER2-enriched to Luminal A after the lapatinib treatment and the rest remained HER2-enriched, suggesting environmental differences between patient samples and the PDX model. However, correlation to Luminal A was significantly higher in all lapatinib treated WHIM35 samples (p=8.3e-12), and notably went back to the initial low levels just one week after removing lapatinib. Likewise, correlation to HER2-enriched (p=1.2e-10) and proliferation signature scores (p=6.2e-12) also got lower while treated with lapatinib, but went back to the initial levels after cessation of treatment. Conclusions: Our findings suggest that the apparent subtype change during HER2-targeting therapy is not permanent, but is more likely a transient state change from a HER2-enriched subtype into a more Luminal A-like state. When we plan additional treatment strategies using residual disease phenotypes, it may not be clear what is the true subtype of the sample due to this inherent plasticity. Citation Format: Tanioka M, Parker JS, Henry LN, Tolaney S, Dang C, Krop IE, Harris L, Polley M, Berry DA, Winer EP, Carey LA, Perou CM. Transient state change, but not permanent subtype change, after HER2-targeted therapy for HER2-positive breast cancer [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 P3-08-04.

Abstract Background: Breast cancer (BC) treatment, including surgery, can impact not only short-term health outcomes but may also affect longer term health-related and psychosocial quality of life (QOL). We sought to describe the impact of BC surgery on QOL among breast cancer survivors followed in a large randomized trial. Methods: The ECOG-ACRIN protocol E5103 was a phase III trial that randomized BC patients (pts) who had undergone definitive BC surgery to receive adjuvant doxorubicin, cyclophosphamide, and paclitaxel with either bevacizumab (bev) or placebo. Telephone based surveys were administered to all pts enrolled between 01/Jan/10 and 08/Jun/10 as part of a Decision-Making/QOL component until 18 mos post enrollment. Functional/psychosocial QOL domains were assessed by the EQ-5D-3L and the FACT B+G. Fisher's exact test compared categorical and Wilcoxon rank sum test compared continuous variables between subgroups. Multivariable regression was used to evaluate factors in addition to primary surgery at enrollment (age, race, ER/PgR status, tumor size, nodal status) associated with overall FACT score at 18 mos. Results: Patient reported outcomes at 18 mos were available from 89.6% (465/519) pts. At enrollment, 57% (266/465) had a mastectomy; 43% (199/465) breast conserving surgery (BCS). Median age at enrollment was 52 (range: 25-76) years. There were no differences in QOL between bev vs placebo treatment arms (EQ-5D-3L Index Score p=0.65; FACT B+G Score p=0.23) at 18 mos so groups were combined. Using EQ-5D-3L, over half of the pts (58%) reported at least some pain/discomfort; 38% symptoms of anxiety/depression. A higher proportion of mastectomy pts reported problems with usual activities compared to BCS pts (Table). Compared to BCS pts, mastectomy pts had lower average EQ5D-3L scores 0.80 vs. 0.84, p=0.04 and FACT B+G scores 109 vs. 114, p=0.01, indicating worse QOL. In univariate analyses, non-white race (p=0.03), ER/PgR+ status (p=0.04) and mastectomy as primary surgery (p=0.01) were significantly associated with worse QOL (lower FACT B+G scores). In multivariable analyses, non-white race (p=0.02) and ER/PgR+ status (p=0.05) remained associated with worse QOL; mastectomy was borderline significant (p=0.06). Conclusions: Among women participating in a contemporary adjuvant BC chemotherapy trial, a substantial proportion of survivors experience symptoms that may be amenable to intervention, including referral to physical rehabilitation, especially among pts undergoing more extensive surgery. Attention to psychosocial health is also essential both during and after completion of active treatment to optimize QOL outcomes. N(%) reporting problems* 5 DimensionsBCSMastectomyOverallp**Mobility44(23)59(23)103(23)1.00Self-care11(6)23(9)34(7)0.21Usual activities49(25)90(34)139(30)0.04Pain/discomfort104(53)161(61)265(58)0.08Anxiety/depression70(36)105(40)175(38)0.44*3L: 3 possible answers: 1) no problems 2) some/moderate problems 3) problems; responses then collapsed into no problems vs. any problems' (=some/moderate problems and problems). ** Fisher's exact test p-value. Citation Format: Rosenberg SM, O'Neill A, Sepucha K, Miller KD, Dang CT, Northfelt DW, Sledge GW, Schneider BP, Partridge AH. The impact of breast cancer surgery on quality of life: Long term results from E5103 [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 GS6-05.

Purpose: The purpose of this study was to characterize reductions in intraocular pressure (IOP) and the need for IOP-lowering medications following phacoemulsification combined with Kahook Dual Blade-assisted goniosynechialysis and excisional goniotomy in eyes with angle-closure glaucoma and cataract. Methods: In this retrospective, interventional case series, preoperative, operative, and postoperative data were collected through 6 months of follow-up from 42 eyes of 24 subjects. Outcomes included mean IOP reduction, reduction in IOP-lowering medications, and the proportion of patients achieving IOP reduction ≥20%, IOP≤18 mm Hg, and reduction of ≥1 medication. Results: Preoperatively, mean (SE) IOP was 25.5 (0.7) mm Hg and the mean number of IOP-lowering medications used was 2.3 (0.1) per eye. Through 6 months of follow-up, mean IOP reductions of 10.1 to 12.8 mm Hg (38.4% to 49.5%; P <0.0001) and mean IOP medication reductions of −2.2 to −2.3 (91.7% to 98.4%; P <0.0001) were seen. At month 6, 92.9% of eyes (39/42) achieved IOP≤18 mm Hg, 100% (42/42) achieved IOP reduction of ≥20%, 100% (42/42) required ≥1 fewer medications for IOP control, and 85.7% (36/42) were medication free. Conclusions: Phacoemulsification combined with Kahook Dual Blade-assisted goniosynechialysis and excisional goniotomy safely provides statistically and clinically meaningful reductions in both IOP and the need for IOP-lowering medications in eyes with angle-closure glaucoma.

These NCCN Guidelines Insights highlight the updated recommendations for use of multigene assays to guide decisions on adjuvant systemic chemotherapy therapy for women with hormone receptor–positive, HER2-negative early-stage invasive breast cancer. This report summarizes these updates and discusses the rationale behind them.