M. J. Kennedy

Increased spontaneous apoptosis, but not survivin expression, is associated with histomorphologic response to neoadjuvant chemoradiation in rectal cancer

PurposeSurvivin has been shown to be an important mediator of cellular radioresistance in vitro. This study aims to compare survivin expression and apoptosis to histomorphologic responses to neoadjuvant radiochemotherapy (RCT) in rectal cancer.Materials and methodsThirty-six pre-treatment biopsies were studied. Survivin mRNA and protein expression plus TUNEL staining for apoptosis was performed. Response to treatment was assessed using a 5-point tumour regression grade.ResultsSurvivin expression was not found to be predictive of response to RCT (p = NS). In contrast, spontaneous apoptosis was significantly (p = 0.0051) associated with subsequent response to RCT. However, no association between survivin expression and levels of apoptosis could be identified.ConclusionsThis in vivo study failed to support in vitro studies showing an association between survivin and response to chemotherapy and radiation therapy. These results caution against the translation of the in vitro properties of survivin into a clinical setting.

Patients over 65 years are assigned lower ECOG PS scores than younger patients, although objectively measured physical activity is no different.

OBJECTIVES The Eastern Cooperative Group Performance Status (ECOG PS) is a widely used standard functional classification in oncology practice, the verbal descriptors of which refer to physical activity (PA). Little is known about the cut-off points of this scale and measured PA levels. This research investigated the relationship between PS assigned, objectively measured PA, and patient age. MATERIALS AND METHODS One hundred ambulatory patients with treatment-naive cancer wore an accelerometer (RT3) for a mean (SD) of 5.6 (1.1) days before initial oncology evaluation and ECOG PS assignment. RESULTS Seventy five participants (75%) were <65 years and 25 were ≥65 years. Eighty nine (89%) were assigned an ECOG PS of 0 or 1 and 11% a PS of 2 or 3. A weak but significant inverse association was found between objectively measured PA and PS (rho = -0.26, p = 0.01). Seventy one participants (80%) with a PS of 0 or 1 spent more than 50% of waking hours resting. Participants assigned a PS of 2-3 spent significantly more time resting than those assigned a PS of 0 (p = 0.01). Age ≥65 years was significantly related to PS assigned (p = 0.04), although the older cohort were no less sedentary than younger patients. CONCLUSION PA levels were low, but PS scoring reflected relative PA levels and differentiated between patients of PS 0 and 2-3. Chronological age was not predictive of activity levels, but older patients were assigned lower PS scores. Incorporation of objective PA measures may merit further investigation especially in the geriatric oncology setting.

Screening for mismatch repair deficiency in colorectal cancer: data from three academic medical centers

Reflex immunohistochemistry (rIHC) for mismatch repair (MMR) protein expression can be used as a screening tool to detect Lynch Syndrome (LS). Increasingly the mismatch repair‐deficient (dMMR) phenotype has therapeutic implications. We investigated the pattern and consequence of testing for dMMR in three Irish Cancer Centres (CCs). CRC databases were analyzed from January 2005–December 2013. CC1 performs IHC upon physician request, CC2 implemented rIHC in November 2008, and CC3 has been performing rIHC since 2004. The number of eligible patients referred to clinical genetic services (CGS), and the number of LS patients per center was determined. 3906 patients were included over a 9‐year period. dMMR CRCs were found in 32/153 (21%) of patients at CC1 and 55/536 (10%) at CC2, accounting for 3% and 5% of the CRC population, respectively. At CC3, 182/1737 patients (10%) had dMMR CRCs (P < 0.001). Additional testing for the BRAF V600E mutation, was performed in 49 patients at CC3 prior to CGS referral, of which 29 were positive and considered sporadic CRC. Referrals to CGS were made in 66%, 33%, and 30% of eligible patients at CC1, CC2, and CC3, respectively. LS accounted for CRC in eight patients (0.8%) at CC1, eight patients (0.7%) at CC2, and 20 patients (1.2%) at CC3. Cascade testing of patients with dMMR CRC was not completed in 56%. Universal screening increases the detection of dMMR tumors and LS kindreds. Successful implementation of this approach requires adequate resources for appropriate downstream management of these patients.

Abstract P3-09-02: Unhealthy lifestyle patterns are prevalent in unaffected BRCA mutation carriers & are associated with increased oxidative stress and telomere length alterations

The lifetime-risk of breast-cancer is greatly increased in women carrying a deleterious mutation in the BRCA1 or BRCA2 genes . Recently, there has been increased penetrance of BRCA1 and BRCA2 mutations which may be due to lifestyle influences. There is a need to identify approaches to reduce the penetrance of BRCA 1/2 mutations. Understanding how modifiable lifestyle-factors affect cancer-risk in BRCA-mutation carriers may have implications for risk-reduction in this group. At the molecular level, oxidative-stress and telomere dysfunction are early events in cancer development and these processes may be considered surrogate markers of cancer-risk. It has been reported that BRCA-mutation carriers are more susceptible to these pro-carcinogenic processes that non-carriers. The aim of this pilot study was to objectively measure lifestyle factors in unaffected BRCA-mutation carriers and to assess the impact of these lifestyle-factors on oxidative-stress profiles and telomere length. Participants (n=75) were recruited from breast-cancer family-risk clinics and cancer-genetics clinics. Body-composition (BMI, waist-circumference), metabolic profiles and physical-activity (triaxial accelerometry) were measured for each participant. Serum levels of the oxidative-stress markers 8-oxo-7,8-dihydro-29-deoxyguanosine (8-oxo-DG) and 4-hydroxynonenal (4-HNE) were measured in a subset of participants (n=30) by ELISA. Telomere length was measured in a subset of participants (n=30) by quantitative PCR (qPCR). Participants demonstrated poor adherence to physical-activity guidelines with 94% not reaching physical-activity levels recommended by the American College of Sports Medicine. The majority of participants were overweight (39%) or obese (32%) with 73% exhibiting abdominal obesity. 21% of participants had the metabolic syndrome (MetS) at the time of study enrolment with the majority of participants (80%) presenting with at least one feature of the MetS. Circulating levels of 8-oxo-DG did not appear to be affected by body composition or MetS status, however, serum levels of the lipid peroxidation marker 4-HNE were significantly higher in participants with the MetS (p This work has provided compelling evidence that in this cohort of BRCA-mutation carriers, unhealthy lifestyle-patterns are prevalent. In addition, these results suggest that the potential may exist to modify pro-carcinogenic processes in this cohort by modifying physical activity levels and targeting the metabolic syndrome and its component features lifestyle interventions and/or medication.The lifetime-risk of breast-cancer is greatly increased in women carrying a deleterious mutation in the BRCA1 or BRCA2 genes . Recently, there has been increased penetrance of BRCA1 and BRCA2 mutations which may be due to lifestyle influences. There is a need to identify approaches to reduce the penetrance of BRCA 1/2 mutations. Understanding how modifiable lifestyle-factors affect cancer-risk in BRCA-mutation carriers may have implications for risk-reduction in this group. At the molecular level, oxidative-stress and telomere dysfunction are early events in cancer development and these processes may be considered surrogate markers of cancer-risk. It has been reported that BRCA-mutation carriers are more susceptible to these pro-carcinogenic processes that non-carriers. The aim of this pilot study was to objectively measure lifestyle factors in unaffected BRCA-mutation carriers and to assess the impact of these lifestyle-factors on oxidative-stress profiles and telomere length. Participants (n=75) were recruited from breast-cancer family-risk clinics and cancer-genetics clinics. Body-composition (BMI, waist-circumference), metabolic profiles and physical-activity (triaxial accelerometry) were measured for each participant. Serum levels of the oxidative-stress markers 8-oxo-7,8-dihydro-29-deoxyguanosine (8-oxo-DG) and 4-hydroxynonenal (4-HNE) were measured in a subset of participants (n=30) by ELISA. Telomere length was measured in a subset of participants (n=30) by quantitative PCR (qPCR). Participants demonstrated poor adherence to physical-activity guidelines with 94% not reaching physical-activity levels recommended by the American College of Sports Medicine. The majority of participants were overweight (39%) or obese (32%) with 73% exhibiting abdominal obesity. 21% of participants had the metabolic syndrome (MetS) at the time of study enrolment with the majority of participants (80%) presenting with at least one feature of the MetS. Circulating levels of 8-oxo-DG did not appear to be affected by body composition or MetS status, however, serum levels of the lipid peroxidation marker 4-HNE were significantly higher in participants with the MetS (p This work has provided compelling evidence that in this cohort of BRCA-mutation carriers, unhealthy lifestyle-patterns are prevalent. In addition, these results suggest that the potential may exist to modify pro-carcinogenic processes in this cohort by modifying physical activity levels and targeting the metabolic syndrome and its component features lifestyle interventions and/or medication. Citation Format: McGarrigle SA, Guinan EM, Hussey J, O9Sullivan J, Boyle T, Hanhauser Y, Al-azawi D, Kennedy MJ, Gallagher DJ, Connolly EM. Unhealthy lifestyle patterns are prevalent in unaffected BRCA mutation carriers & are associated with increased oxidative stress and telomere length alterations [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-09-02.

Abstract P6-01-02: Adipose tissue from breast cancer patients with the metabolic syndrome promotes proliferation and invasion of tumor cells and influences expression of genes involved in carcinogenesis.

Background: Obesity is a public health issue of global proportions and is recognised as a risk factor for post-menopausal breast cancer. Similarly, the metabolic syndrome (MetS) is recognised as a high risk state for cancer in general. Previously we have shown that the MetS is common in postmenopausal breast cancer patients and is associated with a more aggressive tumor biology. However, the molecular mechanisms by which obesity and/or the MetS promote breast cancer remain unclear. Adipose tissue, including mammary fat, is a functionally active endocrine organ. The aims of this study were to determine whether factors secreted by mammary adipose tissue could affect tumor cell biology and to assess the effect of the MetS on this adipose depot and its subsequent effect on tumor cells. Methods: Adipose tissue from fresh mastectomy specimens was cultured in serum free media for 72 h to produce adipose conditioned media (ACM). MCF-7 and MDA-MB 231 cell lines were treated with ACM for 24–48 h. Tumor cell function was then assessed by measuring cell proliferation (BrDU assay) and cell invasion. In addition, expression of 84 genes implicated in pathways involved in carcinogenesis was examined in these cell lines following ACM treatment, using quantitative PCR arrays. Results: In the estrogen receptor (ER) positive MCF-7 cell line, ACM from MetS breast cancer patients promoted significantly greater proliferation compared to ACM from normal weight patients (203.6 ± 34.23 vs 136.8 ± 11.58%, p = 0.022). Similarly, ACM from MetS patients significantly increased invasion of MCF-7 cells compared to ACM from normal weight patients (153.4 ± 6.027 vs 126.3 ± 6.03% RFU, p = 0.006). No differences in cell proliferation or invasion between cells treated with ACM from MetS patients compared to ACM from normal weight patients were found in the ER negative MDA-MB-231 cell line. Treatment of MCF-7 cells with ACM from MetS patients resulted in significant alterations (>2 fold up/down regulation) in expression of 11 genes involved in carcinogenesis. Primarily, genes implicated in invasion/metastasis and adhesion were differentially expressed between ACM-treated cells and cells treated with control media. On the other hand, when MDA-MB-231 cells were treated with ACM from the same patients only one gene, SERPIN B5 was significantly up-regulated > 2 fold. Conclusions: These data demonstrate that factors secreted from mammary adipose tissue from metabolically unhealthy patients promote proliferation and invasion of ER positive tumor cells and influence expression of genes involved in carcinogenesis in these cells. These effects were not observed in ER negative tumor cells suggesting that they may be mediated, at least in part by the estrogen receptor. These results have provided insight into how mammary adipose tissue may act via a paracrine mechanism to influence aspects of carcinogenesis and into how the metabolic syndrome may modulate this. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-01-02.

A comparison of ECOG PS assigned and objectively measured physical activity.

e19526 Background: The ECOG PS scale is a widely used measure of functional status in oncology and is a good predictor of prognosis and treatment benefit. However, the relationship between the phys...

Is Metabolic Syndrome and Central Obesity Relevent to Biology and Progression of Postmenopausal Breast Cancer

Introduction: Obesity isassociated with both an increased risk of postmenopausal breast cancer and increased mortality rates. The mechanism is unclear, and central (visceral) obesity, insulin resistance, altered sex steroids, and altered adipokines, are mooted as possible factors. These features may cluster in the so-called Metabolic Syndrome (MetS), and the focus of this study was to systematically relate MetS to standard clinicopathological indices of breast cancer. Methods: Postmenopausal women with newly diagnosed breast cancer (n=105) were prospectively recruited. A detailed clinical and dietary history was performed, as well as body composition analysis, metabolic screen, and plasma measurement of adipokines and inflammatory markers. MetS was defined according to the International Diabetes Federation definition. Results: One hundred and five patients were recruited, the median age was 68 years (40-94) and the mean BMI was 28.3 ± 5.2 kg/m 2 , with 87% of patients centrally obese. MetS was diagnosed in 39% of patients, and was significantly (p Discussion: MetS and central obesity are common in Irish postmenopausal breast cancer patients. MetS appears to be associated with aggressive tumour biology, and this may have significance in preventive and novel treatment approaches. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1051.

Obesity and postmenopausal breast cancer: impact on risk, tumour stage and survival in an Irish population.

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #6089 Background The evidence that obesity adversely affects womens health is overwhelming and indisputable. The risk of postmenopausal breast cancer increases with obesity. Furthermore it is reported that obesity is associated with poorer prognosis of breast cancer. Objective To assess the relationship between obesity and postmenopausal breast cancer by examining the incidence, tumour size, pathological stage, axillary nodal involvement and survival in an Irish population. Design & Setting A retrospective case control study was undertaken in 200 patients presenting to a tertiary centre between 1998-2006. Data were compared to 519 healthy female controls. Multivariate logistic regression models were used to calculate the odds ratio (OR) of developing postmenopausal cancer according to body mass index (BMI), as well as the impact BMI has on tumour size, nodal involvement, pathological stage and survival. Actuarial survival was calculated from date of diagnosis by the Kaplein-Meier method and comparisons between the groups were made by the log rank test. Results Postmenopausal breast cancer patients were significantly heavier than age matched controls with 65% being overweight or obese versus 54% of controls (p=0.030). A dose dependent relationship existed between BMI and postmenopausal breast cancer incidence. The adjusted odds ratio was 2.2 (95%CI 1.3-3.7) for individuals in the highest BMI quartile compared to the lowest BMI quartile (P=0.002). Using common cut-offs for BMI, obese patients had double the risk of postmenopausal breast cancer compared to normal weight patients OR 2.04 (95%CI 1.3-3.3; p=0.004). There was no difference in symptomatic detection, assessment or treatment of breast cancer, however operative times were significantly longer for obese patients (P=0.05). Obesity was associated with larger tumours (P= 0.002) and a later stage of disease at presentation (P=0.026) but not with axillary nodal involvement (P=0.332). Median and overall survivals were equivalent (P=0.172) when comparing obese to non obese. Conclusion Obese women are twice as likely to get postmenopausal breast cancer compared to normal weight women. Understanding why obese women have a higher breast cancer incidence may lead to more effective breast cancer prevention and treatment interventions. Obesity is a preventable risk factor for breast cancer and given the high and increasing prevalence of obesity in Ireland, obesity needs to be addressed on a national level with targeted lifestyle treatment programs. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6089.

Is metabolic syndrome the link between obesity and postmenopausal breast cancer

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #5040 Background Obesity is associated with an increased incidence of postmenopausal breast cancer and a poorer prognosis. The mechanism by which body weight affects breast cancer outcome is complex and incompletely understood. While there is convincing evidence that an obesity induced increase in estrogen production contributes to this risk, recent literature also recognizes other factors such as hyperinsulinaemia, increased IGF-1, high triglycerides and greater abdominal fat accumulation. The clustering of these risk factors is the cornerstone of metabolic syndrome (MetS) diagnosis. Although studies on MetS and cancer are scarce, the components of MetS have individually being linked to the development of cancer and combined these metabolic abnormalities may have an additive effect leading to a more aggressive tumor phenotype. Objective The primary aim of this study was to describe for the first time the incidence of MetS and central obesity in women with postmenopausal breast cancer and examine the relationship between its presence and tumor size, pathological stage and axillary nodal involvement in an Irish population. Design & Setting This was a prospective study of patients that presented to a specialist Breast Cancer Unit, in St Jamess Hospital, Dublin, with postmenopausal breast cancer between March 2007 and May 2008. Individuals underwent a metabolic and nutritional assessment. Studies performed included anthropometry, segmental body composition analysis by bioelectrical impedance, and quantification of fasting lipids, glucose, insulin, C-reactive protein and Serum Amyloid A. Results Seventy-nine female post-menopausal breast cancer patients were recruited. The median age was 68 years (Range 41-84). The mean Body Mass Index was 28.1 ± 5.1 kg/m2, with 70% patients overweight or obese and a further 84% centrally obese. There was no difference in method of detection, diagnosis or treatment between obese and non-obese patients. Over a third of patients (36%) had MetS, which exceeds the population norms reported at 21%. MetS was significantly associated with an adverse metabolic profile as well as increased total fat, trunk fat, an 8cm greater waistline, insulin resistance and hypertension. Moreover the presence of metabolic syndrome was significantly associated with larger tumors (P=0.006), a later stage of disease (P=0.010), lymphovascular invasion (p=0.006) and axillary node involvement (P=0.014) compared to patients without MetS. Conclusion We report for the first time, a high prevalence of MetS and central obesity in a cohort of Irish postmenopausal breast cancer patients. The presence of the MetS seems to be associated with a more aggressive tumor phenotype. The prevalence of these altered metabolic profiles may be a key factor in determining the metastatic potential and prognosis of postmenopausal breast cancer. Therapeutic strategies that correct these abnormalities represent an exciting avenue for future prevention and treatment of breast cancer. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5040.