Trevor Augustus Jolly

Effect of Cytotoxic Chemotherapy on Markers of Molecular Age in Patients With Breast Cancer

BACKGROUND Senescent cells, which express p16 (INK4a) , accumulate with aging and contribute to age-related pathology. To understand whether cytotoxic agents promote molecular aging, we measured expression of p16 (INK4a) and other senescence markers in breast cancer patients treated with adjuvant chemotherapy. METHODS Blood and clinical information were prospectively obtained from 33 women with stage I to III breast cancer at four time points: before anthracycline-based chemotherapy, immediately after anthracycline-based chemotherapy, 3 months after anthracycline-based chemotherapy, and 12 months after anthracycline-based chemotherapy. Expression of senescence markers p16 (INK4a) and ARF mRNA was determined using TaqMan quantitative reverse-transcription polymerase chain reaction in CD3(+) T lymphocytes, telomere length was determined by Southern analysis, and senescence-associated cytokines were determined by enzyme-linked immunosorbent assay. Findings were independently assessed in a cross-sectional cohort of 176 breast cancer survivors enrolled a median of 3.4 years after treatment; 39% previously received chemotherapy. All statistical tests were two-sided. RESULTS In prospectively analyzed patients, expression of p16 (INK4a) and ARF increased immediately after chemotherapy and remained elevated 12 months after treatment. Median increase in log2 p16 (INK4a) was 0.81 (interquartile range = 0.28-1.62; Wilcoxon signed-rank P < .001), or a 75% absolute increase in expression, equivalent to the increase observed over 14.7 years of chronological aging. ARF expression was comparably increased (P < .001). Increased expression of p16 (INK4a) and ARF was associated with dose-dense therapy and hematological toxicity. Expression of two senescence-associated cytokines (VEGFA and MCP1) was durably increased by adjuvant chemotherapy. Telomere length was not affected by chemotherapy. In a cross-sectional cohort, prior chemotherapy exposure was independently associated with a log2-increase in p16 (INK4a) expression of 0.57 (repeated measures model, P < .001), comparable with 10.4 years of chronological aging. CONCLUSIONS Adjuvant chemotherapy for breast cancer is gerontogenic, inducing cellular senescence in vivo, thereby accelerating molecular aging of hematopoietic tissues.

Geriatric Assessment-Identified Deficits in Older Cancer Patients With Normal Performance Status

BACKGROUND We investigated whether a brief geriatric assessment (GA) would identify important patient deficits that could affect treatment tolerance and care outcomes within a sample of older cancer patients rated as functionally normal (80%-100%) on the Karnofsky performance status (KPS) scale. METHODS Cancer patients aged ≥65 years were assessed using a brief GA that included both professionally and patient-scored KPS and measures of comorbidity, polypharmacy, cognition, function, nutrition, and psychosocial status. Data were analyzed using descriptive statistics and multivariable logistic regression. RESULTS The sample included 984 patients: mean age was 73 years (range: 65-99 years), 74% were female, and 89% were white. GA was conducted before (23%), during (41%), or after (36%) treatment. Overall, 54% had a breast cancer diagnosis (n = 528), and 46% (n = 456) had cancers at other sites. Moreover, 81% of participants (n = 796) had both professionally and self-rated KPS ≥80, defined as functionally normal, and those patients are the focus of analysis. In this subsample, 550 (69%) had at least 1 GA-identified deficit, 222 (28%) had 1 deficit, 140 (18%) had 2 deficits, and 188 (24%) had ≥3 deficits. Specifically, 43% reported taking ≥9 medications daily, 28% had decreased social activity, 25% had ≥4 comorbidities, 23% had ≥1 impairment in instrumental activities of daily living, 18% had a Timed Up and Go time ≥14 seconds, 18% had ≥5% unintentional weight loss, and 12% had a Mental Health Index score ≤76. CONCLUSION Within this sample of older cancer patients who were rated as functionally normal by KPS, GA identified important deficits that could affect treatment tolerance and outcomes.

Feasibility of geriatric assessment in community oncology clinics.

OBJECTIVE Emerging results support the value of geriatric assessment (GA) in determining the risk and benefits of cancer treatment in older adults. A brief GA tool consisting of valid and reliable measures has been developed; however, little data exist on the ability to perform the GA in community oncology clinics. The objective of this study was to determine the feasibility of performing the GA in the community. MATERIALS AND METHODS Patients aged ≥65 were eligible. The GA included a health care provider assessment of performance status, cognitive function, a Timed Up and Go test, and a self-administered patient questionnaire that evaluated measures of functional status, comorbidity, psychological state, social support, and nutritional status. RESULTS From 2009 to 2013, 1088 patients were assessed including 339 (31%) from seven community clinics across North Carolina. The median amount of time to complete the patient-report portion of the GA was 19min in the academic center versus 22min in the community. The median amount of time to complete the entire GA was 23min in the academic center and 30min in community settings. Significantly more patients in the community required assistance completing the questionnaire (24% vs. 14%); however, most patients required no assistance (76%). CONCLUSION A brief GA can be performed in community oncology clinics. The time to complete the professional assessments and patient self-assessments were similar in both settings. Future studies are planned to determine if such assessments can improve cancer care for older patients.

Adjuvant treatment for older women with invasive breast cancer

Older women experience a large share of breast cancer incidence and death. With the projected rise in the number of older cancer patients, adjuvant chemo-, radiation and endocrine therapy management will become a key component of breast cancer treatment in older women. Many factors influence adjuvant treatment decisions including patient preferences, life expectancy and tumor biology. Geriatric assessment predicts important outcomes, identifies key deficits, and can aid in the decision making process. This review utilizes clinical vignettes to illustrate core principles in adjuvant management of breast cancer in older women and suggests an approach incorporating life expectancy and geriatric assessment.

Individualizing Local-Regional Therapy of Breast Cancer in the Elderly

Purpose of ReviewThe treatment of breast cancer in the elderly population requires a tailored approach. We summarize the current best evidence for personalized local-regional therapy in breast cancer patients older than 70.Recent FindingsBreast cancer treatment in older adults incorporates the use of geriatric assessment tools to best evaluate functional status and treatment tolerability while accounting for the biologic profile of the disease. Surgical resection of the primary tumor with lymph node evaluation remains the cornerstone of local-regional control. Recent clinical trials demonstrate that surgery and radiation therapy may, however, be safely omitted in selected patients who are eligible for primary endocrine therapy. In patients with high-risk node-positive disease, DFS can be improved by systemic chemotherapy, but potential toxicity should be carefully considered in this population.SummaryPatient-specific evaluation of the risks of both under- and over-treatment of breast cancer in the older adult is essential for delivering optimal care in this population.

LCCC 1025: a phase II study of everolimus, trastuzumab, and vinorelbine to treat progressive HER2-positive breast cancer brain metastases

PurposeHER2 + breast cancer (BC) is an aggressive subtype with high rates of brain metastases (BCBM). Two-thirds of HER2 + BCBM demonstrate activation of the PI3K/mTOR pathway driving resistance to anti-HER2 therapy. This phase II study evaluated everolimus (E), a brain-permeable mTOR inhibitor, trastuzumab (T), and vinorelbine (V) in patients with HER2 + BCBM.Patients and methodsEligible patients had progressive HER2 + BCBM. The primary endpoint was intracranial response rate (RR); secondary objectives were CNS clinical benefit rate (CBR), extracranial RR, time to progression (TTP), overall survival (OS), and targeted sequencing of tumors from enrolled patients. A two-stage design distinguished intracranial RR of 5% versus 20%.Results32 patients were evaluable for toxicity, 26 for efficacy. Intracranial RR was 4% (1 PR). CNS CBR at 6 mos was 27%; at 3 mos 65%. Median intracranial TTP was 3.9 mos (95% CI 2.2–5). OS was 12.2 mos (95% CI 0.6–20.2). Grade 3–4 toxicities included neutropenia (41%), anemia (16%), and stomatitis (16%). Mutations in TP53 and PIK3CA were common in BCBM. Mutations in the PI3K/mTOR pathway were not associated with response. ERBB2 amplification was higher in BCBM compared to primary BC; ERBB2 amplification in the primary BC trended toward worse OS.ConclusionWhile intracranial RR to ETV was low in HER2 + BCBM patients, one-third achieved CNS CBR; TTP/OS was similar to historical control. No new toxicity signals were observed. Further analysis of the genomic underpinnings of BCBM to identify tractable prognostic and/or predictive biomarkers is warranted. Clinical Trial: (NCT01305941).

Correction to: Measuring and understanding adherence in a home-based exercise intervention during chemotherapy for early breast cancer

In the original publication, the sixth author name was published incorrectly as A. Wood. The correct author name should read as W. A. Wood.

Abstract PD6-07: Genomic sequencing in metastatic breast cancer patients to inform clinical practice at the University of North Carolina at Chapel Hill:

Background: An increasing number of molecularly-targeted therapies for metastatic breast cancer (MBC) are clinically-available (approved and investigational). These anti-cancer agents target specific molecular abnormalities such as mutated, amplified, deleted, or rearranged genes. Reporting of unique tumor genetic alterations is not included in routine clinical/diagnostic panels. In MBC, knowledge of mutational status may foster efficient transitions in clinical care and trial enrollment at disease progression. We describe the development and implementation of a clinically-integrated genomic sequencing program and report how information regarding targetable genomic aberrations in MBC patients (pts) is used to improve clinical practice in an academic setting. Methods: Genomic sequencing of investigative biomarkers was prospectively offered to pts with MBC. DNA libraries were prepared separately from a retrieved archival FFPE tumor sample and a matched normal sample from each pt. Relevant targets were enriched by custom Agilent SureSelect hybrid capture baits using standard protocols. Samples were sequenced on Illumina HiSeq 2000/2500 platforms. Mutational findings were reviewed by a molecular tumor board (MTB); variants identified to be potentially actionable underwent confirmatory testing in a CLIA-approved laboratory. Confirmed findings were inserted into the pt9s EMR accessible by both the pt and the treating oncologist. Results: Of the 725 MBC pts seen at UNC since 1/1/2012, 194 (27%) contributed samples for genomic sequencing. Of those whose tumors were sequenced, average age at MBC diagnosis was 54 (25 - 91); 73% were Caucasian, 16% African American. De novo MBC accounted for 39 (20%) sequenced pts. Of sequenced patients, sites of metastatic disease included bone only (7%), visceral only (46%), and both bone and visceral (47%). Approximately 1/3 of pts were consented for sequencing at time of initial MBC diagnosis, 1/4 after 1st line therapy for MBC, and the remaining at or beyond their 2nd line. In total, 131 (68%) pts have sequencing results available of which 43% of pts had reportable mutations deemed actionable by the MTB. Specific mutations and observed frequency by subtype are shown below. Pts (19%) whose tumors were sequenced were more commonly enrolled in a therapeutic clinical trial for MBC, a higher rate than seen in the non-sequenced group (7%) (p Conclusion: Preemptive genomic sequencing can be integrated into the clinical and operational practice of a comprehensive cancer center. Currently this research tool and program provides valuable information that has the potential to foster both clinical trial eligibility and/or enrollment. With longer follow-up, we hope such an approach ultimately will improve patient outcomes. Citation Format: Grilley-Olsen J, Keith KC, Hayward M, Dees EC, Deal A, Ivanova A, Benbow JM, Parker J, Patel NM, Eberhard D, Mieczkowski P, Weck KE, Hayes DN, Muss H, Jolly T, Reeder-Hayes K, Earp HS, Sharpless N, Carey L, Anders CK. Genomic sequencing in metastatic breast cancer patients to inform clinical practice at the University of North Carolina at Chapel Hill. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD6-07.

Inherited Cancer Susceptibility in an Elderly Adult

advice stems from a study in autosomal-dominant polycystic kidney disease in which tolvaptan was used at much higher doses (average dose 95 mg/d) for longer periods (total duration of the trial was 36 months). So whether the risk is similar when used intermittently in lower doses is unclear. The man in the current study was made aware of this complication and was happy to continue with the current regime with close monitoring. To summarize, chronic hyponatremia due to SIADH is common and mostly asymptomatic and could be managed by fluid restriction, but in individuals with significant morbidity and recurrent hospitalizations due to hyponatremia not responding to fluid restriction, intermittent tolvaptan combined with fluid restriction should be considered. When used appropriately, it is still cheaper than recurrent hospital admissions and the morbidity and mortality associated with hyponatremia.