Genetic testing for hereditary breast and ovarian cancer (HBOC) is recommended for breast cancer patients diagnosed at age ≤ 50 years. Our objective was to examine racial/ethnic differences in ...genetic testing frequency and results among diverse breast cancer patients. A retrospective cohort study among women diagnosed with breast cancer at age ≤ 50 years from January 2007 to December 2017 at Columbia University in New York, NY. Among 1503 diverse young breast cancer patients, nearly half (46.2%) completed HBOC genetic testing. Genetic testing completion was associated with younger age, family history of breast cancer, and earlier stage, but not race/ethnicity or health insurance status. Blacks had the highest frequency of pathogenic/likely pathogenic (P/LP) variants (18.6%), and Hispanics and Asians had the most variants of uncertain significance (VUS), 19.0% and 21.9%, respectively. The percentage of women undergoing genetic testing increased over time from 15.3% in 2007 to a peak of 72.8% in 2015. Over the same time period, there was a significant increase in P/LP and VUS results. Due to uncertainty about the clinical implications of P/LP variants in moderate penetrance genes and VUSs, our findings underscore the need for targeted genetic counseling education, particularly among young minority breast cancer patients.
Women with atypical hyperplasia (AH) or lobular carcinoma in situ (LCIS) have a significantly increased risk of breast cancer, which can be substantially reduced with antiestrogen therapy for ...chemoprevention. However, antiestrogen therapy for breast cancer risk reduction remains underutilized. Improving knowledge about breast cancer risk and chemoprevention among high-risk patients and their healthcare providers may enhance informed decision-making about this critical breast cancer risk reduction strategy.
We are conducting a cluster randomized controlled trial to evaluate the effectiveness and implementation of patient and provider decision support tools to improve informed choice about chemoprevention among women with AH or LCIS. We have cluster randomized 26 sites across the U.S. through the SWOG Cancer Research Network. A total of 415 patients and 200 healthcare providers are being recruited. They are assigned to standard educational materials alone or combined with the web-based decision support tools. Patient-reported and clinical outcomes are assessed at baseline, after a follow-up visit at 6 months, and yearly for 5 years. The primary outcome is chemoprevention informed choice after the follow-up visit. Secondary endpoints include other patient-reported outcomes, such as chemoprevention knowledge, decision conflict and regret, and self-reported chemoprevention usage. Barriers and facilitators to implementing decision support into clinic workflow are assessed through patient and provider interviews at baseline and mid-implementation.
With this hybrid effectiveness/implementation study, we seek to evaluate if a multi-level intervention effectively promotes informed decision-making about chemoprevention and provide valuable insights on how the intervention is implemented in U.S. clinical settings.
NCT04496739
Introduction
The PI3K/AKT/mTOR pathway is an oncogenic driver in breast cancer (BC). In this multi-center, pre-surgical study, we evaluated the tissue effects of the AKT inhibitor MK-2206 in women ...with stage I–III BC.
Materials and methods
Two doses of weekly oral MK2206 were administered at days − 9 and − 2 before surgery. The primary endpoint was reduction of pAkt
Ser473
in breast tumor tissue from diagnostic biopsy to surgery. Secondary endpoints included changes in PI3K/AKT pathway tumor markers, tumor proliferation (ki-67), insulin growth factor pathway blood markers, pharmacokinetics (PK), genomics, and MK-2206 tolerability. Paired
t
tests were used to compare biomarker changes in pre- and post-MK-2206, and two-sample
t
tests to compare with prospectively accrued untreated controls.
Results
Despite dose reductions, the trial was discontinued after 12 patients due to grade III rash, mucositis, and pruritus. While there was a trend to reduction in pAKT after MK-2206 (
p
= 0.06), there was no significant change compared to controls (
n
= 5,
p
= 0.65). After MK-2206, no significant changes in ki-67, pS6, PTEN, or stathmin were observed. There was no significant association between dose level and PK (
p
= 0.11). Compared to controls, MK-2206 significantly increased serum glucose (
p
= 0.02), insulin (
p
< 0.01), C-peptide (
p
< 0.01), and a trend in IGFBP-3 (
p
= 0.06).
Conclusion
While a trend to pAKT reduction after MK-2206 was observed, there was no significant change compared to controls. However, the accrued population was limited, due to toxicity being greater than expected. Pre-surgical trials can identify in vivo activity in the early drug development, but side effects must be considered in this healthy population.
Background
Observational and experimental data support a potential breast cancer chemopreventive effect of green tea.
Methods
We conducted an ancillary study using archived blood/urine from a phase ...IB randomised, placebo‐controlled dose escalation trial of an oral green tea extract, Polyphenon E (Poly E), in breast cancer patients. Using an adaptive trial design, women with stage I–III breast cancer who completed adjuvant treatment were randomised to Poly E 400 mg (n = 16), 600 mg (n = 11) and 800 mg (n = 3) twice daily or matching placebo (n = 10) for 6 months. Blood and urine collection occurred at baseline, and at 2, 4 and 6 months. Biological endpoints included growth factor serum hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), lipid (serum cholesterol, triglycerides), oxidative damage and inflammatory biomarkers.
Results
From July 2007‐August 2009, 40 women were enrolled and 34 (26 Poly E, eight placebo) were evaluable for biomarker endpoints. At 2 months, the Poly E group (all dose levels combined) compared to placebo had a significant decrease in mean serum HGF levels (−12.7% versus +6.3%, P = 0.04). This trend persisted at 4 and 6 months but was no longer statistically significant. For the Poly E group, serum VEGF decreased by 11.5% at 2 months (P = 0.02) and 13.9% at 4 months (P = 0.05) but did not differ compared to placebo. At 2 months, there was a trend toward a decrease in serum cholesterol with Poly E (P = 0.08). No significant differences were observed for other biomarkers.
Conclusions
Our findings suggest potential mechanistic actions of tea polyphenols in growth factor signalling, angiogenesis and lipid metabolism.
Aromatase inhibitors (AIs) improve survival in postmenopausal women with hormone-sensitive breast cancer, but can cause joint pain and stiffness. The purpose of the current study was to evaluate the ...prevalence of and identify risk factors for AI-related joint symptoms.
We performed a cross-sectional survey of consecutive postmenopausal women receiving adjuvant AI therapy for early-stage hormone-sensitive breast cancer at an urban academic breast oncology clinic. Patients completed a 25-item self-administered questionnaire assessing the presence of joint symptoms that started or worsened after initiating AIs. Multivariate regression was used to compare those with AI-related arthralgia with those who did not report symptoms, adjusting for demographic and clinical factors.
Of 200 patients who completed the survey, 94 (47%) reported having AI-related joint pain and 88 (44%) reported AI-related joint stiffness. In multiple logistic regression analysis, being overweight (body mass index of 25 to 30 kg/m(2)) and prior tamoxifen therapy were inversely associated with AI-related joint symptoms. Patients who received taxane chemotherapy were more than four times more likely than other patients to have AI-related joint pain and stiffness (odds ratio OR = 4.08, 95% CI, 1.58 to 10.57 and OR = 4.76; 95% CI, 1.84 to 12.28, respectively).
Our study suggests that AI-related joint symptoms are more prevalent than what has been described previously in clinical trials. The success of AI therapy depends on patients' ability to adhere to treatment recommendations; therefore, additional studies of interventions that may alleviate these symptoms are needed.
Purpose
Reverse Phase Protein Array (RPPA) is a high-throughput antibody-based technique to assess cellular protein activity. The goal of this study was to assess protein marker changes by RPPA in ...tumor tissue from a pre-surgical metformin trial in women with operable breast cancer (BC).
Methods
In an open-label trial, metformin 1500-mg PO daily was administered prior to resection in 35 non-diabetic patients with stage 0–III BC, body mass index ≥25 kg/m
2
. For RPPA, formalin-fixed paraffin-embedded (FFPE) samples were probed with 160 antibodies. Paired and two-sample t-tests were performed (
p
≤ 0.05). Multiple comparisons were adjusted for by fixing the false discovery rate at 25 %. We evaluated whether pre- and post-metformin changes of select markers by RPPA were identified by immunohistochemistry (IHC) in these samples. We also assessed for these changes by western blot in metformin-treated BC cell lines.
Results
After adjusting for multiple comparisons in the 32 tumors from metformin-treated patients vs. 34 untreated historical controls, 11 proteins were significantly different between cases vs. controls: increases in Raptor, C-Raf, Cyclin B1, Cyclin D1, TRFC, and Syk; and reductions in pMAPK
pT202,Y204
, JNK
pT183,pT185
, Bad
pS112
, PKC.alpha
pS657
, and Src
pY416
. Cyclin D1 change after metformin by IHC was not observed. In cell lines, reductions in JNK
pT183
and Bad
pS112
were seen, with no change in Cyclin D1 or Raptor.
Conclusions
These results suggest that metformin modulates apoptosis/cell cycle, cell signaling, and invasion/motility. These findings should be assessed in larger metformin trials. If confirmed, associations between these changes and BC clinical outcome should be evaluated.
Clinicaltrials.gov identifier
NCT00930579.
Abstract
Objective
Clinically significant weight gain of ≥5% from baseline has been commonly reported during chemotherapy treatment for early stage breast cancer and persisting after completion. ...Based on the known poorer outcomes associated with weight gain after a breast cancer diagnosis, we evaluated differential weight gain by race/ethnicity as a potential explanation for disparities in breast cancer clinical outcomes among racial/ethnic minorities compared to non-Hispanic white women.
Methods
We conducted a retrospective cohort study among women diagnosed with stage I-III breast cancer between 2007 and 2016, who received chemotherapy at Columbia University Medical Center (CUMC) in New York, NY. We extracted data on demographics, clinical characteristics, chemotherapy regimens, and height/weight from the electronic health records. Our main exposure variable of interest was race/ethnicity. The outcome variable was dichotomized as ≥5% weight gain or stable weight (defined as <5% weight gain or loss/≥5% weight loss) from baseline at 3, 6, 12, and 18 months after initiating chemotherapy. We used multinomial logistic regression analyses to determine the association between race/ethnicity and weight gain before and after adjusting for confounders.
Results
Among 789 evaluable women, median age was 55 years (range, 19-92) and the study cohort was racially/ethnically diverse: 39.8% non-Hispanic white, 30.4% Hispanic, 18.0% non-Hispanic black, 10.4% Asian, and 1.4% other. Mean baseline body mass index (BMI) was highest among black women (30.7 kg/m2 ± 7.0), followed by Hispanic (29.4 kg/m2 ± 5.2), non-Hispanic white (27.9 kg/m2 ± 6.9), and Asian (25.5 kg/m2 ± 5.4) women. The proportion of women with ≥5% weight gain increased over time with 13.6% at 3 months, 15.2% at 6 months, 19.0% at 12 months, and 23.6% at 18 months. Compared to non-Hispanic whites, Asian women had a 63% lower odds of ≥5% weight gain (95% Confidence Interval CI: 0.15-0.92) at 3 months after initiating chemotherapy. No statistically significant associations were found between other racial/ethnic groups and ≥5% weight gain. Factors associated with weight gain after chemotherapy included younger age at diagnosis, lower baseline BMI, longer duration of chemotherapy, and having Medicaid insurance coverage.
Conclusions
Race/ethnicity was not significantly associated with weight gain after chemotherapy among women with early stage breast cancer. Socioeconomic status (SES) rather than race/ethnicity may be a contributing factor in disparities in weight gain and breast cancer clinical outcomes. Future weight loss programs should target younger, pre-menopausal women and those with lower SES.
Citation Format: Wu R, Crew KD. Racial and ethnic differences in weight gain during and after chemotherapy among women with early-stage 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 P1-10-04.
The demographics of esophageal and gastric cancer have been changing dramatically in the United States over the past several decades. While incidence rates for esophageal squamous cell carcinoma and ...distal gastric carcinoma have been declining, the trends for adenocarcinoma of the esophagus and proximal stomach have been rising rapidly, particularly among white males. The incidence of these upper gastrointestinal (GI) malignancies varies widely based on geographic location, race, and socioeconomic status. The primary causes of squamous cell carcinoma of the esophagus are tobacco use and alcohol consumption, whereas the main risk factors for adenocarcinoma of the esophagus are gastroesophageal reflux disease and obesity. Dietary factors and Helicobacter pylori infection play an important role in the development of gastric cancer. Understanding the epidemiology and etiologies of esophageal and gastric carcinomas will lead to the development of interventions for screening and prevention in high-risk populations.
Vitamin D deficiency is a potentially modifiable risk factor that may be targeted for breast cancer prevention. We examined the safety, feasibility, and biomarker effects of high-dose vitamin D among ...women at high risk for breast cancer. Forty high-risk women, defined as a 5-year breast cancer risk ≥1.67% per the Gail model, lobular or ductal carcinoma
, were assigned to a 1-year intervention of vitamin D3 20,000 IU or 30,000 IU weekly. Participants were monitored for toxicity every 3 months, underwent serial blood draws at baseline, 6 and 12 months, and a digital mammogram at baseline and 12 months. Biomarker endpoints included serum 25-hydroxyvitamin D 25(OH)D, 1,25-dihydroxyvitamin D 1,25(OH)
D, parathyroid hormone (PTH), insulin-like growth factor (IGF-1), IGF binding protein (IGFBP-3), and mammographic density (MD) using Cumulus software. From November 2007 to January 2011, we enrolled 40 women; 37 were evaluable at 6 months and 30 at 12 months. One patient was taken off study for hypercalciuria; otherwise, the intervention was well tolerated. From baseline to 12 months, mean serum 25(OH)D and 1,25(OH)
D rose from 20.0 to 46.9 ng/ml and 69.7 to 98.1 pg/ml, respectively (p<0.01). Serum PTH decreased by 12% at 6 months and IGF-1/IGFBP-3 ratio decreased by 4.3% at 12 months (p<0.05). There was no significant change in MD regardless of menopausal status or dose level. We demonstrated that 1 year of high-dose vitamin D3 was associated with a significant increase in circulating vitamin D levels and favorable effects on IGF signaling, but no significant change in MD.
Abstract
Background: There are shared risk factors between breast cancer (BC) and diabetes mellitus (DM). BC treatments including chemotherapy given in combination with glucocorticoids can induce ...hyperglycemia and steroid related DM. Patients with DM are at increased risk of developing chemotherapy related toxicities such as chemotherapy induced peripheral neuropathy (CIPN) compared to those without DM. The incidence of hyperglycemia during chemotherapy in non-diabetic patients with early-stage breast cancer is unknown.
Methods: We performed a retrospective analysis of non-diabetic women with stage I-III breast cancer treated with chemotherapy at Columbia University Medical Center from 9/1/2016-8/31/2017 to evaluate hyperglycemia incidence during chemotherapy and up to six months after chemotherapy completion. Eligible patients were identified in the electronic health record (EHR) by ICD9 and 10 codes (ICD9 174.x and ICD10 C50.x) and a record of chemotherapy administration. Non-diabetic patients were defined by chart review as no recorded history of diabetes and no receipt of a diabetes medication in the EHR. Breast cancer stage was determined by chart review. Glucose values were recorded prior to chemotherapy, during chemotherapy, and for six-months after chemotherapy completion. We defined hyperglycemia as a glucose value of ≥200 mg/dl. Median time to hyperglycemia was also calculated.
Results: We identified 82 eligible patients. The majority of patients received dexamethasone during their chemotherapy course (79 patients, 96.3%). The most frequent chemotherapy regimen was doxorubicin/cyclophosphamide and paclitaxel (32 patients, 39.0%). At baseline, 20 patients (24.4%) had a normal body mass index (BMI), 27 patients (32.9%) were overweight, and 31 patients (37.8%) were obese. Hyperglycemia occurred in 8 patients (9.8%) after initiation of chemotherapy. Among patients with hyperglycemia, the maximum blood glucose was between 200-299 mg/dl in seven patients (87.5%), and between 500-599 in one patient (12.5%). The median time to hyperglycemia was 84 days. Among patients who did not experience hyperglycemia, the maximum blood glucose was between 140-159 mg/dl in six patients (8.1%), between 160-179 mg/dl in eight patients (10.8%), and between 180-199 mg/dl in three patients (4.1%). Three patients were diagnosed with DM following chemotherapy completion.
Conclusion: Hyperglycemia occurred in almost 10% of non-diabetic patients who received chemotherapy for early-stage breast cancer. Additionally, over 30% of patients had a blood glucose of 140 mg/dl or higher after chemotherapy initiation. The impact of hyperglycemia on the development of chemotherapy related toxicities in this group is unknown. Future research is needed to identify effective interventions for glucose control during chemotherapy, and to determine if glucose control during treatment can reduce the risk of chemotherapy related toxicities, specifically CIPN.
Citation Format: Accordino MK, Lin A, Wright JD, Trivedi MS, Kalinsky K, Crew KD, Hershman DL. Incidence of hyperglycemia in non-diabetic patients with early-stage breast cancer treated with chemotherapy 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 P1-20-02.
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