BPG: Seamless, automated and interactive visualization of scientific data.

BACKGROUND: We introduce BPG, a framework for generating publication-quality, highly-customizable plots in the R statistical environment. RESULTS: This open-source package includes multiple methods of displaying high-dimensional datasets and facilitates generation of complex multi-panel figures, making it suitable for complex datasets. A web-based interactive tool allows online figure customization, from which R code can be downloaded for integration with computational pipelines. CONCLUSION: BPG provides a new approach for linking interactive and scripted data visualization and is available at http://labs.oicr.on.ca/boutros-lab/software/bpg or via CRAN at https://cran.r-project.org/web/packages/BoutrosLab.plotting.general.

Genomic hallmarks of localized, non-indolent prostate cancer.

Prostate tumours are highly variable in their response to therapies, but clinically available prognostic factors can explain only a fraction of this heterogeneity. Here we analysed 200 whole-genome sequences and 277 additional whole-exome sequences from localized, non-indolent prostate tumours with similar clinical risk profiles, and carried out RNA and methylation analyses in a subset. These tumours had a paucity of clinically actionable single nucleotide variants, unlike those seen in metastatic disease. Rather, a significant proportion of tumours harboured recurrent non-coding aberrations, large-scale genomic rearrangements, and alterations in which an inversion repressed transcription within its boundaries. Local hypermutation events were frequent, and correlated with specific genomic profiles. Numerous molecular aberrations were prognostic for disease recurrence, including several DNA methylation events, and a signature comprised of these aberrations outperformed well-described prognostic biomarkers. We suggest that intensified treatment of genomically aggressive localized prostate cancer may improve cure rates.

Spatial genomic heterogeneity within localized, multifocal prostate cancer.

Herein we provide a detailed molecular analysis of the spatial heterogeneity of clinically localized, multifocal prostate cancer to delineate new oncogenes or tumor suppressors. We initially determined the copy number aberration (CNA) profiles of 74 patients with index tumors of Gleason score 7. Of these, 5 patients were subjected to whole-genome sequencing using DNA quantities achievable in diagnostic biopsies, with detailed spatial sampling of 23 distinct tumor regions to assess intraprostatic heterogeneity in focal genomics. Multifocal tumors are highly heterogeneous for single-nucleotide variants (SNVs), CNAs and genomic rearrangements. We identified and validated a new recurrent amplification of MYCL, which is associated with TP53 deletion and unique profiles of DNA damage and transcriptional dysregulation. Moreover, we demonstrate divergent tumor evolution in multifocal cancer and, in some cases, tumors of independent clonal origin. These data represent the first systematic relation of intraprostatic genomic heterogeneity to predicted clinical outcome and inform the development of novel biomarkers that reflect individual prognosis.

Tumour genomic and microenvironmental heterogeneity for integrated prediction of 5-year biochemical recurrence of prostate cancer: a retrospective cohort study.

BACKGROUND: Clinical prognostic groupings for localised prostate cancers are imprecise, with 30-50% of patients recurring after image-guided radiotherapy or radical prostatectomy. We aimed to test combined genomic and microenvironmental indices in prostate cancer to improve risk stratification and complement clinical prognostic factors. METHODS: We used DNA-based indices alone or in combination with intra-prostatic hypoxia measurements to develop four prognostic indices in 126 low-risk to intermediate-risk patients (Toronto cohort) who will receive image-guided radiotherapy. We validated these indices in two independent cohorts of 154 (Memorial Sloan Kettering Cancer Center cohort [MSKCC] cohort) and 117 (Cambridge cohort) radical prostatectomy specimens from low-risk to high-risk patients. We applied unsupervised and supervised machine learning techniques to the copy-number profiles of 126 pre-image-guided radiotherapy diagnostic biopsies to develop prognostic signatures. Our primary endpoint was the development of a set of prognostic measures capable of stratifying patients for risk of biochemical relapse 5 years after primary treatment. FINDINGS: Biochemical relapse was associated with indices of tumour hypoxia, genomic instability, and genomic subtypes based on multivariate analyses. We identified four genomic subtypes for prostate cancer, which had different 5-year biochemical relapse-free survival. Genomic instability is prognostic for relapse in both image-guided radiotherapy (multivariate analysis hazard ratio [HR] 4·5 [95% CI 2·1-9·8]; p=0·00013; area under the receiver operator curve [AUC] 0·70 [95% CI 0·65-0·76]) and radical prostatectomy (4·0 [1·6-9·7]; p=0·0024; AUC 0·57 [0·52-0·61]) patients with prostate cancer, and its effect is magnified by intratumoral hypoxia (3·8 [1·2-12]; p=0·019; AUC 0·67 [0·61-0·73]). A novel 100-loci DNA signature accurately classified treatment outcome in the MSKCC low-risk to intermediate-risk cohort (multivariate analysis HR 6·1 [95% CI 2·0-19]; p=0·0015; AUC 0·74 [95% CI 0·65-0·83]). In the independent MSKCC and Cambridge cohorts, this signature identified low-risk to high-risk patients who were most likely to fail treatment within 18 months (combined cohorts multivariate analysis HR 2·9 [95% CI 1·4-6·0]; p=0·0039; AUC 0·68 [95% CI 0·63-0·73]), and was better at predicting biochemical relapse than 23 previously published RNA signatures. INTERPRETATION: This is the first study of cancer outcome to integrate DNA-based and microenvironment-based failure indices to predict patient outcome. Patients exhibiting these aggressive features after biopsy should be entered into treatment intensification trials. FUNDING: Movember Foundation, Prostate Cancer Canada, Ontario Institute for Cancer Research, Canadian Institute for Health Research, NIHR Cambridge Biomedical Research Centre, The University of Cambridge, Cancer Research UK, Cambridge Cancer Charity, Prostate Cancer UK, Hutchison Whampoa Limited, Terry Fox Research Institute, Princess Margaret Cancer Centre Foundation, PMH-Radiation Medicine Program Academic Enrichment Fund, Motorcycle Ride for Dad (Durham), Canadian Cancer Society.

NBN gain is predictive for adverse outcome following image-guided radiotherapy for localized prostate cancer.

Despite the use of clinical prognostic factors (PSA, T-category and Gleason score), 20-60% of localized prostate cancers (PCa) fail primary local treatment. Herein, we determined the prognostic importance of main sensors of the DNA damage response (DDR): MRE11A, RAD50, NBN, ATM, ATR and PRKDC. We studied copy number alterations in DDR genes in localized PCa treated with image-guided radiotherapy (IGRT; n=139) versus radical prostatectomy (RadP; n=154). In both cohorts, NBN gains were the most frequent genomic alteration (14.4 and 11% of cases, respectively), and were associated with overall tumour genomic instability (p<0.0001). NBN gains were the only significant predictor of 5yrs biochemical relapse-free rate (bRFR) following IGRT (46% versus 77%; p=0.00067). On multivariate analysis, NBN gain remained a significant independent predictor of bRFR after adjusting for known clinical prognostic variables (HR=3.28, 95% CI 1.56-6.89, Wald p-value=0.0017). No DDR-sensing gene was prognostic in the RadP cohort. In vitro studies correlated NBN gene overexpression with PCa cells radioresistance. In conclusion, NBN gain predicts for decreased bRFR in IGRT, but not in RadP patients. If validated independently, Nibrin gains may be the first PCa predictive biomarker to facilitate local treatment decisions using precision medicine approaches with surgery or radiotherapy.

Hotspot activating PRKD1 somatic mutations in polymorphous low-grade adenocarcinomas of the salivary glands.

Polymorphous low-grade adenocarcinoma (PLGA) is the second most frequent type of malignant tumor of the minor salivary glands. We identified PRKD1 hotspot mutations encoding p.Glu710Asp in 72.9% of PLGAs but not in other salivary gland tumors. Functional studies demonstrated that this kinase-activating alteration likely constitutes a driver of PLGA.

Two phases of disulfide bond formation have differing requirements for oxygen.

Most proteins destined for the extracellular space require disulfide bonds for folding and stability. Disulfide bonds are introduced co- and post-translationally in endoplasmic reticulum (ER) cargo in a redox relay that requires a terminal electron acceptor. Oxygen can serve as the electron acceptor in vitro, but its role in vivo remains unknown. Hypoxia causes ER stress, suggesting a role for oxygen in protein folding. Here we demonstrate the existence of two phases of disulfide bond formation in living mammalian cells, with differential requirements for oxygen. Disulfide bonds introduced rapidly during protein synthesis can occur without oxygen, whereas those introduced during post-translational folding or isomerization are oxygen dependent. Other protein maturation processes in the secretory pathway, including ER-localized N-linked glycosylation, glycan trimming, Golgi-localized complex glycosylation, and protein transport, occur independently of oxygen availability. These results suggest that an alternative electron acceptor is available transiently during an initial phase of disulfide bond formation and that post-translational oxygen-dependent disulfide bond formation causes hypoxia-induced ER stress.

The prognostic value of temporal in vitro and in vivo derived hypoxia gene-expression signatures in breast cancer.

BACKGROUND AND PURPOSE: Recent data suggest that in vitro and in vivo derived hypoxia gene-expression signatures have prognostic power in breast and possibly other cancers. However, both tumour hypoxia and the biological adaptation to this stress are highly dynamic. Assessment of time-dependent gene-expression changes in response to hypoxia may thus provide additional biological insights and assist in predicting the impact of hypoxia on patient prognosis. MATERIALS AND METHODS: Transcriptome profiling was performed for three cell lines derived from diverse tumour-types after hypoxic exposure at eight time-points, which include a normoxic time-point. Time-dependent sets of co-regulated genes were identified from these data. Subsequently, gene ontology (GO) and pathway analyses were performed. The prognostic power of these novel signatures was assessed in parallel with previous in vitro and in vivo derived hypoxia signatures in a large breast cancer microarray meta-dataset (n=2312). RESULTS: We identified seven recurrent temporal and two general hypoxia signatures. GO and pathway analyses revealed regulation of both common and unique underlying biological processes within these signatures. None of the new or previously published in vitro signatures consisting of hypoxia-induced genes were prognostic in the large breast cancer dataset. In contrast, signatures of repressed genes, as well as the in vivo derived signatures of hypoxia-induced genes showed clear prognostic power. CONCLUSIONS: Only a subset of hypoxia-induced genes in vitro demonstrates prognostic value when evaluated in a large clinical dataset. Despite clear evidence of temporal patterns of gene-expression in vitro, the subset of prognostic hypoxia regulated genes cannot be identified based on temporal pattern alone. In vivo derived signatures appear to identify the prognostic hypoxia induced genes. The prognostic value of hypoxia-repressed genes is likely a surrogate for the known importance of proliferation in breast cancer outcome.

Parallels between the development of therapeutic drugs and cancer health disparity programs: implications for Disparities Reduction.

BACKGROUND: There are analogies between the development of therapeutic drugs for cancer and the development of interventions for reducing cancer health disparities. In both cases, it can take between 12 and 15 years for the benefits to become apparent. METHODS: The initial preclinical phase of drug development is analogous to the development of community partnerships and helping the community learn about cancer. The preclinical phase of in vitro and in vivo testing is analogous to identifying the disparities in the community. Then clinical testing begins with phase 1, toxicity, and dose-establishing studies. Analogously, community-based participatory research is used to develop disparities-reducing interventions (DRIs) within the community. RESULTS: The phase 2 clinical studies to determine whether the drug has activity are analogous to the DRI being implemented in the community to determine whether it can cause behavioral changes that will reduce cancer health disparities. If a drug passes phase 1 and 2 studies, phase 3 clinical trials are initiated. These are controlled studies to examine the efficacy of the drug. The similar activity for disparities research is to determine whether the DRI is better than the current standard/usual practice in controlled trials. If the drug is beneficial, the final phase is the dissemination and adoption of the drug. Analogously in disparities, if the DRI is beneficial, it is disseminated and is culturally adapted to other racial/ethnic groups and finally adopted as standard practice. CONCLUSIONS: The process of creating an effective DRI can be envisioned to have 4 stages, which can be used to aid in measuring the progress being made in reducing cancer health disparities.

Reducing cancer health disparities: perspective of the National Cancer Institute.

BACKGROUND: The National Cancer Institute created the Special Population Network (SPN) to develop cancer awareness, research and training with partnerships from community and research organizations. METHODS: Eighteen SPNs were funded with the goals of enlisting community partnerships, enhancing training opportunities for minority scientists, and conducting pilot research projects. RESULTS: The SPN program concluded in 2005 after achieving many major milestones. CONCLUSION: This paper provides background information about the SPN and one of its programs, the Pacific Islander Cancer Control Network.

Determinants of cancer health disparities: barriers to cancer prevention, screening, diagnosis and treatment.

BACKGROUND: Many health disparities occur when beneficial medical interventions are not shared by all. OBJECTIVE: To examine the barriers that cause the disparities. METHODS: In terms of obtaining beneficial medical interventions, the individual with disparities is influenced by his/her community, healthcare provider and healthcare system. The determinants of cancer health disparities include cultural, socio-economic and environmental factors, and the effects of social injustice. RESULTS/CONCLUSION: These factors create inadequate information and knowledge about cancer, risk-promoting behaviors, inadequate conditions for seeking medical procedures, diminished access to and use of healthcare and inadequate healthcare services. The use of patient navigators may serve to address many of these factors.

Cancer incidence and mortality patterns among specific Asian and Pacific Islander populations in the U.S.

OBJECTIVES: We report cancer incidence, mortality, and stage distributions among Asians and Pacific Islanders (API) residing in the U.S. and note health disparities, using the cancer experience of the non-Hispanic white population as the referent group. New databases added to publicly available SEER*Stat software will enable public health researchers to further investigate cancer patterns among API groups. METHODS: Cancer diagnoses among API groups occurring from 1 January 1998 to 31 December 2002 were included from 14 Surveillance, Epidemiology, and End Results (SEER) Program state and regional population-based cancer registries covering 54% of the U.S. API population. Cancer deaths were included from the seven states that report death information for detailed API groups and which cover over 68% of the total U.S. API population. Using detailed racial/ethnic population data from the 2000 decennial census, we produced incidence rates centered on the census year for Asian Indians/Pakistanis, Chinese, Filipinos, Guamanians, Native Hawaiians, Japanese, Kampucheans, Koreans, Laotians, Samoans, Tongans, and Vietnamese. State vital records offices do not report API deaths separately for Kampucheans, Laotians, Pakistanis, and Tongans, so mortality rates were analyzed only for the remaining API groups. RESULTS: Overall cancer incidence rates for the API groups tended be lower than overall rates for non-Hispanic whites, with the exception of Native Hawaiian women (All cancers rate = 488.5 per 100,000 vs. 448.5 for non-Hispanic white women). Among the API groups, overall cancer incidence and death rates were highest for Native Hawaiian and Samoan men and women due to high rates for cancers of the prostate, lung, and colorectum among Native Hawaiian men; cancers of the prostate, lung, liver, and stomach among Samoan men; and cancers of the breast and lung among Native Hawaiian and Samoan women. Incidence and death rates for cancers of the liver, stomach, and nasopharynx were notably high in several of the API groups and exceeded rates generally seen for non-Hispanic white men and women. Incidence rates were lowest among Asian Indian/Pakistani and Guamanian men and women and Kampuchean women. Asian Indian and Guamanian men and women also had the lowest cancer death rates. Selected API groups had less favorable distributions of stage at diagnosis for certain cancers than non-Hispanic whites. CONCLUSIONS: Possible disparities in cancer incidence or mortality between specific API groups in our study and non-Hispanic whites (referent group) were identified for several cancers. Unfavorable patterns of stage at diagnosis for cancers of the colon and rectum, breast, cervix uteri, and prostate suggest a need for cancer control interventions in selected groups. The observed variation in cancer patterns among API groups indicates the importance of monitoring these groups separately, as these patterns may provide etiologic clues that could be investigated by analytic epidemiological studies.

Measures of racial/ethnic health disparities in cancer mortality rates and the influence of socioeconomic status.

OBJECTIVES: In the 1990s, U.S. cancer mortality rates declined due to reductions in tobacco use among men and beneficial cancer interventions, such as mammography and Pap smears. We examined the cancer rates by racial/ethnic group, socioeconomic status and time period to identify disparities underlying the overall mortality trend. METHODS: We examined racial/ethnic disparities by measuring excess cancer burden [rate ratio (RR) and ratio differences (RD)] and trends in their cancer rates for nine cancer sites. The trend (T) is calculated as a ratio of the average annual cancer mortality rate for 1995-2000 relative to the rate for 1990-1994 for three levels of poverty (counties with <10% living below the poverty level, 10% - <20% and > or =20%) for the major racial/ethnic populations. We also compared the trend for each racial/ethnic SES group to the trend for lowest SES white group (TD). RESULTS: Blacks have RR disparities relative to whites for each cancer site examined, except for female lung cancer, while the other minorities had RR disparities for cervical cancer (RR>1). There are increases in RR disparities from 1990-1994 to 1995-2000 (RD>0) for colorectal cancer, prostate cancer and breast cancer for each racial/ethnic minority. Whites and blacks had declining trends for every SES group (T<1) and positive high SES gradients (the highest SES group had the best trend and the lowest SES group had the worst trend) at each cancer site, except female lung cancer (T>1). In contrast, American Indians/Alaska natives, Hispanics and Asians/ Pacific Islanders had increasing trends for some of their cancer sites, and their trends did not have the SES gradients. CONCLUSIONS: Increases in racial/ethnic disparities (RD>0) for colorectal, breast and prostate cancer were largest in the lowest SES groups. At some cancer sites, the highest SES group for minorities had worse trend results than the trends for the lowest SES white group (TD>0).

Cambodian cancer incidence rates in California and Washington, 1998-2002.

BACKGROUND: Among the many diverse Asian ethnic groups living in the US, Cambodian immigrants comprise a small fraction (1.8%) of the total Asian population. Because of their small numbers, Cambodian vital statistics are often combined into Southeast Asian (SA) cancer data consisting of Vietnamese, Thais, Laotians, and Hmong. METHODS: The 2000 Census counts were used for 2 Cambodian populations, Cambodians alone and Cambodians alone and in combination with any other racial/ethnic group for California and for Seattle (Puget Sound area), Washington. Then the cancer incidence rates were calculated using cancer cases from the California and Puget Sound cancer registries between 1998-2002. The 1998-2002 annual age-adjusted incidence rates, upper bound rates (based on the Cambodian alone population), lower bound rates (based on the Cambodians alone or in combination population) are reported and compared with the rates in the non-Hispanic White (NHW) population in these regions. RESULTS: The top 5 cancers in Cambodian males are lung and bronchus, liver, prostate, colorectal, and stomach cancers. The sites where the rates are higher in male Cambodians than NHW males are (in ascending rank) nasopharynx, liver, stomach, myeloma, and lung and bronchus. The top 5 cancers for female Cambodians are breast, lung, colon and rectum, cervix, and thyroid. The sites where female rates are greater than NHW female rates are (in ascending rank) nasopharynx, liver, stomach, cervix uteri, oral cavity, and thyroid. CONCLUSIONS: The challenges to address the health issues of Cambodians are complicated by historical events that caused their emigration to the US. Many of the immigrants are survivors of the holocaust in Cambodia. Health programs for Cambodians must deal with the consequences of these issues as well as cultural issues of language and religion in helping Cambodians to reduce their cancer disparities.

Special Populations Networks--how this innovative community-based initiative affected minority and underserved research programs.

The Special Populations Networks (SPN) Program was created to address both community needs for cancer information and NCI's desire to obtain community-based answers to research questions and promote training opportunities for racial/ethnic minority and underserved researchers in populations with an unequal burden of cancer. The SPN program included 3 components: 1) infrastructure and capacity building combined with cancer awareness, 2) community-based research, and 3) community-centered training. The 18 SPN grantees conducted more than 1000 cancer awareness activities. More than 2000 community lay health workers were trained. Communities formalized more than 300 partnerships with Memoranda of Understanding (MOU). More than 255 pilot research project applications were submitted by junior researchers and over 135 were funded. Approximately 90% of the applications were submitted by minority junior researchers; of which more than 100 were funded. More than 290 scientific publications thus far have resulted from the work of the SPNs. In the first 3 years of the program, the SPNs also secured an additional $20 million in outside funding. The SPN program effected a paradigm shift for minority research programs by combining community-based cancer awareness, research, and training into a single program. By engaging research leaders of minority and underserved populations to aid their own, train their own, and develop research to help their own, the SPN program activated the power of their commitment to their own. That commitment was reflected in the trust and participation offered by their communities. Cancer 2006. (c) 2006 American Cancer Society.

1999-2001 Cancer mortality rates for Asian and Pacific Islander ethnic groups with comparisons to their 1988-1992 rates.

We report upper and lower boundary estimates of the 1999-2001 site-specific cancer mortality rates for Asian Indians, Chinese, Filipinos, Koreans, Vietnamese, Native Hawaiians, and Samoans. These rates are for the seven states (California, Hawaii, Illinois, New Jersey, New York, Texas, and Washington) that officially record mortality data for these ethnicities. The rates are based on the 2000 Census, which reports two population counts as follows: persons who identify themselves as belonging to a single ethnic group (which forms the basis for an upper boundary estimate of the rates) and persons who identify themselves as belonging to a single ethnic group or to multiple groups that include the single ethnic group (which forms the basis for a lower boundary estimate for the rates). The top five cancers for each Asian and Pacific Islander ethnic group by gender are reported. In addition, the 1988-1992 cancer mortality rates based on the 1990 Census for Chinese, Filipino, Japanese, and Native Hawaiians are determined. Their 1999-2001 and 1988-1992 rates are compared.

Determinants of cancer disparities: barriers to cancer screening, diagnosis, and treatment.

There is a critical disconnect between what we discover and what we deliver to all Americans in the form of prevention, screening, detection, diagnosis, and treatment of cancer. We must identify and eliminate all barriers that prevent the benefits of research from reaching all people. Such barriers may be experienced at any point along the continuum of prevention, screening, diagnosis and treatment, and palliative care. In communities of low socioeconomic status, patient navigation has proved to be an effective intervention in promoting such timely diagnosis and treatment when applied at the point of abnormal finding. Geographic areas with excess cancer mortality should be delineated and targeted with an intense approach to providing culturally relevant education, appropriate access to screening diagnosis and treatment, and improved support systems, including navigation.

Distinct incidence patterns among in situ and invasive breast carcinomas,with possible etiologic implications.

BACKGROUND: Incidence patterns are well-established for invasive breast carcinoma (InvBC) overall and for InvBC defined by estrogen receptor (ER) expression, but are not as well-defined for breast carcinoma in situ (CIS). METHODS: We, therefore, examined and compared the incidence patterns for CIS and InvBC in the SEER program to define these patterns and to generate etiologic hypotheses. Data were stratified by age < 50 and > or =50 years to approximate menopause. RESULTS: During the years 1973-2000, annual age-adjusted incidence rates rose 660% for CIS and 36% for InvBC, with the most rapid increases occurring in women age > or =50 years. Age-specific incidence rate curves for CIS increased until age 50 years, and then flattened, irrespective of ER expression. On the other hand, rates for InvBC overall and for InvBC defined by ER-positive expression increased continuously with aging, whereas rates for InvBC defined by ER-negative expression flattened after 50 years. Age frequency distribution for CIS and for ER-negative InvBC demonstrated bimodal populations, with a predominant early onset peak incidence at age 50 years. Age frequency distribution for ER-positive InvBC showed bimodal populations with a predominant late-onset mode at age 71 years. CONCLUSION: Over the last three decades, age-adjusted incidence trends differed for CIS and InvBC in the United States, possibly due to screening mammography and/or etiologic diversity. Indeed, age-specific incidence patterns suggested that carcinogenic events operating early in reproductive life had greater impact upon CIS and InvBC defined by ER-negative expression than upon InvBC overall and InvBC defined by ER-positive expression.

Comparison of age-specific incidence rate patterns for different histopathologic types of breast carcinoma.

OBJECTIVE: The age-specific incidence rate curve for breast carcinoma overall increases rapidly until age 50 years, and then continues to increase at a slower rate for older women. In this analysis, our objective was to compare age-specific incidence rate patterns for different morphologic types of breast carcinoma. MATERIALS AND METHODS: We analyzed age-specific incidence rate curves by histopathologic subclassification using records from 11 standard National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) registries, diagnosed during the years 1992 to 1999. Data were examined by age <50 and > or /=50 years to simulate menopause. RESULTS: Age-specific incidence rate curves showed three dominant patterns: (1) Rates for infiltrating duct carcinoma of no special type (duct NST), tubular, and lobular carcinomas increased rapidly until age 50 years then rose more slowly. (2) Rates for medullary and inflammatory breast carcinomas increased rapidly until age 50 years then failed to increase. (3) Rates for papillary and mucinous carcinomas increased steadily at all ages. Rate patterns varied by estrogen receptor expression but were unaffected by SEER registry, race, nodal status, or grade. CONCLUSION: Age-specific incidence rates for breast carcinomas differed by histopathologic type. Rates that failed to increase after 50 years suggested that menopause had greater impact on medullary and inflammatory carcinomas than on duct NST, tubular, and lobular carcinomas. Menopause did not seem to have any effect on papillary or mucinous carcinomas as evidenced by steadily rising rates at all ages. Future etiologic and/or prevention studies should consider the impact of age-specific risk factors and/or exposures on different histopathologic types of breast carcinomas.