Incidence Of Early-onset Breast Cancer Research Articles

Abstract P3-03-21: Biological and Cultural Drivers of Early-Onset Breast Cancer: a mixed-method study

Abstract Background: The incidence of early-onset breast cancer (BC) in adults < 40 years old has increased dramatically in the US over recent decades. The increase in incidence means that identifying higher risk individuals through family-history based guidelines will miss many young adults. As no population-based screening is recommended for adults under 40, so how they detect their BC remains unclear. Using data from a nested case-control study in the Breast Cancer Family Registry, we found that the steroid metabolome may improve risk assessment. If replicated in larger studies, it will be important to know more about the clinical contexts in which this biomarker screening could be implemented from both the provider and patient perspectives. One way to fill these gaps is to identify biocultural drivers of risk that deepen our etiologic understanding and inform risk assessment. We use quantitative and qualitative (mixed) methods to integrate “emics”—the on the ground perspective—from young adults with BC into metabolomic studies. Methods: For the provider perspective, we administered a survey to Obstetricians/gynecologists (OBGYNs) about their knowledge of American College of Obstetrics and Gynecology (ACOG) breast cancer screening guidelines for women under 40 and determined the proportion of correct responses. For the patient perspective, we examined qualitative data from the Young Survival Coalition (YSC). The YSC hosts an online forum where young adults with breast cancer “tell their story” in posts. We reviewed text from posts published between March 2009 and December 2019 and coded text (n=750 posts) according to themes: “first signs and symptoms,” “steps to diagnosis,” “staging type,” and “patient-provider feelings.” Then, we used natural language processing and machine learning with the support vector machine algorithm to build classification models and detect the themes in all posts (n=571,602). We repeated this process for sub-themes. Results: ACOG guidelines recommend that women at “average risk” of breast cancer are counseled about breast self-awareness, and 75% of OBGYN respondents answered this survey question correctly. Our qualitative, “emic” data suggest that the vast majority of young adults find their BC through self-awareness and first seek care from OBGYNs. They first noticed signs (n=3,266) of breast changes through self-detection of lumps (56.5%), self-detected breast and health changes (25.0%), and through a provider (17.2%). The first steps to diagnosis (n=31,640) mainly started with clinic visits (66.5%), others with surgery (23.3%). Stage at diagnoses (n=71,879) were Stage 4 (7.3%), followed by Stage 0 (7.2%), Stage 2-3 (5.5%), and Stage 1 (4.8%), while others mentioned being diagnosed with any invasive cancer (7.3%). Out of 24,648 posts, 70.3% were not satisfied with their providers and felt ignored, their treatment delayed, lacked trust, and felt their providers were not informed. One person said, “My doctor has not had a patient as young as me get diagnosed with cancer and has not suggested ANYONE.” Conclusions: In addition to counseling about breast self-awareness as a means of detection, the OBGYN setting may be a place to implement biomarker-based screening for early-onset BC. These results are derived from our mixed-methods approach, designed to identify biocultural drivers of cancer prevention by incorporating “omics” and “emics”. In the era of “omics,” when molecular markers are incorporated into cancer risk reduction and early detection, “emics” are equally important to identify what is feasible in “real-world” settings. Citation Format: Lauren Houghton, Kathleene T. Ulanday, Maxim Topaz, Desiree Walker, Stacy Lewis, Mary Beth Terry. Biological and Cultural Drivers of Early-Onset Breast Cancer: a mixed-method study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-03-21.

Germline mutation PTCH2 1172-1173delCT in Chinese population with early-onset breast cancer.

e13049 Background: Early-onset breast cancer has more aggressive clinicopathological characteristics and worse prognosis. The peak age of breast cancer in China is about 40 years old, 10 years ahead of that in Europe and the United States. PTCH2 was characterized as susceptibility gene in early-onset breast cancer by whole exons sequencing in preliminary work. PTCH2 performs as a tumor suppressor in the Hedgehog signaling pathway, but it has never been reported in breast cancer. Methods: 259 women with early-onset breast cancer and 571 women with non-early-onset breast cancer with peripheral blood samples were included for genetic testing. According to the ACMG guidlines, PTCH2 1172-1173delCT was defined as likely pathogenic mutation. To make an in-depth exploration of the function and molecular mechanism of PTCH2 gene, we performed experiments at molcular, cellular and animal level. Results: The frequency 2.3%(6/259)of PTCH2 germline mutation in early-onset breast cancer was significantly higher than that(2/571) in non-early-onset breast cancer( P ＜ 0.05), and increased with the age at diagnosis younger. Bioinformatics analysis showed that the patients with lower expression of PTCH2 had worse prognosis. PTCH2 knockout cells lines promoted the cell proliferation and enhanced the ability of colony formation and tumorigenic ability of nude mice. Furthermore, the expression level of pten in the PTCH2 knockout cell lines was significantly downregulated. Conclusions: Patients with PTCH2 1172-1173delCT mutation had aggressive clinicopathological characteristics and worse prognosis. As a tumor suppressor gene, PTCH2 may promote the incidence of early-onset breast cancer by downregulating the expression of pten and cross-regulating Hedgehog and PI3K/AKT signaling pathways. PTCH2 could be acted as a diagnostic and prognostic biomarker for early-onset breast cancer.

Abstract A44: The identification of germline mutations in DNA repair genes in Brazilian individuals at-risk for hereditary breast cancer

Abstract Hereditary breast cancer corresponds to 10-15% of all diagnosed cases of breast cancer in the world. The majority germline mutations are identified in BRCA1/2 genes, however the application of multigene panels has increased the number of pathogenic variations detected in DNA repair genes. According to the current version of NCCN Guideline, mutations in BRCA1/2, TP53 and PTEN confers high risk to develop breast cancer, and mutations in CDH1, CHEK2, PALB2, ATM and BRIP can increases over than 20% this risk. We analyzed 157 individuals from Northeastern region of Brazil with personal and/or familial breast cancer history. Genomic DNA was isolated from peripheral blood through saline-based extraction and samples were analyzed using next-generation sequencing (NGS). We identified 15 pathogenic variants and 4 VUS (Variants of Uncertain Significance) in 27 individuals (27/157; 17%), in which three are asymptomatic. Six novel variants in 4 genes were identified: BRCA1_c.3409A>G; BRCA2_c.5800C>T; BRCA2_c.5228G>A; BRCA2_c.5305delG; ATM_c.634delT and ATR_c.3043C>T. Sixty-eight percent (13/19; 68%) of variants was detected in BRCA1/2 genes, while 32% (6/19) were identified in moderate risk genes ATM (2/19); ATR (1/19); CDH1 (1/19); MLH1 (1/19) and MSH6 (1/19). The individuals were separated in two groups for comparative analysis: high-risk genes and moderate risk genes. Among three asymptomatic individuals, two present variants in moderate risk genes ATM and MLH1. Among breast cancer individuals, eighteen patients (18/24; 75%) presents mutations in high-risk genes, while six (6/24; 25%) harbors mutations in moderate risk genes. Both groups had a high incidence of early-onset breast cancer, 83%. The group of individuals harboring variants in high-risk genes presented a greater occurrence of high-grade tumors (83% vs. 67%, P= 0.0090). In the group of individuals harboring mutation in moderate risk genes, tumors presented a more aggressive phenotype with bilateral cancer (33% vs. 11%, P= 0.0002), occurrence of metastasis (33% vs. 5.6%, P<0.0001) and incidence of deaths (33% vs. 5.6%, P<0.0001). Altogether, 1/3 of variants were identified in moderate risk genes in patients presenting a more aggressive phenotype. These results reinforce the importance of applying multigene analysis in individuals at-risk for breast cancer, especially in a heterogeneous population as Brazilian. Citation Format: Ana Rafaela de Souza Timoteo, Jorge Estefano Santana de Souza, Tirzah Braz Petta Lajus. The identification of germline mutations in DNA repair genes in Brazilian individuals at-risk for hereditary breast cancer [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr A44.

Differential Patterns of Risk Factors for Early-Onset Breast Cancer by ER Status in African American Women.

Given the disproportionately high incidence of early-onset breast cancer and aggressive subtypes, such as estrogen receptor (ER)-negative tumors, in African American (AA) women, elucidation of risk factors for early onset of specific subtypes of breast cancer is needed. We evaluated associations of reproductive, anthropometric, and other factors with incidence of invasive breast cancer by age at onset (<45, ≥45) in 57,708 AA women in the prospective Black Women's Health Study. From 1995 to 2013, we identified 529 invasive breast cancers among women <45 years of age (151 ER-, 219 ER+) and 1,534 among women ≥45 years (385 ER-, 804 ER+). We used multivariable Cox proportional hazards regression to estimate hazard ratios (HRs) for associations by age and ER status. Higher parity, older age at first birth, never having breastfed, and abdominal adiposity were associated with increased risk of early-onset ER- breast cancer: HRs were 1.71 for ≥3 births versus one birth; 2.29 for first birth after age 25 versus <20 years; 0.61 for ever having breastfed versus never; and 1.64 for highest versus lowest tertile of waist-to-hip ratio. These factors were not associated with ER- cancer in older women or with ER+ cancer regardless of age. Differences in risk factors by ER subtype were observed for breast cancer diagnosed before the age of 45 years. Etiological heterogeneity by tumor subtype in early-onset breast cancer, in combination with a higher prevalence of the risk factors in AA women, may explain, in part, racial disparities in breast cancer incidence. Cancer Epidemiol Biomarkers Prev; 26(2); 270-7. ©2016 AACR.

Abstract 1779: Risk factors for early-onset ER- and ER+ breast cancer in African American women

Abstract Introduction: Relative to white women, African American (AA) women have a disproportionately high incidence of early-onset breast cancer, particularly higher incidence of aggressive breast cancer subtypes such as estrogen receptor (ER) negative tumors. Elucidation of risk factors for early-onset of specific subtypes of breast cancer is needed. Methods: We evaluated associations of reproductive and lifestyle factors with early-onset invasive breast cancer, defined as diagnosis before age 50, in 47,212 AA women ages 21-49 in the Black Women's Health Study (BWHS). The BWHS is an ongoing prospective cohort study in the U.S. that began in 1995. Risk factor information is updated every two years via mailed questionnaires. Incident cases were self-reported on biennial questionnaires or identified through death records and confirmed by medical records and cancer registry data. Through 2013, we identified 192 ER- and 322 ER+ invasive breast cancers diagnosed before age 50. We used multivariable Cox proportional hazards regression, stratified by age, to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of family history of breast cancer, age at menarche, parity, age at first birth, years since last birth, lactation, body mass index (recent and at age 18), waist-to-hip ratio, oral contraceptive use, alcohol consumption, smoking history, and physical activity, with risk of ER- and ER+ early-onset breast cancer, separately. Results: The strongest associations were observed for family history of breast cancer, early age at menarche, and lower body mass index at age 18, and these factors were associated with increased incidence of both ER- and ER+ breast cancer. Oral contraceptive use within the past 10 years was also associated with increased risk of both subtypes. High waist-to-hip ratio (HR for top tertile vs. bottom: 1.46, 95% CI: 0.98, 2.19) and high parity (HR for 3+ births vs. 1: 1.43, 95% CI: 0.88, 2.32) were associated with increased risk of ER- breast cancer, while breastfeeding was associated with a reduced risk (HR for ever vs. never: 0.68, 95% CI: 0.47, 0.97). In contrast, higher parity was associated with a reduced risk of ER+ cancer (HR for 3+ births vs. 1: 0.68, 95% CI: 0.45, 1.01). Recent pregnancy (HR for &amp;lt;10 years vs. 10 or more years: 1.33, 95% CI: 0.94, 1.88) and greater alcohol consumption (HR for 7+ drinks/week vs. &amp;lt;1/week: 1.33, 95% CI: 0.81, 2.17) were associated with an increased risk of ER+ tumors. Conclusions: Differential associations of risk factors for ER- vs. ER+ breast cancers in young AA women suggest etiological heterogeneity by tumor subtypes. These differences could explain, in part, disparities in breast cancer incidence and mortality between black and white women. Some identified risk factors are potentially modifiable, suggesting possible opportunities for prevention. Citation Format: Kimberly A. Bertrand, Lynn Rosenberg, Julie R. Palmer. Risk factors for early-onset ER- and ER+ breast cancer in African American women. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1779.

MSH2 rs2303425 Polymorphism is Associated with Early-Onset Breast Cancer in Taiwan.

Accumulated evidence indicates that the incidence of early-onset breast cancer has rapidly increased in Taiwan and other Asian compared to Western countries. The mismatch repair (MMR) pathway might be one of the crucial mechanisms of predisposition to early breast cancer. In this study, we explored whether MMR gene polymorphisms contribute to the risk of breast cancer in young women. This was a 2-stage case-control study including 737 cases and 719 controls. After eight single nucleotide polymorphisms (SNPs) were genotyped in MMR pathway genes in the stage I study, a promising SNP, MSH2 rs2303425, was selected for validation in the stage II study. A luciferase reporter assay was used to evaluate the transcriptional activity of MSH2. Logistic regression analysis showed that individuals with the MSH2 rs2303425 C/C genotype had a significantly increased risk of breast cancer compared to those with the T/T genotype (adjusted odds ratio 2.0; 95% confidence interval 1.1-3.8), particularly in early-onset breast cancer patients with the luminal A subtype. The luciferase assay in three cell lines indicated that the MSH2 rs2303425 T/C substitution decreased MSH2 expression, which is consistent with the finding of an association study. A common variant SNP in MSH2 may contribute to the susceptibility to early-onset breast cancer functionally, particularly for the luminal A subtype.

Standards of the Polish Ultrasound Society - update. Sonomammography examination.

Epidemiologic data suggest that the incidence of breast cancer is on the rise, as is the incidence of early-onset breast cancer in premenopausal women. Breast cancer is the most common malignancy worldwide. According to data of the International Agency for Research on Cancer (IARC), over one million women are newly diagnosed with breast cancer each year, and the annual mortality rate is 410,000. In view of this situation, ultrasound is gaining an increasing role as a breast imaging modality. It is the most widely used complementary imaging modality supplementing mammography in the workup of unclear breast lesions in young women, in women with a family history of breast cancer, and in women with dense breasts. Therefore, ultrasonography should have high sensitivity and specificity in characterizing focal breast lesions. An important prerequisite is a standardized examination procedure and documentation of findings. The Polish Ultrasound Society adopted the BIRADS classification in 2010. As described in the article of W. Jakubowski, K. Dobruch-Sobczak and B. Migda in the “Journal of Ultrasonography”(1), the sonographic characterization of focal breast lesions relies on morphologic evaluation. Besides a focus on how to differentiate between malignant and benign lesions, the authors provide a comprehensive overview of the use of elastography in conjunction with inspection, palpation, B-mode ultrasound, and histology. Evaluation of tissue compressibility is part of standard breast ultrasound in the characterization of focal lesions. A tumor that cannot be compressed in the B-mode examination is more likely to be malignant. Many international studies have shown the new technique of elastography to improve the specificity of ultrasound in characterizing breast lesions. The 2003 version of the BIRADS classification of the American College of Radiology (ACR) does not yet include elastography among breast imaging modalities. The Polish authors highlight the classification of breast lesions according to BIRADS categories 1 to 6 including histology and clinical consequences. In contrast to other European countries, the Polish policy is to perform annual ultrasound examinations already in women after age 30. The authors not only present the technical prerequisites and required skills but also provide an excellent overview of interpretation algorithms according to the BIRADS classification. This can ultimately improve the comparability of publications and the quality of documentation of sonographic findings on an international scale. In summary, the authors provide a detailed and comprehensive overview on the interpretation of breast ultrasound findings in Poland. The classification allows estimating the probability of malignancy of a focal breast lesion. The sonographic findings should be interpreted in conjunction with the patient's history, palpation and clinical findings, and other imaging findings such as mammography and MRI. Elastography is a novel technique; however, many studies have proven its benefit, and it should be included in the ACR BIRADS lexicon. Taken together, the results of major international publications(2, 3) indicate that the use of elastography can be recommended in women with suspicious B-mode findings (subjective classification) and in high-risk women (SR calculation). The elastography findings should be classified according to the BIRADS lexicon.

Mutational analysis of BRCA1 and BRCA2 in Mediterranean Spanish women with early-onset breast cancer: identification of three novel pathogenic mutations.

In Spain, the contribution of BRCA mutations to the population incidence of early-onset breast cancer was unknown. We carried out a mutational analysis of the BRCA1 and BRCA2 genes in 124 Spanish women diagnosed with breast cancer before the age 41 and who were not selected for a family history of this disease. The genetic study was performed by PCR-SSCP analysis and DNA sequencing. We identified 6 pathogenic BRCA mutations in 7 unrelated probands (5.6%; 95% CI=2.3% to 11.3%): 1 BRCA1 (c.2080delA) and 5 BRCA2 (p.Y3006X, p.Q1994X, c.9204_9217del14, c.9254_9258del5 and c.295+2T>C). Three out of 6 mutations were novel (BRCA2 p.Y3006X, c.9204_9217del14, and c.295+2T>C), and two further mutations had not been previously found in Spain (BRCA1 c.2080delA and BRCA2 p.Q1994X). The one remaining (BRCA2 c.9254_9258del5) was detected in two probands of our sample. Additionally, we identified two new missense mutations: BRCA1 p.P1812A and BRCA2 p.G2044A. Our data support the notion that Spaniards represent a heterogeneous population with its own spectrum of BRCA mutations, some of which appear as founding mutations. We categorized patients into familial or non-familial groups on the basis of her family history of breast/ovarian cancer; this analysis indicated that among Spanish women with early-onset breast cancer, an even moderate family history is a good predictor of being a BRCA mutation carrier.