Purpose
It is not known whether chemotherapy-related symptom experiences differ between Black and White women with early breast cancer (Stage I–III) receiving current chemotherapy regimens and, in ...turn, influences dose delay, dose reduction, early treatment discontinuation, or hospitalization.
Methods
Patients self-reported their race and provided symptom reports for 17 major side effects throughout chemotherapy. Toxicity and adverse events were analyzed separately for anthracycline and non-anthracycline regimens. Fisher’s exact tests and two-sample t-tests compared baseline patient characteristics. Modified Poisson regression estimated relative risks of moderate, severe, or very severe (MSVS) symptom severity, and chemotherapy-related adverse events.Please check and confirm that the authors and their respective affiliations have been correctly identified and amend if necessary.no changes
Results
In 294 patients accrued between 2014 and 2020, mean age was 58 (SD13) and 23% were Black. For anthracycline-based regimens, the only significant difference in MSVS symptoms was in lymphedema (41% Black vs 20% White,
p
= .04) after controlling for axillary surgery. For non-anthracycline regimens, the only significant difference was MSVS peripheral neuropathy (41% Blacks vs. 23% White) after controlling for taxane type (
p
= .05) and diabetes (
p
= .05). For all other symptoms, severity scores were similar. Dose reduction differed significantly for non-anthracycline regimens (49% Black vs. 25% White,
p
= .01), but not for anthracycline regimens or in dose delay, early treatment discontinuation, or hospitalization for either regimen.
Conclusion
Except for lymphedema and peripheral neuropathy, Black and White patients reported similar symptom severity during adjuvant chemotherapy. Dose reductions in Black patients were more common for non-anthracycline regimens. In this sample, there were minimal differences in patient-reported symptoms and other adverse outcomes in Black versus White patients.
Symptom control is one of the primary goals of hospice care. We prospectively followed patients with advanced cancer receiving outpatient hospice care to determine if the use of antimicrobials for a ...clinically suspected infection improved infection-related symptoms. During a 24-month period, 1,731 patients with a cancer diagnosis were admitted to a community-based outpatient hospice program. Over 89% of the patients had a Karnofsky performance of ≤60%. Six hundred twenty-three of 1,598 study patients were diagnosed with a total of 685 infections. Six hundred thirty-three of the infections were treated with antimicrobials for a clinically suspected infection. Symptoms were recorded, clinically indicated cultures were obtained, and antimicrobials were instituted at the discretion of the attending physician. Patients were subsequently monitored to determine the effects of antimicrobials on infection-related symptoms. A complete or a partial response of infection-related symptoms was observed in 79% of 265 patients with urinary tract infections, 43% of 221 patients with respiratory tract infections, 46% of 63 patients with oral cavity infections, 41% of 59 patients with skin or subcutaneous infections, and none of 25 patients with bacteremia. Fifty-two of the infections were not evaluable due to refusal of antimicrobials or receipt of less than 72 hours of antimicrobials. Patient survival in this study was not affected by the presence of infection or the use of antimicrobials. Although the use of antimicrobials improved symptoms in the majority of patients with urinary tract infections, symptom control was less successful in infections of the respiratory tract, mouth/pharynx, skin/subcutaneous tissue, or blood. Physicians should be aware of the limitations of the use of antimicrobials in patients with advanced cancer receiving hospice care. Treatment guidelines are proposed emphasizing the importance of patient preferences and the use of symptom control as the major indication for the use of antimicrobials in this patient population.
This study sought to evaluate whether myeloid-derived suppressor cells (MDSC) could be affected by chemotherapy and correlate with pathologic complete response (pCR) in breast cancer patients ...receiving neo-adjuvant chemotherapy. Peripheral blood levels of granulocytic (G-MDSC) and monocytic (M-MDSC) MDSC were measured by flow cytometry prior to cycle 1 and 2 of doxorubicin and cyclophosphamide and 1st and last administration of paclitaxel or paclitaxel/anti-HER2 therapy. Of 24 patients, 11, 6 and 7 patients were triple negative, HER2+ and hormone receptor+, respectively. 45.8% had pCR. Mean M-MDSC% were <1. Mean G-MDSC% and 95% confidence intervals were 0.88 (0.23–1.54), 5.07 (2.45–7.69), 9.32 (4.02–14.61) and 1.97 (0.53–3.41) at draws 1–4. The increase in G-MDSC by draw 3 was significant (
p
< 0.0001) in all breast cancer types. G-MDSC levels at the last draw were numerically lower in patients with pCR (1.15; 95% CI 0.14–2.16) versus patients with no pCR (2.71; 95% CI 0–5.47). There was no significant rise in G-MDSC from draw 1 to 3 in African American patients, and at draw 3 G-MDSC levels were significantly lower in African Americans versus Caucasians (
p
< 0.05). It was concluded that G-MDSC% increased during doxorubicin and cyclophosphamide therapy, but did not significantly differ between patients based on pathologic complete response.
Cardiovascular disease (CVD) has become an increasingly common limitation to effective anticancer therapy. Yet, whether CVD events were consistently reported in pivotal trials supporting contemporary ...anticancer drugs is unknown.
The authors sought to evaluate the incidence, consistency, and nature of CVD event reporting in cancer drug trials.
From the Drugs@FDA, clinicaltrials.gov, MEDLINE, and publicly available U.S. Food and Drug Administration (FDA) drug reviews, all reported CVD events across latter-phase (II and III) trials supporting FDA approval of anticancer drugs from 1998 to 2018 were evaluated. The primary outcome was the report of major adverse cardiovascular events (MACE), defined as incident myocardial infarction, stroke, heart failure, coronary revascularization, atrial fibrillation, or CVD death, irrespective of treatment arm. The secondary outcome was report of any CVD event. Pooled reported annualized incidence rates of MACE in those without baseline CVD were compared with reported large contemporary population rates using relative risks. Population risk differences for MACE were estimated. Differences in drug efficacy using pooled binary endpoint hazard ratios on the basis of the presence or absence of reported CVD were also assessed.
Overall, there were 189 trials, evaluating 123 drugs, enrolling 97,365 participants (58.5 ± 5 years, 46.0% female, 72.5% on biologic, targeted, or immune-based therapies) with 148,138 person-years of follow-up. Over a median follow-up of 30 months, 1,148 incidents of MACE (375 heart failure, 253 myocardial infarction, 180 strokes, 65 atrial fibrillation, 29 revascularizations, and 246 CVD deaths; 792 in the intervention vs. 356 in the control arm; p < 0.01) were reported from the 62.4% of trials noting any CVD. The overall weighted-average incidence was 542 events per 100,000 person-years (716 per 100,000 in the intervention arm), compared with 1,408 among similar-aged non-cancer trial subjects (relative risk: 0.38; p < 0.01), translating into a risk difference of 866. There was no association between reporting CVD events and drug efficacy (hazard ratio: 0.68 vs. 0.67; p = 0.22).
Among pivotal clinical trials linked to contemporary FDA-approved cancer drugs, reported CVD event rates trail expected population rates.
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To assess metastatic breast cancer (MBC) patient psychological factors, perceptions, and comprehension of tumor genomic testing.
In a prospective, single institution, single-arm trial, patients with ...MBC underwent next-generation sequencing at study entry with sequencing results released at progression. Patients who completed surveys before undergoing sequencing were included in the present secondary analysis (n = 58). We administered four validated psychosocial measures: Center for Epidemiologic Studies Depression Scale, Beck Anxiety Inventory, Trust in Physician Scale, and Communication and Attitudinal Self-Efficacy scale for Cancer. Genetic comprehension was assessed using 7-question objective and 6-question subjective measures. Longitudinal data were assessed (n = 40) using paired Wilcoxon signed rank and McNemar's test of agreement.
There were no significant differences between the beginning and end of study in depression, anxiety, physician trust, or self-efficacy (median time on study: 7.6 months). Depression and anxiety were positively associated with each other and both negatively associated with self-efficacy. Self-efficacy decreased from pre- to post-genomic testing (p = 0.05). Objective genetics comprehension did not significantly change from pre- to post-genomic testing, but patients expressed increased confidence in their ability to teach others about genetics (p = 0.04). Objective comprehension was significantly lower in non-white patients (p = 0.02) and patients with lower income (p = 0.04).
This is the only study, to our knowledge, to longitudinally evaluate multiple psychological metrics in MBC as patients undergo tumor genomic testing. Overall, psychological dimensions remained stable over the duration of tumor genomic testing. Among patients with MBC, depression and anxiety metrics were negatively correlated with patient self-efficacy. Patients undergoing somatic genomic testing had limited genomic knowledge, which varied by demographic groups and may warrant additional educational intervention.
NCT01987726, registered November 13, 2013.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Chemotherapy induced ovarian failure (CIOF) results in rapid bone loss.•Osteoprotegerin (OPG) interrupts osteoclast activation and bone resorption.•We studied the relationship between bone loss in ...women with CIOF and OPG.•OPG levels initially increased, then decreased to values greater than baseline.•This phenomenon is described in other diseases, but never before in CIOF.
Chemotherapy induced ovarian failure (CIOF) results in rapid bone loss. Receptor Activator of Nuclear Factor Kappa-B (RANK)-RANK ligand (RANK-L) signaling balances bone resorption and formation. Osteoprotegerin (OPG) acts as a decoy receptor for RANK, interrupting osteoclast activation and bone resorption. This study examined the relationship between OPG and bone loss in women with CIOF.
Premenopausal women with stage I/II breast cancers receiving adjuvant chemotherapy were evaluated at chemotherapy initiation, 6 and 12 months. Bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN), follicle stimulating hormone (FSH), ionized calcium, osteocalcin, and OPG were serially measured. CIOF was defined as a negative pregnancy test, FSH levels >30 MIU/mL, and ≥3 months of amenorrhea.
Forty women were enrolled; 31 (77.5%) met CIOF criteria. BMD significantly decreased (p < 0.001) in the CIOF group at both time points: LS BMD decreased from a median of 0.993 g/cm2 to 0.976 g/cm2 and 0.937 g/cm2 at 6 and 12 months, respectively. OPG was significantly elevated at 6 months (median increase 0.30 pmol/L, p = 0.015) and then decreased at 12 months to levels still above baseline (median difference 0.2 pmol/L, p = 0.70).
In what was likely a compensatory response to rapid bone loss, CIOF patients' OPG levels increased at 6 months and then decreased at 12 months to values greater than baseline assessments. This phenomenon is described in other diseases, but never before in CIOF.
Abstract Background Peak internal knee abduction moment is a common surrogate variable associated with medial compartment knee loading. Stair descent has been shown to yield a greater peak knee ...abduction moment compared to level-walking. Changes in step width (SW) may lead to changes in frontal plane lower extremity limb alignment in the frontal plane and alter peak knee abduction moment. The purpose of this study was to investigate the effects of increased SW on frontal plane knee biomechanics during stair descent in healthy older adults. Methods Twenty healthy adults were recruited for the study. A motion analysis system was used to obtain three-dimensional lower limb kinematics during testing. An instrumented 3-step staircase with two additional customized wooden steps was used to collect ground reaction forces (GRF) data during stair descent trials. Participants performed five stair descent trials at their self-selected speed using preferred, wide (26% leg length), and wider (39% leg length) SW. Results The preferred normalized SW in older adults during stair descent was 20% of leg length. Wide and wider SW during stair descent reduced both first and second peak knee adduction angles and abduction moments compared to preferred SW in healthy adults. Conclusions Increased SW reduced peak knee adduction angles and abduction moments. The reductions in knee abduction moments may have implications in reducing medial compartment knee loads during stair descent.
Abstract
Background: Triple-negative breast cancer (TNBC) is a heterogeneous disease. Clinically, we observe three distinct TNBC outcomes: 1) rapid relapse (rrTNBC) characterized by aggressive drug ...resistant disease; 2) late relapse (lrTNBC) characterized by indolent or treatment responsive disease; and 3) no relapse (NoRTNBC). We hypothesized that distinct clinical and genomic features of primary tumors define rapid versus late relapse in TNBC.
Approach: Using three publicly-available datasets (METABRIC, TCGA, and a prior gene expression meta-analysis), we identified 455 patients diagnosed with primary TNBC with adequate follow-up to be characterized as rrTNBC (relapse or death within 2 years of diagnosis), lrTNBC (relapse or death more than 2 years after diagnosis), or NoRTNBC (no relapse/death with at least 5 years follow-up). We compiled basic clinical (n=455 patients) and primary tumor multi-omic data, including whole transcriptome (n=455), whole genome copy number (n=317), and mutation data for 171 cancer-related genes (n=317). We evaluated intrinsic subtypes (PAM50, TNBCtype), 125 gene expression signatures, CIBERSORT immune subsets, copy number, and mutation frequency.
Results: We first evaluated patients with relapse (rrTNBC+lrTNBC) vs. NoRTNBC. There was no significant difference in age, grade, stage at diagnosis, or PAM50 or TNBC subtype proportion between relapse and NoRTNBC. Among 125 expression signatures, five immune signatures were significantly higher in NoRTNBCs (FDR p<0.05) suggesting increased immune activity in patients who do not relapse. Using CIBERSORT inferred immune subsets, anti-tumor CD8 T-cell, M1 macrophage, and gamma-delta T-cell subsets were all highly correlated to these immune signatures (all Pearson's r >= 0.3, all p<1.2e-8). Among genomic features, patients who relapsed were significantly more likely to harbor a mutation in PIK3CA (Fisher exact FDR p=0.02) but there was no significant difference in tumor mutation burden or percent genome altered (Student's t-test p=0.83 and p=0.99, respectively). We then evaluated primary TNBC genomic data in patients who ultimately developed rapid vs. late relapse. Patients with rrTNBC were more likely to be higher stage (p<0.0001) while lrTNBC were more likely to be non-basal PAM50 subtype (p=0.03). Among 11 significantly altered gene expression signatures (FDR p<0.05), 6 estrogen/luminal signatures were significantly higher in lrTNBC. Mutations in DNAH11 and PIK3CA were more common in lrTNBC (Fisher exact FDR p=0.04 and p=0.05, respectively) but there were no significant differences in tumor mutation burden or copy number burden (Student's t-test p=0.13 and p=0.45, respectively). Using 317 cases with full genomic data divided into training and validation datasets, we will report a comparison of machine learning models for predicting relapse versus no relapse and rapid versus late relapse.
Conclusions: Primary TNBC tumors destined for rapid, late, or no relapse reflect distinct genomic features. Anti-tumor immune signatures and subsets are enriched in patients who do not relapse yet no difference in mutational or copy number burden. Relative to rapid relapse TNBCs, late relapse TNBCs are enriched for non-basal tumors, estrogen/luminal expression signatures, and mutations in DNAH11 and PIK3CA.
Citation Format: Zhang Y, Nock W, Asad S, Adams E, Singh J, Damicis A, Lustberg MB, Noonan A, Reinbolt R, Sardesai S, VanDeusen J, Wesolowski R, Williams N, Ramaswamy B, Stover DG. Multi-omic predictor of rapid and late relapse in primary triple negative 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 P3-07-08.
Abstract
Background: Our understanding of mediators of immune infiltration in breast cancer and normal breast tissue remains limited. We hypothesize that patient factors known to be associated with ...inflammation and immune subsets, including body mass index, alcohol intake, and age and diagnosis, may play an important role in the tumor-immune microenvironment. Analyses of immune gene expression and signatures facilitate interrogation of the immune microenvironment in large patient cohorts.
Methods: Participants from the Nurses' Health Study cohorts I and II diagnosed with invasive breast cancer were included. Total RNA extracted and microarray performed for 882 tumor and 695 tumor-adjacent samples, of which 623 tumors have matched tumor-adjacent data. CD8+ T-cell expression metrics were assessed: CD8A single gene expression (CD8Agene), a CD8 T-cell signature (CD8sig), and a tumor infiltrating lymphocyte signature derived from the GeparSixto clinical trial (GSAct). Standard clinicopathologic features were evaluated, as well as body mass index (BMI) one year prior to diagnosis, cumulative average alcohol intake, and age at diagnosis.
Results: Overall, tumor and adjacent normal tissue demonstrated positive correlation of CD8Agene, CD8sig, and GSAct (n=623 pairs, Pearson's r = 0.46, 0.36, 0.31, respectively; all p<0.001). Similar correlations were present in TCGA breast cancer, an independent cohort (n=112 pairs, Pearson's r = 0.34, 0.17, 0.45, respectively; all p<0.001). We evaluated paired tumor and adjacent normal samples within individual immunohistochemical (IHC) subtype or PAM50 subtype by Wilcoxon signed-rank test. There was not a consistent trend for CD8Agene, CD8sig, nor GSAct to be greater in tumor or normal within subtypes. We then evaluated patient features/exposures and tumor immune expression metrics. For tumor-adjacent normal, there was no significant association of alcohol intake, BMI, or age at diagnosis with CD8 gene/expression metrics. For tumor tissue, a multivariate model demonstrated that BMI one year before diagnosis was significantly associated with CD8Agene expression. There was no significant association of alcohol intake or age at diagnosis with CD8 gene/expression metrics. We are currently evaluating the association of these CD8 T-cell gene expression signatures with CD8 T-cell immunohistochemistry in a subset of patients, which will be reported at the time of abstract presentation.
Conclusion: In this cohort of over 600 tumor:normal pairs and a separate validation cohort, multiple distinct CD8+ T-cell expression metrics are correlated between breast cancer and tumor-adjacent normal breast tissue. This suggests that the adjacent normal breast may reflect an altered immune microenvironment in the context of breast cancer. While age at diagnosis and alcohol intake are not significantly associated with tumor CD8 expression metrics, BMI was significantly associated with tumor CD8Agene expression in a multivariate model.
Citation Format: Damicis A, Heng YJ, Kensler K, Asad S, Adams E, Singh J, Zhang Y, Nock W, Wesolowski R, Williams N, Reinbolt R, Sardesai S, VanDeusen J, Noonan A, Lustberg MB, Ramaswamy B, Eliassen AH, Hankinson SE, Tamimi R, Stover DG. CD8+ T-cell gene expression and signatures in breast cancer and adjacent normal breast tissue: Association with body mass index, alcohol intake, and age at diagnosis 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 P1-09-01.
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