1Dept. of 1Anesthesiology, University of California, Los Angeles, CA 90024, USA 2Dept. of Oncology, University of California, Los Angeles, CA 90024, USA 3Dept. of Psychophysiology, New York State Psychiatric Institute, New York, NY 10032, USA
Abstract Cognitive difficulties after cancer treatment are among the most feared outcomes voiced by patients who are approaching the start of chemotherapy. This phenomenon, sometimes referred to as “chemo brain” or “chemo fog,” is quite common during the acute course of chemotherapy treatment. This may result from direct antieneoplastic drug toxicity, use of premedications and anxiolytics to prevent nausea and vomiting, as well as the expected anxiety, depression, and sleep deprivation that accompanies a new diagnosis of cancer and initiation of treatment. For most patients, this fog clears after the completion of acute treatments, and as with many physical symptoms, resolves in the following months. However, 15–25% of post-treatment patients, cognitive complaints persist long after treatment ends. Reports of difficulty concentrating, remembering recent events, multi-tasking, and paying attention are frequent in such patients. For those used to carrying on demanding executive function activities prior to cancer treatment, this can lead to substantial disruption in work and home life. Most of the studies conducted to date with early stage breast cancer have not accounted for the impact of adjuvant endocrine therapy alone or added to adjuvant chemotherapy. This presentation will review emerging data regarding self-reported cognitive complaints, neuropsychological testing, and brain imaging as they related to adjuvant therapies for breast cancer. In addition, some of the developing information about potential mechanisms associated with this late effect will be discussed. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr ES4-2.
596 Background: Vit D supplementation is common in BC. Given reports that Vit D modulates aromatase activity, we examined the relationship between Vit D and estrogen levels in PM BC. Methods: 125 PM women within 2 years of diagnosis of T1-3, N0-3, M0 BC were recruited in Toronto and Los Angeles between Mar 2009 and Jan 2010. Data included: anthropometrics (measured); medications and Vit D supplementation (structured interview); and tumor/treatment variables (clinical records). Serum was analyzed for 25(OH)D by radioimmunoassay (RIA) and estradiol (E2) and estrone (E1) by extraction-column chromatography-RIA. Statistical analyses used t-tests, Pearson correlation (r) and regression models after suitable transformation of variables. Results: Hormone therapies included AIs (n=56), tamoxifen (n=30) and none (n=39). The tamoxifen and no hormone groups did not differ for important variables, and were combined (non-AI, n=69). Mean age was 62 years, BMI 27 kg/m2, Vit D supplementation 1244 IU/day, 25(OH)D 98 nmol/L; these attributes were similar in AI users and non-users. Mean E2 and E1 levels (pmol/L) were significantly lower in AI users (19.9 and 26.2) than non-users (39.6 and 123.7), both p<0.0001. The relationship between 25(OH)D and E2 differed qualitatively in AI users vs non-users (interaction p = 0.002): in AI users, 25(OH)D was positively correlated with E2 (r = + 0.31, p=0.02); in non-AI users this correlation was negative (r = − 0.26, p=0.03). 25(OH)D was not associated with E1 in either group. BMI was not associated with either E1 or E2 in AI-users (r = +0.09, p=0.52; r = − 0.03, p=0.84), but was univariably associated with E1 but not E2 in non-AI users (r = +0.44, p=0.0001, and r = +0.22, p=0.07). In multivariable analyses [age, BMI, 25(OH)D], 25(OH)D was positively associated with E2 in AI users (p=0.04) and negatively in non-AI users (p=0.05). BMI was associated with E1 in non-AI users (p=0.002). Measurement of AI levels is underway. Conclusions: In PM BC survivors, serum 25(OH)D was associated with higher E2 among AI users but not non-AI users. If replicated, this finding has implications for BC survivors receiving AIs. Funded by the Breast Cancer Research Foundation.
1501 Background: Women with B1 and B2 mutation are at increased risk of breast and ovarian cancer, which is significantly reduced by RRSO. The reduction in breast cancer risk may be greatest prior to age 40; however, such early menopause can lead to significant menopausal symptoms and other health problems. Two small prior studies have suggested that HRT following RRSO does not increase the risk of breast cancer, but further data are needed. Methods: From the PROSE consortium, 1,299 B1 (n= 795) and B2 (n=504) mutation carriers who underwent RRSO following study ascertainment and in whom HRT status was known were followed prospectively. Data were collected on HRT use and subsequent breast cancer diagnosis. Results: In both B1 and B2 mutation carriers with ever use of HRT following RRSO, no increased risk of breast cancer was observed compared to those with no RRSO. In B1 carriers, HRT use both with (HR 0.52) and without (HR 0.29) RRSO was associated with a decreased risk of breast cancer. No increased risk of breast cancer was seen with either combination HRT or estrogen-only HRT. Conclusions: In this prospective study of 1,299 B1 and B2 mutation carriers, HRT following RRSO was not associated with an increased risk of breast cancer. HRT use Never Ever Never Post-RRSO RRSO: No No Yes Yes Controls Mean age at RRSO – – 45.0 (20.5-79.0) 40.8 (29.4-63.4) Mean age in controls 34.4 (18.1-90.4) 45.6 (18.7-90.0) – – Mean follow-up to BC 4.8 (0.5-17.6) 7.4 (0.9-20.6) 2.7 (0.5-6.0) 4.9 (0.8-20.2) Mean follow-up to censoring 5.1 (0.5-27.8) 5.9 (0.5-27.7) 3.6 (0.5-18.8) 5.4 (0.6-27.4) Total sample (N) 867 111 177 144 BC in follow-up 194 (22%) 19 (17%) 22 (12%) 20 (14%) HR (95% CI) [1] 0.51 (0.32-0.80) 0.62 (0.38-1.01) 0.46 (0.28-0.76) BRCA1 (N) 520 55 115 105 BC in follow-up 118 (23%) 5 (9%) 16 (14%) 17 (16%) HR (95% CI) [1] 0.29 (0.13-0.69) 0.63 (0.35-1.14) 0.52 (0.30-0.92) BRCA2 (N) 347 56 62 39 BC in follow-up 76 (22%) 14 (25%) 6 (10%) 3 (8%) HR (95% CI) [1] 0.73 (0.42-1.27) 0.52 (0.21-1.27) 0.24 (0.05-1.03)
Abstract Background: Healthy breast tissue appears older than matched peripheral blood, when using a biologic aging measurement based on DNA methylation markers. The underlying cause of this acceleration is not known. We hypothesize that cumulative estrogen exposure is associated with accelerated breast epigenetic aging. In this study, we examined factors associated with breast epigenetic age in a healthy population of women. Methods: We used breast tissue samples from 232 healthy women donors (119 pre-menopausal, 113 post-menopausal) to the Komen Tissue Bank, with data available on variables related to cumulative estrogen exposure, including age at menarche, gravidity, parity, and menopausal status. DNA methylation experiments were performed using the Illumina EPIC 850K array platform. DNA methylation age (DNAm age) was calculated using the epigenetic clock methods developed by Horvath (2013). Total years of estrogen exposure was calculated as the difference between age at menopause (or current age) - number of live births x 9 months – number of miscarriages x 3 months. Nonparametric group testing was used to compare mean levels of the difference between DNAm age and chronologic age for pre- and post-menopausal groups. We examined the outcome “age acceleration”, calculated using the residuals of the regression of DNAm age versus chronologic age, because it is age-adjusted and independent of cell distribution. Multivariate linear regression models were used to examine for associations between age acceleration and each of our covariates. Results: Our sample included women aged 19-90 years (mean age 50.7, SD 11.8), with 114 nulliparous women. We confirmed that DNAm age in breast tissue is strongly correlated with chronologic age (ρ=0.89, p<0.0001). The difference between DNAm age and chronologic age is greater at earlier ages, and is significantly greater in premenopausal women (mean 8.9 years, SE 0.04), compared with postmenopausal women (mean 2.7 years, SE 0.05) (p<0.0001). Age acceleration was significantly associated with earlier age at menarche (β=-0.395 for each year, p=0.036). For women with limited total years of exposure to estrogen (<19 years), there was a significant association between age acceleration and total estrogen exposure and β=0.673 for each year, p=0.028). Conclusion: Acceleration of epigenetic age in breast tissues occurs in healthy women and is most pronounced in the pre-menopausal period. Earlier age at menarche and total years of estrogen exposure are associated with higher degree of acceleration, suggesting that cumulative estrogen exposure drives this process. Citation Format: Sehl ME, Henry JE, Storniolo AM, Horvath S, Ganz PA. Hormonal factors associated with elevation of DNA methylation age in breast tissue of healthy women [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 P1-09-08.
Abstract This phase III post-NC trial evaluates if CWRNRT post-Mx or whole breast irradiation (WBI) with RNRT after BCS significantly reduces the IBCR-FI rate in pts with PPAx nodes that are pathologically negative after NC. Secondary aims are OS, LRR-FI, DR-FI, DFS-DCIS, second primary cancer, and comparison of RT effect on cosmesis in reconstructed Mx pts. Correlative science examines RT effect by tumor subtype, molecular outcome predictors for residual disease, and predictors for the degree of reduction in loco-regional recurrence. Methods: Clinical T1-3, N1 IBC PPAx nodes (FNA or core needle biopsy) pts complete ≥8 weeks of NC (anthracycline and/or taxane). HER2+ pts receive anti-HER2 therapy. Following NC, BCS or Mx, sentinel node biopsy (≥2 nodes) and/or Ax dissection with histologically negative nodes is performed. ER/PR and HER-2neu status before NC is required. Pts may receive appropriate adjuvant systemic therapy. Radiation credentialing with a facility questionnaire/case benchmark is required. Random assignment for Mx pts is to no CWRNRT or CWRNRT and for BCS pts to WBI or WBI+RNRT. Statistics: 1,636 pts are to be enrolled over 5 yrs (definitive analysis at 7.5 yrs). Study is powered at 80% to test that RT reduces the annual hazard rate of events for IBCR-FI by 35% for an absolute risk reduction of 4.6% (5-yr cumulative rate). Intent-to-treat analysis with 3 interim analyses (43, 86, and 129 events) and a 4th/final analysis at 172 events. Pt-reported outcomes focusing on RT effect will be provided by 736 pts before random assignment and at 3, 6, 12, and 24 mos. Accrual as of 6-21-18 is 967 (59.11%). Contacts: Protocol: CTSU member website https://www.ctsu.org. Questions: NRG Oncology Pgh Clin Coord Dpt: 1-800-477-7227 or ccd@nsabp.org. Pt entry: OPEN at https://open.ctsu.org or the OPEN tab on CTSU member website. NCT01872975 Support: U10 CA-2166; -180868, -180822; 189867; Elekta Citation Format: Mamounas EP, Bandos H, White JR, Julian TB, Khan AJ, Shaitelman SF, Torres MA, Vicini FA, Ganz PA, McCloskey SA, Paik S, Gupta N, Li XA, DiCostanzo DJ, Curran WJ, Wolmark N. Phase III trial to determine if chest wall and regional nodal radiotherapy (CWRNRT) post mastectomy (Mx) or the addition of RNRT to whole breast RT post breast-conserving surgery (BCS) reduces invasive breast cancer recurrence-free interval (IBCR-FI) in patients (pts) with pathologically positive axillary (PPAx) nodes who are ypN0 after neoadjuvant chemotherapy (NC): NRG Oncology/NSABP B-51/RTOG 1304 [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 OT2-04-01.
Abstract Adjuvant studies utilizing trastuzumab in early HER2+ breast cancer demonstrated a large reduction in recurrence and death. Post-enrollment central testing showed HER2 non-amplified participants derived similar benefit. Among HER2−amplified patients, multiple studies showed no effect on benefit by degree of amplification. Extensive testing including blinded external review confirmed the non-amplified nature of the HER2 normal group. Detailed relevant background and confirmatory studies will be provided. As a result of these findings, NSABP study B-47, sponsored by the NCI, was activated January 2011. The study is NCI central IRB approved, open in the CTSU, and endorsed by SWOG as of April 2011. Study: Selection of one of the two chemotherapy regimens is by physician choice: The non-anthracycline regimen is TC (docetaxel 75 mg/m2, cyclophosphamide 600 mg/m2) administered IV every 3 weeks for 6 cycles; the anthracycline regimen is AC followed by WP (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 administered IV either every 3 weeks or every 2 weeks [per investigator discretion] for 4 cycles followed by paclitaxel 80 mg/m2 IV weekly for 12 doses). Patients will be randomly assigned to receive chemotherapy with or without trastuzumab therapy. For patients receiving the TC chemotherapy regimen, trastuzumab will be given every 3 weeks during and following chemotherapy until 1 year after the first trastuzumab dose (8 mg/kg loading dose; 6 mg/kg for the remaining doses). For patients receiving the AC followed by WP chemotherapy regimen, trastuzumab will begin with the first dose of weekly paclitaxel and will be given weekly for 12 doses (4 mg/kg loading dose; 2 mg/kg for the remaining weekly doses). Following completion of WP, trastuzumab therapy will continue with 6 mg/kg doses given every 3 weeks for a total of 1 year. Patients will also receive adjuvant radiation therapy and endocrine therapy, as clinically indicated. Detailed menstrual history, concurrent medications, weight changes, and biomarkers (estrogen, stress, inflammation status) will be collected throughout the study. Collection of circulating tumor cells as an ancillary study is planned. Eligibility: Eligibility includes: node positive or high risk node negative female breast cancer patients; HER2 IHC 1+ or 2+ scores, but non amplified by FISH; normal cardiac, renal, and liver function. Detailed eligibility will be provided. Statistical: The primary aim is to determine whether the addition of trastuzumab to chemotherapy improves invasive disease-free survival (IDFS). 3260 patients will be enrolled to provide statistical power of 0.9 to detect a 33% reduction in the hazard rate of IDFS using a one-sided alpha level of 0.025. Projected accrual time is approximately 3 years. Progress: Protocol was activated in January 2011. First patient was entered in February 2011. As of June 16, 2011, 115 of 3260 patients have been enrolled. Supported by NCI U10-12027, -37377, 69651, 69974, and Genentech, Inc. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT1-02-07.
Abstract BACKGROUND: Abnormalities of the PI3kinase/AKT/mTOR signaling network are some of the most common molecular anomalies in breast cancer. This pathway has been associated with resistance to endocrine therapies among HR-positive breast tumors. Everolimus, an mTOR-inhibitor, has been shown to increase the biological activity of aromatase inhibitors. In the metastatic setting, everolimus in combination with tamoxifen or exemestane increased the progression-free survival in patients previously treated with endocrine therapy. S1207 proposes to evaluate the role of everolimus used in combination with endocrine therapy in the adjuvant setting. SPECIFIC AIMS/TRIAL DESIGN: S1207 is a SWOG/NSABP randomized phase III double-blind, placebo-controlled clinical trial. The primary objective of the study is to assess whether the addition of one year of everolimus to standard adjuvant endocrine therapy improves invasive disease-free survival (DFS) among patients with high risk HR-positive breast cancer. Secondary objectives include overall survival, distant recurrence-free survival, safety, adherence and quality of life. Submission of tissue specimens/blood samples is required for translational studies. Patients will be randomized to receive standard adjuvant endocrine therapy (selected by treating physician) in combination with one year of everolimus (10 mg PO daily) or standard adjuvant endocrine therapy in combination with one year of matched placebo. ELIGIBILITY CRITERIA: Patients with histologically confirmed invasive breast cancer HER2-negative and HR-positive with high risk features including: 1) node-negative disease with tumors ≥2cm and a recurrence score (RS) >25; 2) 1–3 positive nodes and RS >25; 3) patients with ≥4 positive lymph nodes regardless of RS. Patients with ≥4 positive lymph nodes after completing neoadjuvant chemotherapy are also eligible. All patients must have completed surgery, adjuvant/neoadjuvant chemotherapy, and radiation therapy (if indicated) before registration. Prior exposure to mTOR inhibitors is not allowed. STATISTICAL METHODS/TARGET ACCRUAL: This is a parallel randomization design with equal allocation to the two treatment groups (everolimus and placebo). Randomization is stratified by 4 risk groups. All analyses are intent-to-treat by randomized assignment of eligible patients. The study plans to randomize 3,500 patients over a 3.5-year accrual period with the primary analysis conducted 3 years after the last patient is randomized. The study has 90% power (with 2-sided α=0.05) to detect an effective hazard ratio of 0.75 for everolimus versus placebo, corresponding to a gain in DFS of approximately 4.3% at 5 years. All patients will be followed for 10 years to assess overall survival and late adverse events. The expected trial duration from activation to reporting of DFS is about 7 years. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT2-2-04.
