Does diabetes affect breast cancer survival?

OBJECTIVES: The objective of this study is to investigate the influence of diabetes on breast cancer-specific survival among women with breast cancer in Aotearoa/New Zealand. METHODS: This study included women diagnosed with invasive breast cancer between 2005 and 2020, with their information documented in the Te Rehita Mate Utaetae-Breast Cancer Foundation National Register. Breast cancer survival curves for women with diabetes and those without diabetes were generated using the Kaplan-Meier method. The hazard ratio (HR) of breast cancer-specific mortality for women with diabetes compared to women without diabetes was estimated using the Cox proportional hazards model. RESULTS: For women with diabetes, the 5-year and 10-year of cancer-specific survival were 87% (95% CI: 85%-88%) and 79% (95% CI: 76%-81%) compared to 89% (95% CI: 89%-90%) and 84% (95% CI: 83%-85%) for women without diabetes. The HR of cancer-specific mortality for patients with diabetes compared to those without diabetes was 0.99 (95% CI: 0.89-1.11) after adjustment for patient demographics, tumor characteristics, and treatments. Age at cancer diagnosis and cancer stage had the biggest impact on the survival difference between the two groups. When stratified by cancer stage, the cancer-specific mortality between the two groups was similar. CONCLUSIONS: While differences in survival have been identified for women with diabetes when compared to women without diabetes, these are attributable to age and the finding that women with diabetes tend to present with more advanced disease at diagnosis. We did not find any difference in survival between the two groups due to differences in treatment.

The growing cancer burden: Age-period-cohort projections in Aotearoa New Zealand 2020-2044.

BACKGROUND: Cancer is a major cause of premature death and inequity, and global case numbers are rapidly expanding. This study projects future cancer numbers and incidence rates in Aotearoa New Zealand. METHODS: Age-period-cohort modelling was applied to 25-years of national data to project cancer cases and incidence trends from 2020 to 2044. Nationally mandated cancer registry data and official historical and projected population estimates were used, with sub-groups by age, sex, and ethnicity. RESULTS: Cancer diagnoses were projected to increase from 25,700 per year in 2015-2019 to 45,100 a year by 2040-44, a 76% increase (2.3% per annum). Across the same period, age-standardised cancer incidence increased by 9% (0.3% per annum) from 348 to 378 cancers per 100,000 person years, with greater increases for males (11%) than females (6%). Projected incidence trends varied substantially by cancer type, with several projected to change faster or in the opposite direction compared to projections from other countries. CONCLUSIONS: Increasing cancer numbers reinforces the critical need for both cancer prevention and treatment service planning activities. Investment in developing new ways of working and increasing the workforce are required for the health system to be able to afford and manage the future burden of cancer.

Cancer incidence, mortality and survival for Pacific Peoples in Aotearoa New Zealand.

AIMS: Pacific Peoples comprise over 16 culturally diverse ethnic groups and experience a disproportionate burden of preventable cancers, attributable to infectious diseases and obesity. This study aims to provide updated evidence on cancer incidence, mortality and survival rates among Pacific Peoples in Aotearoa New Zealand. METHODS: The study extracted incident cases of cancer diagnosed between 2007-2019 from the New Zealand Cancer Registry (NZCR) and linked them to the national Mortality Collection to determine individuals who died of cancer over the study period. The study also compared cancer survival rates between Pacific and European peoples in Aotearoa New Zealand. The most commonly diagnosed cancers and the most common causes of cancer death among Pacific Peoples were identified, and key findings were summarised. The European population was utilised as the comparator group for the analyses. The study employed a total ethnicity approach, wherein anyone with a record of Pacific ethnicity was classified as Total Pacific, regardless of other ethnicities. The age- and sex-standardised incidence and mortality rates were calculated, and 1-, 3- and 5-year survival rates determined. We used Cox proportional-hazards models to compare survival outcomes between Pacific and European peoples. CONCLUSIONS: The study results revealed that Pacific Peoples in Aotearoa New Zealand experience higher cancer incidence and a lower survival rate for several cancers, including lung, liver and stomach cancers, when compared to the European population. This study underscores the need for intervention to reduce the burden of cancer among Pacific Peoples and improve cancer outcomes. This study's findings can inform planning and delivery of interventions to achieve equitable outcomes across the cancer continuum for Pacific Peoples in Aotearoa New Zealand.

Equity of Cancer and Diabetes Co-Occurrence: A National Study With 44 Million Person-Years of Follow-Up.

PURPOSE: The co-occurrence of diabetes and cancer is becoming increasingly common, and this is likely to compound existing inequities in outcomes from both conditions within populations. METHODS: In this study, we investigate the co-occurrence of cancer and diabetes by ethnic groups in New Zealand. National-level diabetes and cancer data on nearly five million individuals over 44 million person-years were used to describe the rate of cancer in a national prevalent cohort of peoples with diabetes versus those without diabetes, by ethnic group (Maori, Pacific, South Asian, Other Asian, and European peoples). RESULTS: The rate of cancer was greater for those with diabetes regardless of ethnic group (age-adjusted rate ratios, Maori, 1.37; 95% CI, 1.33 to 1.42; Pacific, 1.35; 95% CI, 1.28 to 1.43; South Asian, 1.23; 95% CI, 1.12 to 1.36; Other Asian, 1.31; 95% CI, 1.21 to 1.43; European, 1.29; 95% CI, 1.27 to 1.31). Maori had the highest rate of diabetes and cancer co-occurrence. Rates of GI, endocrine, and obesity-related cancers comprised a bulk of the excess cancers occurring among Maori and Pacific peoples with diabetes. CONCLUSION: Our observations reinforce the need for the primordial prevention of risk factors that are shared between diabetes and cancer. Also, the commonality of diabetes and cancer co-occurrence, particularly for Maori, reinforces the need for a multidisciplinary, joined-up approach to the detection and care of both conditions. Given the disproportionate burden of diabetes and those cancers that share risk factors with diabetes, action in these areas is likely to reduce ethnic inequities in outcomes from both conditions.

Impact of diabetes on surgery and radiotherapy for breast cancer.

PURPOSES: This study aims to examine whether diabetes has an impact on the use of surgery and adjuvant radiotherapy in treating women with localised breast cancer. METHODS: Women diagnosed with stage I-III breast cancer between 2005 and 2020 were identified from Te Rehita Mate Utaetae-Breast Cancer Foundation New Zealand National Register, with diabetes status determined using New Zealand's Virtual Diabetes Register. The cancer treatments examined included breast conserving surgery (BCS), mastectomy, breast reconstruction after mastectomy, and adjuvant radiotherapy after BCS. Logistic regression modelling was used to estimate the adjusted odds ratio (OR) and 95% confidence interval (95% CI) of having cancer treatment and treatment delay (> 31 days) for patients with diabetes at the time of cancer diagnosis compared to patients without diabetes. RESULTS: We identified 25,557 women diagnosed with stage I-III breast cancer in 2005-2020, including 2906 (11.4%) with diabetes. After adjustment for other factors, there was no significant difference overall in risk of women with diabetes having no surgery (OR 1.12, 95% CI 0.94-1.33), although for patients with stage I disease not having surgery was more likely (OR 1.45, 95% CI 1.05-2.00) in the diabetes group. Patients with diabetes were more likely to have their surgery delayed (adjusted OR of 1.16, 95% CI 1.05-1.27) and less likely to have reconstruction after mastectomy compared to the non-diabetes group-adjusted OR 0.54 (95% CI 0.35-0.84) for stage I cancer, 0.50 (95% CI 0.34-0.75) for stage II and 0.48 (95% CI 0.24-1.00) for stage III cancer. CONCLUSIONS: Diabetes is associated with a lower likelihood of receiving surgery and a greater delay to surgery. Women with diabetes are also less likely to have breast reconstruction after mastectomy. These differences need to be taken in to account when considering factors that may impact on the outcomes of women with diabetes especially for Maori, Pacific and Asian women.

Association of diabetes and breast cancer characteristics at diagnosis.

PURPOSE: This study aims to examine the association of diabetes and breast cancer characteristics at diagnosis in Aotearoa/New Zealand. METHODS: Patients diagnosed with invasive breast cancer between 2005 and 2020 were identified from the National Breast Cancer Register. Logistic regression modeling was used to estimate the adjusted odds ratio (OR) of having stage III-IV cancer and the OR of having stage IV cancer for women with diabetes compared to those without diabetes. The adjusted OR of having screen-detected breast cancers for patients aged 45-69 years with diabetes compared to patients without diabetes was estimated. RESULTS: 26,968 women were diagnosed with breast cancer, with 3,137 (11.6%) patients having diabetes at the time of cancer diagnosis. The probability of co-occurrence of diabetes and breast cancer increased with time. Maori, Pacific and Asian women were more likely to have diabetes than European/Others. The probability of having diabetes also increased with age. For patients with diabetes, the probability of being diagnosed with stage III-IV cancer and stage IV cancer was higher than for patients without diabetes (OR 1.14, 95% CI 1.03-1.27; and 1.17, 95% CI 1.00-1.38). Women aged 45-69 years with diabetes were more likely to have screen-detected cancer than those without diabetes (OR 1.13, 95% CI 1.02-1.26). CONCLUSIONS: The co-occurrence of diabetes and breast cancer is becoming more common. Overall there is a small but significant adverse impact of having advanced disease for women with diabetes that is found at the time of breast cancer diagnosis, and this may contribute to other inequities that occur in the treatment pathway that may impact on patient outcomes.

Cancer and diabetes co-occurrence: A national study with 44 million person-years of follow-up.

The number of new cases of cancer is increasing each year, and rates of diabetes mellitus are also increasing dramatically over time. It is not an unusual occurrence for an individual to have both cancer and diabetes at the same time, given they are both individually common, and that one condition can increase the risk of the other. In this manuscript, we use national-level diabetes (Virtual Diabetes Register) and cancer (New Zealand Cancer Registry) data on nearly five million individuals over 44 million person-years of follow-up to examine the occurrence of cancer amongst a national prevalent cohort of patients with diabetes. We completed this analysis separately by cancer for the 24 most commonly diagnosed cancers in Aotearoa New Zealand, and then compared the occurrence of cancer among those with diabetes to those without diabetes. We found that the rate of cancer was highest amongst those with diabetes for 21 of the 24 most common cancers diagnosed over our study period, with excess risk among those with diabetes ranging between 11% (non-Hodgkin's lymphoma) and 236% (liver cancer). The cancers with the greatest difference in incidence between those with diabetes and those without diabetes tended to be within the endocrine or gastrointestinal system, and/or had a strong relationship with obesity. However, in an absolute sense, due to the volume of breast, colorectal and lung cancers, prevention of the more modest excess cancer risk among those with diabetes (16%, 22% and 48%, respectively) would lead to a substantial overall reduction in the total burden of cancer in the population. Our findings reinforce the fact that diabetes prevention activities are also cancer prevention activities, and must therefore be prioritised and resourced in tandem.

Grading of clear cell renal cell carcinoma should be based on nucleolar prominence.

Fuhrman grading of renal cell carcinoma focuses on features of nuclear size, nuclear shape, and nucleolar prominence. Despite the reported widespread usage of Fuhrman grading in clinical studies, there is debate as to the prognostic significance and reproducibility of its criteria. It has been noted that many pathologists rely on assessment of nucleolar prominence alone when grading renal cell carcinoma; however, the validity of this remains unconfirmed. This study was undertaken to determine the relationship of the 3 morphologic components of the Fuhrman grading system with one another and to determine which, if any of these, can be correlated with outcome for clear cell renal cell carcinoma. One hundred twenty-one organ-confined clear cell renal cell carcinomas were examined in this study. Parameters of nuclear size (area, major axis, perimeter) and nuclear shape (shape factor, nuclear compactness) were assessed by image analysis, whereas nucleolar prominence was assigned (grades 1 to 3) using the criteria of Fuhrman. On the basis of the predominant grade present, there were 17 nucleolar grade 1, 90 nucleolar grade 2, and 14 nucleolar grade 3 tumors. When the high-power field in each tumor with the worst nucleolar grade was assessed, there was 1 nucleolar grade 1, 68 nucleolar grade 2, and 52 nucleolar grade 3 tumors. Predominant and worst nucleolar grade correlated with all measures of nuclear size, but not nuclear shape. Worst nucleolar grade and all parameters of nuclear size were significantly associated with outcome. On multivariate analysis, worst nucleolar grade retained a significant association with survival when modeled with nuclear area. Neither worst nucleolar grade nor major nuclear axis/nuclear perimeter was significantly associated with survival when modeled together. In this study, we have shown that worst nucleolar grade and nuclear size are of prognostic significance for clear cell renal cell carcinoma. We have further shown the association of worst nucleolar grade with outcome to be independent of nuclear area, whereas it is a dependent variable when tested against other parameters of nuclear size. These findings indicate that worst nucleolar grading alone is a valid grading parameter for clear cell renal cell carcinoma.

Exploiting the role of endogenous lymphoid-resident dendritic cells in the priming of NKT cells and CD8+ T cells to dendritic cell-based vaccines.

Transfer of antigen between antigen-presenting cells (APCs) is potentially a physiologically relevant mechanism to spread antigen to cells with specialized stimulatory functions. Here we show that specific CD8+ T cell responses induced in response to intravenous administration of antigen-loaded bone marrow-derived dendritic cells (BM-DCs), were ablated in mice selectively depleted of endogenous lymphoid-resident langerin+ CD8α+ dendritic cells (DCs), suggesting that the antigen is transferred from the injected cells to resident APCs. In contrast, antigen-specific CD4+ T cells were primed predominantly by the injected BM-DCs, with only very weak contribution of resident APCs. Crucially, resident langerin+ CD8α+ DCs only contributed to the priming of CD8+ T cells in the presence of maturation stimuli such as intravenous injection of TLR ligands, or by loading the BM-DCs with the glycolipid α-galactosylceramide (α-GalCer) to recruit the adjuvant activity of activated invariant natural killer-like T (iNKT) cells. In fact, injection of α-GalCer-loaded CD1d-/- BM-DCs resulted in potent iNKT cell activation, suggesting that this glycolipid antigen can also be transferred to resident CD1d+ APCs. While iNKT cell activation per se was independent of langerin+ CD8α+ DCs, some iNKT cell-mediated activities were reduced, notably release of IL-12p70 and transactivation of NK cells. We conclude that both protein and glycolipid antigens can be exchanged between distinct DC species. These data suggest that the efficacy of DC-based vaccination strategies may be improved by the incorporation of a systemic maturation signal aimed to engage resident APCs in CD8+ T cell priming, and α-GalCer may be particularly well suited to this purpose.

Potent anti-tumor responses to immunization with dendritic cells loaded with tumor tissue and an NKT cell ligand.

Cancer immunotherapy is well tolerated and specific, but its efficacy remains variable. To enhance anti-tumor CD8(+) T-cell responses induced by immunization with antigen-loaded dendritic cells (DCs), we explored the impact of eliciting a potent source of T-cell help from activated invariant natural killer (NK)-like T cells (iNKT cells) using the specific glycolipid ligand alpha-galactosylceramide (alpha-GalCer). As cytokines released by iNKT cells may drive proliferation of CD4(+)CD25(+) regulatory T cells (Tregs), we assessed this immunization strategy in animals treated with anti-CD25 antibody to inactivate Treg function. Combining DC immunization with iNKT cell activation was found to significantly enhance anti-tumor activity, which was improved further by the prior inactivation of Tregs. The improved anti-tumor activity with Treg inactivation was associated with a prolonged proliferative burst of responding CD8(+) T cells. We could find no evidence that inclusion of alpha-GalCer in the vaccine enhanced Treg numbers, or that the 'helper' function of iNKT cells was improved in the absence of Treg activity. Rather, the two activities appeared to act independently to improve the tumor-specific T-cell response. Inactivating regulatory T cells and eliciting iNKT cell activation are therefore two useful strategies that can be used in combination to improve anti-tumor immunization with antigen-loaded DCs.

Fuhrman grading is not appropriate for chromophobe renal cell carcinoma.

This study was undertaken to assess the prognostic effectiveness of Fuhrman nuclear grading and the individual components of this grading system, in a series of chromophobe renal cell carcinomas. Eighty-seven cases of chromophobe renal cell carcinoma were investigated. There were 47 males and 40 females, 28 to 78 years of age. The carcinomas ranged from 25 to 180 mm in size and on TNM staging there were 38 stage I, 25 stage II, 22 stage III, and 2 stage IV tumors. Whole tumor Fuhrman grading was grade 1, 6 cases; grade 2, 72 cases; grade 3, 8 cases; and grade 4, 1 case, whereas focal (single high power field) grading was grade 1, 1 case; grade 2, 62 cases; grade 3, 21 cases; and grade 4, 3 cases. On assignment of nucleolar grading using Fuhrman criteria there were 37 grade 1, 44 grade 2, and 4 grade 3 tumors on whole tumor assessment and 3 grade 1, 63 grade 2, and 21 grade 3 tumors on assessment of the high power field showing the greatest degree of nuclear pleomorphism. Measurements of nuclear size showed nuclear area to range from 26.14 to 100.74 microm2, nuclear perimeter from 19.73 to 39.28 microm, and nuclear major axis from 6.49 to 13.21 microm, whereas the ranges of measures of nuclear shape were; shape factor 0.798 to 0.890, compactness 14.260 to 15.843, and feret diameter 5.694 to 11.242. Follow-up ranged from 1 to 150 months and 8 patients died of tumor-related causes 5 to 53 months from diagnosis. On log rank testing against survival, only patient age (P=0.016) and tumor maximum diameter (P=0.0055) were significant, whereas patient sex and TNM stage were not significant. Whole tumor and focal Fuhrman grading, as well as all measures of nucleolar prominence, nuclear size, and nuclear shape showed no significant association with outcome. It is concluded that neither Fuhrman grading, nor any of the components of the Fuhrman grading system, is useful as prognostic indicators for this tumor type.

Nucleolar grade but not Fuhrman grade is applicable to papillary renal cell carcinoma.

This study was undertaken to determine the validity of Fuhrman grading in a series of papillary renal cell carcinomas (PRCCs), to examine the interrelationship and prognostic significance of the individual components of the grading system, and further to determine whether any observed predictive value was independent of other prognostic indicators. Ninety cases of PRCC were studied. Fifty-nine tumors were of type 1 and 31 were of type 2. There were 33 TNM stage 1, 26 stage 2, 18 stage 3, and 12 stage 4 tumors, whereas division of cases according to pT category showed 14 pT1a, 20 pT1b, 25 pT2, 15 pT3a, 4 pT3b, and 11 pT4 tumors. Ten tumors were grade 1, 58 grade 2, and 22 grade 3 when predominant Fuhrman grade was assigned, whereas grading according to the high-power field containing the highest grade (focal grade) showed 40 grade 2, 49 grade 3, and 1 grade 4 tumors. Measurements of nuclear size (area, major axis, perimeter) and shape (shape factor, compactness) were undertaken using image analysis. Nuclear area ranged from 27.63 to 116.39 microM, major axis length 6.70 to 14.06 microM, and nuclear perimeter 20.05 to 41.77 microM. Shape factor ranged from 0.805 to 0.878 and compactness from 14.33 to 15.66. Predominant nucleolar grade using the criteria of the Fuhrman classification was nucleolar grade 1 for 13 tumors, nucleolar grade 2 for 56 tumors, and nucleolar grade 3 for 21 tumors. Focal nucleolar grade based on the high-power field showing the greatest degree of nuclear pleomorphism, was grade 2 for 38 tumors and grade 3 for 52 tumors. pT category, TNM stage, focal Fuhrman grade, and PRCC type were significantly associated with survival. Of the various measures of the components of the Fuhrman classification, only focal nucleolar grade was associated with survival, on univariate analysis. On multivariate analysis, focal nucleolar grade and tumor diameter were independently associated with survival, whereas TNM stage retained significance independent of other parameters. It is concluded that assessment of nucleolar prominence rather than Fuhrman grade is applicable for stratification of tumors within TNM stage or pT category for PRCC and that this should be based upon the high-power field showing the greatest degree of nuclear pleomorphism.