Breast Cancer In General Population Research Articles

Abstract PO1-09-02: Universal genetic testing for women with newly diagnosed breast cancer identified many mutations, impacted clinical management and caused no psychological distress to patients

Abstract Background: For newly diagnosed breast cancer (BC) patients, identification of pathogenic germline mutations in hereditary breast cancer (HBC) genes can inform clinical management and risk mitigation strategies and identify patients who would benefit from targeted therapy and clinical trials. Offering germline testing based on NCCN or other guidelines fails to identify all patients with germline HBC gene mutations, potentially with adverse consequences for patients and their families. As an integral part of the study, we have explored the acceptance of universal testing among patients and clinicians. Methods: This is the largest Australian multi-centre prospective study exploring the prevalence of hereditary pathogenic variants in the Australian BC population. 650 newly diagnosed consecutive, consented patients with non-metastatic breast cancer or high-grade DCIS were recruited from May 2020 to March 2023 in 2 phases. Phase 1 (n=157) offered a combination of germline and somatic sequencing. Germline testing was performed by whole genome sequencing on DNA from blood or saliva, and the data analyzed for actionable HBC gene mutations, including large genomic rearrangements. Germline variants were interrogated for pathogenic variants in BRCA1, BRCA2, PALB2, ATM, CHEK2, BARD1, BRIP1, RAD51B, RAD51C, RAD51D, MLH1, MSH2, MSH6, PMS2, CDH1, PTEN, STK11, TP53 and NTHL1.Tumour sequencing will be reported separately. Phase 2 (n=493) included germline exome sequencing with no somatic sequencing. The objectives were to assess the additional actionable HBC gene mutations identified by universal testing compared to algorithmic based (MANCHESTER and BOADICEA scores) and NCCN guidelines, the clinical impact of this identification and the prevalence of germline mutations in the general BC population. A 3-generation pedigree was constructed for every patient for accurate estimation of NCCN, MANCHESTER, and BOADICEA scores. Phase 1 patients completed surveys of perceptions of universal testing, psychological distress and cancer-specific worry pre- and post-testing. Results: 50 carriers of actionable germline mutations were identified: (7.7%). BRCA1 (n=10), BRCA2 (n=12), PALB2 (n=7), CHEK2 (n=10), ATM (n=4), PMS2 (n=2), MSH6 (n=1), RAD51C (n=2), and BARD1 (n=3). One carrier had both PALB2 and CHEK2 mutations. Updated NCCN guidelines (2023 version) identified 44/50 pathogenic germline variant carriers (88%). The BOADICEA and MANCHESTER scores only identified 22 carriers (44%). Immediate clinical management changed due to the discovery of HBC gene in 40/50 (80%). Among 105 participants, cancer-specific distress declined from pre- to post-testing. Anxiety, stress and depression did not change. 90/103 participants agreed that genetic testing should be routine, 100/104 reported their decision to undergo testing as correct. All (n=25) BC clinicians reported that genetic test results were helpful for important treatment decisions and none that testing was distressing to patients. Conclusion: HBC gene mutation prevalence was 7.7%. Universal germline HBC gene testing is the best method for detecting carriers. Current testing guidelines would have missed HBC genes which would have impacted clinical management. Updated NCCN guidelines were sensitive in the detection of HBC gene mutation, but more than half of HBC gene mutations were missed by Australian standards. Discovery of HBC gene mutations led to changed management in most cases. Universal testing is highly acceptable to clinicians and patients who reported no adverse impact on psychological distress or cancer-specific worry and no decision regret. Germline mutations identified and their impact on management Citation Format: Dilanka De Silva, Lesley Stafford, Anita Skandarajah, Michelle Sinclair, Lisa Devereux, Kirsten Hogg, Maira Kentwell, Allan Park, luxi Lal, Magnus Zethoven, Madawa Jayawardena, Fiona Chan, Paul James, Geoffrey Lindeman, Ian Campbell, Bruce Mann. Universal genetic testing for women with newly diagnosed breast cancer identified many mutations, impacted clinical management and caused no psychological distress to patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-09-02.

Abstract PO3-02-09: Breast cancer in women under the age of 40 years.A south Wales UK reflection on incidence, tumour biology and outcomes over 10 years

Abstract Introduction: The incidence of breast cancer in the under 40-year-old age group is approximately 7% (Anders et al., 2009). Studies suggests that the management of Breast cancer in adolescent and young women is more challenging, with this age group under-represented in clinical trials. We investigated the management and outcomes of a cohort of 98 patients seen between 2013 and 2023 in the Hywel Dda NHS University Health Board, Wales, UK. Methods: A retrospective review was performed. Demographic, surgical and outcome data for patients under the age of 40 years was collated and analysed. Results: The cohort size was 98, representing 2.45% of the breast cancer population treated in the Health Board during this timeframe. The age of the cohort ranged from 23 years to 40 years, 12 out of 98 (12.24%) were under 30 years. Mean age was 35.28 years. Unfortunately, 8.16% (8/98) of the cohort died between 12 months to 96 months. Two patients were lost to follow up. Tumour biology results confirmed that most of the cohort had invasive ductal carcinoma (IDC), with 13.27% Grade 1, 37.76 % Grade 2 and 40.82% Grade 3. There were 4 (4.08%) invasive lobular carcinomas (ILC) in the cohort, 2 Grade 2 and 2 Grade 3. The remaining tumour groups were, 1 case of DCIS (Grade-2 intermediate grade), Grade-1 mucinous carcinoma, 1 Grade-1 ductal-lobular breast cancer and 1 medullary carcinoma. 10.20% of the cohort had triple negative cancers (ER, PR, Her-2 negative) and 10.20% were ER, PR, HER2 positive [Triple positive]. 40.82% metastatic axillary lymph nodes involvement on histology either on presentation or following sentinel node biopsy. Operative details confirmed that the 51.02% (50/98) of the cohort underwent mastectomy. 10 out of those 50 patients underwent contralateral risk reducing mastectomy .46 patients had breast conservation surgery. One patient is awaiting surgery, the other has been diagnosed with metastatic breast cancer at diagnosis. Patients received both neoadjuvant and adjuvant chemotherapy depending on initial assessment and MDT discussion [ACP, FEC, Taxane and platinum-based chemotherapy, Anti Her-2]. NAC was provided for all HER-2+ patients. Endocrine treatment and ovarian function suppression, and adjuvant Radiotherapy was also given. Some patients had a complete pathological response to NAC; however, some did not respond well. In addition, 10.20% of the cohort underwent bilateral salpingo-oophorectomy during their treatment and follow up. Genetic assessment confirmed that 3/98 (3.06%) of the cohort were BRCA2 positive, one BRCA1 carrier, 2 patients were BRCA negative, two have been referred for genetics assessment and two still awaiting consultation with genetics. In one patient somatic mutation was found in PTEN, BIRC3, HRAS, TP53, PMS, (5 gene panel). In one patient, panel was reassuring. PALB-2, TP53 was also reassuring in one patient. One patient who passed away at the age of 34 did not have any alteration in 5 gene panel. Three patients developed other malignancies during the 10-year period: 1 uterine, 1 cervix, 1 papillary thyroid cancer. 6/98 (6.12%) developed metastatic disease and one developed a local recurrence. One patient developed metastasis while pregnant, and by contrast one patient gave birth to a baby after stopping her endocrine treatment. One patient who passed away had no response to neoadjuvant chemotherapy (NAC). Discussion: The results from the cohort confirm that the incidence of TNBC and triple positive cancers is like that found in the general breast cancer population (10-15%). Our engagement with the genetics team has increased since the initial 2013 cohort. There is now an established system for referrals for young women with breast cancer. It is probably not surprising that other primary invasive cancers were found, whilst on follow up. Citation Format: Sohail Khan, Saira Khawaja, Yousef Sharaiha, Asma Munir, Anita Huws. Breast cancer in women under the age of 40 years.A south Wales UK reflection on incidence, tumour biology and outcomes over 10 years [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-02-09.

Breast Carcinogenesis during Pregnancy: Molecular Mechanisms, Maternal and Fetal Adverse Outcomes.

Breast cancer is a common type of cancer diagnosed during pregnancy, with increasing incidence over the last years, as more women choose to delay childbearing. Compared to breast cancer in general population, pregnancy-associated breast cancer (PABC) is significantly different in its terms of epidemiology, diagnostic and therapeutic management, while it exhibits particularly aggressive behavior, deriving from its unique molecular and biological profile. Although not fully elucidated, the pathophysiological basis of PABC can be traced back to a combination of hormonal and immune changes during pregnancy, breast involution and altered gene expression. There is considerable controversy in the existing literature about the influence of PABC on pregnancy outcomes, regarding both short- and long-term effects on maternal and fetal/neonatal health. The majority of PABC patients have advanced-stage disease at initial diagnosis and face a significantly poorer prognosis, with decreased survival rates. The most commonly reported adverse obstetrical-fetal events are preterm delivery and prematurity-associated neonatal morbidity, while other neonatal treatment-associated complications might also occur, even when safe therapeutic options are applied during pregnancy. The objective of the present comprehensive review was to summarize current knowledge and up-to-date evidence about the pathophysiological, molecular and biological basis of PABC, as well as its association with adverse maternal, obstetrical, fetal and neonatal outcomes.

Abstract C047: UBE2C a poor prognostic biomarker in Black women with estrogen receptor positive (ER+) breast cancer in TCGA

Abstract Introduction: The majority of estrogen receptor positive (ER+) breast cancer carry a good prognosis; however, there is a subset, luminal B breast cancer (LBC), that is highly aggressive. LBC is more common in Black/African American (BAA) women who have a four-times higher death rate from ER+ breast cancer compared to other races. There is evidence that LBC shares biologic similarities with triple negative breast cancer (TNBC); common differentially expressed genes have been identified in TNBC and LBC, particularly among BAA women. Specifically, ubiquitin-conjugating enzyme 2C (UBE2C) expression is elevated in both. UBE2C is a driver of the cell cycle and involved in Wnt/β-catenin signaling, epithelial to mesenchymal transition (EMT), invasion and metastasis. Here we interrogate the association of UBE2C mRNAseq expression with survival in BAA women with ER+ breast cancer in The Cancer Genome Atlas (TCGA). Methods: TCGA Breast (BRCA) cohorts were queried to investigate the differential UBE2C mRNA seq expression in normal vs tumor patient samples in the general breast cancer population and specifically in the ER+ patients. Expression was also compared across races (BAA vs. White). Kaplan-Meier (KM) curves were generated to determine overall survival by gene expression using median as threshold. Results: In TCGA, compared to normal (n=112), UBE2C mRNAseq expression was statistically significantly higher in tumor in all breast cancer patients (n=1092) as well as specifically in the ER+ cohort (n=805). UBE2C mRNAseq expression was higher in the ER- (n=237) compared to the ER+ breast cancer patients (n=805) (p=3.7e-45). Expression was also significantly higher in the progesterone receptor (PR) negative (n=342) compared to the PR positive patients (n=697) (p=1.89e-40). Higher UBE2C mRNAseq expression was associated with poorer disease-free survival in all breast cancer patients as well as specifically in the ER+ patients. When examining the BAA population compared to White, UBE2C mRNA seq expression was significantly higher among BAA (n=183) compared to White (n=753) patients (FC=1.9; p=6.02e-15). Genes involved in cell cycle pathways were significantly correlated with UBE2C mRNAseq expression among BAA ER+ patients (n=110) including CDCA5 (p=1.42e-26, r=0.81), CDK2 (p=1.13e-05, r=0.41), and CDK4 (p=4.67e-06, r=0.42). The proliferation gene MKI67 was also significantly correlated with UBE2C mRNA seq expression (p=6.24e-18, r=0.71). UBE2C mRNAseq high expression was significantly associated with poor progression-free survival for BAA patients with breast cancer (n=179, p= 0.0353). UBE2C mRNAseq high expression was positively associated with African ancestry and negatively associated with European ancestry. Conclusion: UBE2C is a poor prognostic marker in BAA women with ER+ breast cancer using the TCGA dataset. UBE2C plays an integral role in the cell cycle. Given the prevalence of resistance to cell cycle targets, such as CDK 4/6 inhibitors, UBE2C demonstrates a potential drug target to improve outcomes in LBC and mitigate disparities. Citation Format: Veronica Jones, Yate-Ching Yuan, Melissa Davis, Victoria Seewaldt, Rick Kittles. UBE2C a poor prognostic biomarker in Black women with estrogen receptor positive (ER+) breast cancer in TCGA [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C047.

Current Considerations in Surgical Treatment for Adolescents and Young Women with Breast Cancer.

Adolescents and young women (AYA) with breast cancer represent a unique patient population, compared to the general population with breast cancer. We performed a literature review to evaluate the factors that influenced the surgical outcomes in this patient population. Fifty-two studies were identified, which evaluated breast surgery type, axillary surgery, contralateral prophylactic mastectomy (CPM), surgical timing, psychological factors, disparities, and imaging use. AYA patients had equivalent oncologic outcomes with breast conserving surgery (BCS) or mastectomy. CPM did not improve survival. There are limited data on axillary management in the AYA population, and while more data would be beneficial, this is currently extrapolated from the general breast cancer population. A shorter time to initiate treatment correlated to better outcomes, and disparities need to be overcome for optimal outcomes. AYA patients appreciated involvement in clinical decisions, and shared decision making should be considered whenever possible. Providers must keep these factors in mind when counseling AYA patients, regarding the surgical management of breast cancer.

808 Metastatic Breast Cancer to the Spine: Outcomes After the Introduction of Small Molecule Inhibitors

INTRODUCTION: Over the past decade, with the development of small molecule inhibitors and immunotherapies, expanded attention is being paid to the somatic mutations expressed within a patient’s individual breast tumor, especially in the case of advanced or metastatic disease. A number of mutations have been found to occur most commonly in patients with metastatic breast cancer, including TP53, PI3K, CDH1, and MAP3K. Specifically, with regards to patients with metastases to bone, PIK3 mutations have been found to increase in frequency. METHODS: This is a retrospective study of patients who underwent treatment (surgery/radiation) at a tertiary care center for their diagnosis of breast cancer metastatic to the spine between 2010 and 2020. Review of peripheral sample gene sequencing reports was conducted to calculate the prevalence of different somatic gene mutations within our population. The use of small molecule inhibitors in the post-treatment period was determined and patient post-treatment mortality was calculated in order to elucidate the effect of systemic therapy on overall survival. RESULTS: 77 patients were included in our final analysis. Within our population of spine metastases patients, 44 (57%) were found to have a PI3K mutation, followed by 20 (26%) with a TP53 mutation. Furthermore, those patients given targeted molecular therapies in the post-treatment period were found to have a median overall survival of 1356 days. In comparison, those who did not receive targeted molecular therapies were found to have a median overall survival of 503 days (p<0.001). CONCLUSIONS: The results of the present study demonstrate that not only is there an increased prevalence of PI3K mutations within spine metastases in comparison to the general metastatic breast cancer population, there is also a significant mortality benefit with adding targeted molecular therapies to the patient’s post-operative treatment plan.

Factors Contributing For Breast Cancer In Pakistan

Breast cancer is the most common malignancy among women around the Globe. Asian countries have highest ratio of breast cancer. About 60 % cases from Asian countries due to lack of health care facilities and awareness about breast cancer in general population. Classification based on age, stage of disease, location of development and family history. Breast cell tumor due to gene mutation prognosis the disease into malignancies. Symptoms may appear in early stage or late stages of disease.Material and method:The literature review was conducted through different sources such as Google scholars, PubMed, MEDLINE and data base. The key words was used breast cancer incidence in Pakistan, prevalence of breast cancer, causes of breast cancer in Pakistan. Only those studies was selected published during the period of 2010 to 2020 and published in English.Results:From this literature review, following factors has been identified, effecting on breast cancer development. Lack of knowledge about breast cancer development. Lack of health care facilities in rural areas, family history and economic problems.Conclusion:Pakistani women are unaware of breast cancer knowledge. Low health care budget, early identification of disease, family history of breast cancer are major contributing factors of breast cancer.

PredictCBC-2.0: a contralateral breast cancer risk prediction model developed and validated in ~ 200,000 patients

BackgroundPrediction of contralateral breast cancer (CBC) risk is challenging due to moderate performances of the known risk factors. We aimed to improve our previous risk prediction model (PredictCBC) by updated follow-up and including additional risk factors.MethodsWe included data from 207,510 invasive breast cancer patients participating in 23 studies. In total, 8225 CBC events occurred over a median follow-up of 10.2 years. In addition to the previously included risk factors, PredictCBC-2.0 included CHEK2 c.1100delC, a 313 variant polygenic risk score (PRS-313), body mass index (BMI), and parity. Fine and Gray regression was used to fit the model. Calibration and a time-dependent area under the curve (AUC) at 5 and 10 years were assessed to determine the performance of the models. Decision curve analysis was performed to evaluate the net benefit of PredictCBC-2.0 and previous PredictCBC models.ResultsThe discrimination of PredictCBC-2.0 at 10 years was higher than PredictCBC with an AUC of 0.65 (95% prediction intervals (PI) 0.56–0.74) versus 0.63 (95%PI 0.54–0.71). PredictCBC-2.0 was well calibrated with an observed/expected ratio at 10 years of 0.92 (95%PI 0.34–2.54). Decision curve analysis for contralateral preventive mastectomy (CPM) showed the potential clinical utility of PredictCBC-2.0 between thresholds of 4 and 12% 10-year CBC risk for BRCA1/2 mutation carriers and non-carriers.ConclusionsAdditional genetic information beyond BRCA1/2 germline mutations improved CBC risk prediction and might help tailor clinical decision-making toward CPM or alternative preventive strategies. Identifying patients who benefit from CPM, especially in the general breast cancer population, remains challenging.

Breast cancer in Indigenous women living in Canada: a scoping review protocol.

The objective of this review is to describe and synthesize the current state of knowledge pertaining to breast cancer in Indigenous women living in Canada. We will examine the continuum of breast cancer care in this population, including breast cancer screening, diagnosis, treatment, and surveillance. Breast cancer in Indigenous women is an evolving health care concern in Canada, with mounting evidence suggesting that these women present at later stages, and have poorer survival rates compared with the general population. A comprehensive overview of the state of knowledge of breast cancer in this population is required. The population of interest will include Indigenous women living in Canada aged 18 years or older who have been screened or require screening for breast cancer, or who have been diagnosed with breast cancer. "Indigenous" will include women who identify as First Nations, Métis, or Inuit. Eligible sources must report on breast cancer risk factors, tumor characteristics, health systems access, screening, diagnosis, treatment, surveillance, or breast cancer outcomes. We will include analytic studies, surveys, case series, reviews, meta-analyses, and gray literature. We will conduct a search of five health sciences databases for relevant studies published in English or French from database inception onward. We will utilize dual independent screening for titles, abstracts, and full-text articles, and will utilize a similar method for gray literature sources. Data will be synthesized using a narrative approach, and outcomes of interest will be compared with data from the general breast cancer population. Open Science Framework https://osf.io/xkde5.

Use of comorbidity indices in patients with any cancer, breast cancer, and human epidermal growth factor receptor-2-positive breast cancer: A systematic review.

ObjectiveTo identify comorbidity indices that have been validated in cancer populations, with a focus on breast cancer and human epidermal growth factor receptor-2-positive (HER2+) breast cancer.Study design and settingA systematic review of the literature on the use of comorbidity indices in any cancer, breast cancer, and HER2+ breast cancer using Ovid and PubMed.ResultsThe final data set comprised 252 articles (252 any cancer, 39 breast cancer, 7 HER2+ breast cancer). The most common cancers assessed were hematologic and breast, and the most common comorbidity index used was the Charlson Comorbidity Index (CCI) or a CCI derivative. Most validity testing of comorbidity indices used predictive validity based on survival outcomes. Hazard ratios for survival outcomes generally found that a higher comorbidity burden (measured by CCI) increased mortality risk in patients with breast cancer. All breast-cancer studies that validated comorbidity indices used CCI-based indices. Only one article validated a comorbidity index in HER2+ breast cancer.ConclusionCCI-based indices are the most appropriate indices to use in the general breast-cancer population. There is insufficient validation of any comorbidity index in HER2+ breast cancer to provide a recommendation, indicating a future need to validate these instruments in this population.

A retrospective study of characteristics and survival in patients with breast cancer brain metastases classified by subtype using NCI SEER registry.

1031 Background: Breast cancer brain metastasis (BCBM) de novo is associated with the worst prognosis among all types of metastases in breast cancer (BC). Analysis of factors associated with BCBM stratified by subtype of BC could lead to earlier identification of metastasis. Methods: 1,268 patients with BCBM at the time of BC diagnosis and known clinical subtype (580 HR+/HER2-, 225 HR+/HER2+, 176 HR-/HER2+, and 287 HR-/HER2-) who were ≥ 20 years of age from 2010 to 2017 were identified using the NCI’s Surveillance, Epidemiology, and End Results (SEER) Program 18 registry. Baseline characteristics and survival were analyzed using Chi-Square and Kaplan-Meier methods. Results: Patients with HR-/HER2+ BC were the most likely to present with BCBM, compared to all BC patients (prevalence of 13.9% vs. 4.7%; p<0.001). Further analysis demonstrated that HER2+ patients had an odds ratio of presenting with BCBM of 2.52 (95% CI: 2.24-2.84) compared to HER2- patients. Interestingly, in patients ages 20-39 with HR-/HER2+ BC, higher rates of brain metastases are noted within the BCBM group compared to all HR-/HER2+ breast cancer cases (28% vs. 7.6%; p<0.001). The same trend is seen within the HR-/HER2+ African American population, with those in the BCBM group experiencing higher rates of brain metastases compared to all BC cases with the same subtype (14.3% vs. 5.9%; p<0.001). Upon exploring insurance demographics, uninsured patients with HR-/HER2+ BCBM had much higher rates of brain metastases compared to all HR-/HER2+ BC cases (14.8% vs 6.4%; p=0.001). When examining TNM status, significant associations were noted between brain metastases and increased tumor and nodal status. Patients with T4 or N3 status with HR-/HER2+ BCBM exhibited much higher rates of metastasis compared to all BC cases with the same subtype (p<0.001). Analysis of survival outcomes showed a median overall survival of 12 months for patients with HR-/HER2+ BCBM. The results displayed in the table below show that HR-/HER2- BCBM patients had the lowest 5-year percent survival, while HR+/HER2+ BCBM patients had the highest 5-year survival. Conclusions: This SEER database study provides insight into the demographics, clinical variables, and outcomes for BC clinical subtypes, specifically HR-/HER2+, from 2010 to 2017 in the United States. HR-/HER2+ breast cancer patients within the noted high-risk populations should be made aware of the increased rates of brain metastases compared to the general BC population, as earlier identification of brain metastases within the HR-/HER2+ cohort could improve patient survival.[Table: see text]

Prognostic Role of Tumor Budding in Breast Cancer Patients Receiving Neo-Adjuvant Therapy.

Background: Isolated tumor cells or small clusters of tumor cells observed in the vicinity of the main tumor mass in pathology sections, termed tumor budding, are common in cancers and have been associated with prognosis in some settings. This study examined the clinical associations and treatment efficacy implications of tumor budding in breast cancer patients receiving neo-adjuvant therapy. Methods: Breast cancer patients that received neo-adjuvant therapy before definitive surgical treatment in a single cancer center over a 7-year period were included, and their records were reviewed. Data extracted included patient demographics, tumor characteristics and pathologic response to treatment at surgery. The initial breast cancer biopsy before any therapy was reviewed by two pathologists, and a hot spot area was evaluated for tumor budding (defined as 1 to 5 cancer cells observed detached from the main tumor mass). Results: Seventy-five patients who received neo-adjuvant therapy (73 received chemotherapy and 2 received hormonal therapy) were included. Tumor budding was observed in two-thirds of the patients. There were no significant differences in patient (age and menopause status) and tumor (stage, histology and molecular sub-type equivalent) characteristics between the group that had tumor budding and the group that did not have tumor budding in the pre-treatment biopsy. Likewise, no statistically significant differences were observed in the frequency of complete or partial responses between the two groups. Conclusion: In this cohort of breast cancer patients receiving neo-adjuvant therapy, tumor budding was frequent, but it was not associated with tumor characteristics or pathologic responses to treatment. The value of tumor budding as a prognostic factor in the neo-adjuvant setting within the general breast cancer population could not be confirmed, but such a value in specific sub-groups deserves further investigation, given the pathophysiologic rationale and data from other settings.

Posttraumatic stress in breast cancer survivors diagnosed at a young age.

Young breast cancer patients experience greater psychosocial distress compared with older patients, which raises concern for their risk of posttraumatic stress disorder (PTSD). We sought to characterize the prevalence of clinically significant symptoms of PTSD and associated factors among breast cancer survivors diagnosed at a young age. The Young Women's Breast Cancer Study, an ongoing prospective cohort study, enrolled 1302 women diagnosed with breast cancer at age ≤ 40 between 2006 and 2016. Participants complete serial surveys, and we obtained additional information from medical record review. Socio-demographics, anxiety and depression, social support, and psychiatric co-morbidities and medications were assessed at study baseline (median, 5 months post-diagnosis). We defined a participant as having clinically significant posttraumatic stress symptoms (PTSS) by scoring ≥50 on the PTSD Checklist-Specific Version, administered on the 30-month survey. Among 700 women with stage 1-3 disease, the prevalence of PTSS was 6.3% (95%CI = 4.5-8.1). In multivariable analyses, PTSS was significantly associated with anxiety (OR 12.43, 95%CI = 5.81-26.59, P < .0001) and stage 2 vs 1 disease (OR 2.26, 95%CI = 1.04-4.93, P = .04). PTSS was inversely associated with having a college degree (OR 0.29, 95%CI = 0.13-0.62, P = .002) and greater social support (OR 0.44, 95%CI = 0.21-0.94, P = .03). We found similar rates of cancer-related PTSS in breast cancer survivors diagnosed at a young age compared with the general breast cancer population despite their well-documented increased risk of overall distress. Nevertheless, factors associated with posttraumatic stress should be considered at diagnosis and in survivorship to identify young patients who may benefit from psychosocial resources.

Radiation-Associated Secondary Malignancies in BRCA Mutation Carriers Treated for Breast Cancer

Radiation therapy (RT), a standard breast cancer (BC) treatment modality, is associated with a small increased risk of in-field second primary malignancy (SPM). SPM rates after RT in BRCA mutation carriers have rarely been reported. An elevated risk of SPM would affect the safety of breast conservation for early BC or prophylactic radiation as a method of prevention. We analyzed a population of BRCA carriers irradiated for BC to determine whether there is an elevated rate of SPM. Patients with BC who were BRCA1 or BRCA2 carriers and were treated with breast and/or chest wall RT with or without regional lymph nodes between 1991 and 2012 at a single institution were retrospectively identified. Only those with ≥5 years of follow-up with adequate demographic, tumor, and radiation data were included. SPMs were recorded, and previously delivered RT doses to the organ and site of malignancy were determined. Two hundred thirty women, of whom 80% carried an Ashkenazi Jewish founder mutation, met entry criteria with 3-dimensional RT delivered to 266 breasts or chest walls, including regional nodes in 110 (41%). With a median follow-up of 10 years (range, 5-27; mean 11.4) comprising 3042 person-years, 6 SPMs developed, of which only 1 (papillary thyroid carcinoma) was within the radiation field (crude rate of 0.38% of irradiated breasts or chest walls), diagnosed 17 years after RT. This corresponds to an incidence of 0.32 per 1000 woman-years. The Kaplan-Meier estimate of 20-year freedom from a radiation-induced SPM is 99.5%. Calculated dose exposure to the out-of-field SPMs ranged from 0.1 to 1 Gy. No patient developed an in-field skin cancer or sarcoma. In this largest cohort of women treated with radiation therapy for BRCA-associated breast cancer, we identified no signal for an increased risk of radiation-induced SPMs compared with the general BC population, and the risk is extraordinarily small. Although larger cohorts and longer follow-up are needed, these results support the safety of RT in BRCA carriers.

Abstract P5-07-12: Prediction and clinical utility of a contralateral breast cancer risk model

Abstract Background: Breast cancer survivors are at risk for contralateral breast cancer (CBC), with the consequent burden of further treatment and potentially less favorable prognosis. We aimed to develop and validate a CBC risk prediction model, and evaluate its applicability for clinical decision-making. Methods: We included data of 132,756 invasive non-metastatic breast cancer patients from 20 studies with 4,682 CBC events and a median follow-up of 8.8 years. We developed a multivariable Fine and Gray prediction model (PredictCBC-1A) including patient, primary tumor, and treatment characteristics, and BRCA1/2 germline mutation status, accounting for the competing risks of death and distant metastasis. We also developed a model without BRCA1/2 mutation status (PredictCBC-1B). Prediction performance was evaluated using calibration and discrimination, calculated by a time-dependent Area-Under-the-Curve (AUC) at 5 and 10 years after diagnosis of primary breast cancer, and an internal-external cross-validation procedure. Decision curve analysis was performed to evaluate the net benefit of the model to quantify clinical utility. Results: In the multivariable model, BRCA1/2 germline mutation status, family history and systemic adjuvant treatment showed the strongest associations with CBC risk. The AUC of PredictCBC-1A was 0.63 (95% prediction interval (PI) at 5 years: 0.52–0.74; at 10 years: 0.53–0.72). Calibration in-the-large was -0.13 (95%PI: -1.62–1.37) and the calibration slope was 0.90 (95%PI: 0.73–1.08). The AUC of Predict-1B at 10 years was 0.59 (95% PI: 0.52–0.66); calibration was slightly lower. Decision curve analysis for preventive contralateral mastectomy showed potential clinical utility of PredictCBC-1A between thresholds of 4-10% 10-year CBC risk for BRCA1/2 mutation carriers and non-carriers. Conclusions: We developed a reasonably calibrated model to predict the risk of CBC in women of European-descent, however, prediction accuracy was moderate. Our model shows potential for improved risk counseling, but decision regarding contralateral preventive mastectomy, especially in the general breast cancer population, remains challenging. Citation Format: Daniele Giardiello, Ewout W Steyerberg, Michael Hauptmann, Muriel A Adank, Agnes Jager, Hester OA Oldenburg, Maartje J Hooning, Marjanka K Schmidt, Breast Cancer Association Consortium. Prediction and clinical utility of a contralateral breast cancer risk model [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-07-12.

Prediction and clinical utility of a contralateral breast cancer risk model

BackgroundBreast cancer survivors are at risk for contralateral breast cancer (CBC), with the consequent burden of further treatment and potentially less favorable prognosis. We aimed to develop and validate a CBC risk prediction model and evaluate its applicability for clinical decision-making.MethodsWe included data of 132,756 invasive non-metastatic breast cancer patients from 20 studies with 4682 CBC events and a median follow-up of 8.8 years. We developed a multivariable Fine and Gray prediction model (PredictCBC-1A) including patient, primary tumor, and treatment characteristics and BRCA1/2 germline mutation status, accounting for the competing risks of death and distant metastasis. We also developed a model without BRCA1/2 mutation status (PredictCBC-1B) since this information was available for only 6% of patients and is routinely unavailable in the general breast cancer population. Prediction performance was evaluated using calibration and discrimination, calculated by a time-dependent area under the curve (AUC) at 5 and 10 years after diagnosis of primary breast cancer, and an internal-external cross-validation procedure. Decision curve analysis was performed to evaluate the net benefit of the model to quantify clinical utility.ResultsIn the multivariable model, BRCA1/2 germline mutation status, family history, and systemic adjuvant treatment showed the strongest associations with CBC risk. The AUC of PredictCBC-1A was 0.63 (95% prediction interval (PI) at 5 years, 0.52–0.74; at 10 years, 0.53–0.72). Calibration-in-the-large was -0.13 (95% PI: -1.62–1.37), and the calibration slope was 0.90 (95% PI: 0.73–1.08). The AUC of Predict-1B at 10 years was 0.59 (95% PI: 0.52–0.66); calibration was slightly lower. Decision curve analysis for preventive contralateral mastectomy showed potential clinical utility of PredictCBC-1A between thresholds of 4–10% 10-year CBC risk for BRCA1/2 mutation carriers and non-carriers.ConclusionsWe developed a reasonably calibrated model to predict the risk of CBC in women of European-descent; however, prediction accuracy was moderate. Our model shows potential for improved risk counseling, but decision-making regarding contralateral preventive mastectomy, especially in the general breast cancer population where limited information of the mutation status in BRCA1/2 is available, remains challenging.

PCN468 SYSTEMATIC REVIEW OF UTILITY ESTIMATES IN TRIPLE-NEGATIVE BREAST CANCER PATIENTS

This study was conducted to gather data from the literature on health state utility values (HSUVs) relevant to triple-negative breast cancer (TNBC) patients. Two systematic literature reviews (SLRs) were completed in April 2019, one to identify studies measuring health-related quality of life (HRQoL) outcomes and the other to identify economic studies in TNBC patients. The SLRs covered EMBASE, MEDLINE, EconLit, and CENTRAL as well as conference proceedings and health technology assessment (HTA) databases. Of the 4 bibliographic databases (2007-2019), 7 congresses (2017-2019), and 11 HTA databases (2007-2019) reviewed, 4 studies that reported HRQoL outcomes and 9 studies that reported economic outcomes were identified. None of the included HRQoL studies reported HSUVs in TNBC patients. Of the 9 economic studies identified, 4 (a value of information analysis, two cost-utility analyses, and an HTA submission) included HSUVs. In all 4 studies, the utility values were derived from published literature on the general breast cancer (BC) population. The utilities values reported were associated with a variety of health states. In the HTA submission, the mean utility values derived using a standard gamble technique for progression-free survival, response, stable disease, and progressive disease associated with metastatic BC were 0.73, 0.81, 0.65, and 0.45, respectively. The other economic evaluations used utility estimates for relapse (0.73), disease-free/well (0.78-1.0), and breast cancer in general (0.77). The methods for selection and synthesis of these HSUVs were not well-reported in the economic analyses. An SLR employing a highly sensitive search strategy for humanistic burden did not identify any HSUVs in TNBC patients. Existing economic models for TNBC employ utilities for different health states in the general breast cancer population; further research is necessary to derive HSUVs specific to TNBC that can be used in economic evaluations.

Trends in vitamin D supplement use in a general female and breast cancer population in Ireland: A repeated cross-sectional study.

BackgroundVitamin D has been linked with improved survival after breast cancer diagnosis but little is known about prescribing rates. This study investigates trends in vitamin D supplement use in both a general female and breast cancer population.MethodsWomen with a breast cancer diagnosis were identified from the National Cancer Registry of Ireland (n = 19870). Women who had any vitamin D claim between 2005 and 2011 were identified from pharmacy claims data (n = 8556). Prevalence rates were calculated as a proportion of all eligible women and by age (< 55 years, ≥ 55 years). Poisson regression was used to compare rates of vitamin D prescribing across years (risk ratio (RR), 95% CI).ResultsThere was a statistically significant increase in women with a claim for vitamin D between 2005–2011, with the largest increase among breast cancer patients aged ≥ 55 years (RR = 2.26; 95% CI, 2.11–2.42).ConclusionThis may have significant public health implications if associations between vitamin D and improved breast cancer survival prove to be causal.

Breast cancer metastasis to gynaecological organs: a clinico-pathological and molecular profiling study.

Breast cancer metastasis to gynaecological organs is an understudied pattern of tumour spread. We explored clinico‐pathological and molecular features of these metastases to better understand whether this pattern of dissemination is organotropic or a consequence of wider metastatic dissemination. Primary and metastatic tumours from 54 breast cancer patients with gynaecological metastases were analysed using immunohistochemistry, DNA copy‐number profiling, and targeted sequencing of 386 cancer‐related genes. The median age of primary tumour diagnosis amongst patients with gynaecological metastases was significantly younger compared to a general breast cancer population (46.5 versus 60 years; p < 0.0001). Median age at metastatic diagnosis was 54.4, time to progression was 4.8 years (range 0–20 years), and survival following a diagnosis of metastasis was 1.95 years (range 0–18 years). Patients had an average of five involved sites (most frequently ovary, fallopian tube, omentum/peritoneum), with fewer instances of spread to the lungs, liver, or brain. Invasive lobular histology and luminal A‐like phenotype were over‐represented in this group (42.8 and 87.5%, respectively) and most patients had involved axillary lymph nodes (p < 0.001). Primary tumours frequently co‐expressed oestrogen receptor cofactors (GATA3, FOXA1) and harboured amplifications at 8p12, 8q24, and 11q13. In terms of phenotype conversion, oestrogen receptor status was generally maintained in metastases, FOXA1 increased, and expression of progesterone receptor, androgen receptor, and GATA3 decreased. ESR1 and novel AR mutations were identified. Metastasis to gynaecological organs is a complication frequently affecting young women with invasive lobular carcinoma and luminal A‐like breast cancer, and hence may be driven by sustained hormonal signalling. Molecular analyses reveal a spectrum of factors that could contribute to de novo or acquired resistance to therapy and disease progression.

Abstract P2-02-06: Biomarker analysis by next generation circulating tumor DNA (ctDNA) sequencing in patients with advanced breast cancer

Abstract Background: Next-generation sequencing is of increasing interest to identify specific targets for both drug development and treatment. The study of metastatic cancer is complicated by lack of tissue and the potential for change in biology over treatment. We evaluated ctDNA in patients with advanced breast cancer to explore the relationship between specific DNA mutations and prognosis as well as therapeutic decision making. Methods:Peripheral blood was collected in EDTA at the time of diagnosis of advanced disease. Samples were sent to Geneplus-Beijing for sequencing. Indexed Illumina libraries were prepared from germline and circulating DNA using the KAPA Library Preparation Kit; the capture probe was designed based on genomic regions selected with 1021 genes, covering the most frequently mutated genes and exons in solid tumors. Clinical characteristics, treatment and outcome data were collected. We analyzed progression free survival (PFS) from first-line therapy and overall survival (OS), endpoints were correlated with observed gene mutations. Results: 54 patients were enrolled; 27 (50%) HER2+, 22 (41%) hormone receptor + (HR+)/HER2-, and 5 (9%) triple negative (TNBC). Median age was 48 (range 26-74). The median follow-up was 8 years (range 12-180 months). First-line therapy included chemotherapy with trastuzumab for HER2+ disease, chemotherapy with endocrine maintenance (17) or endocrine therapy alone (5) for HR+/HER2- disease, and chemotherapy for TNBC. Mutations were found in TP53, PIK3CA, PIK3CA 3140 A&amp;gt;G(p.H1047R) and ERBB (including ERBB1-4), at 40.7%, 35.2%, 20.4% and 25.9%, respectively. In univariate analysis, patients with tumor mutations in TP53 had a shorter OS (median 64 vs 121 months, p=0.006). The PIK3CA 3140 A&amp;gt;G mutation was more frequent in HER2+ (7/27, 25.9%) than HR+/HER2- (4/22 (18.2%) or TNBC (0/5), and was associated with shorter median PFS in HER2+ disease (mutant vs. wild type: 4 (range 2-9) vs. 8 (range 2-22) months, p=0.006). The frequency of ERBB mutation was similar in HER2- 7/27(25.9%) (p=0.707) or HER2+ 7/27(25.9%) disease (p=0.066); there was no significant impact on PFS in any subset. Multivariate analysis for HER2+ disease including age, ER, Ki67, TP53, PIK3CA, PIK3CA 3140 A&amp;gt;G and ERBB), demonstrated that the PIK3CA 3140 A&amp;gt;G mutation was the only factor associated with shorter PFS (p=0.025); further analysis by receiver operating characteristic (ROC) curve showed that the PIK3CA 3140 A&amp;gt;G mutation and the mutation in PIK3CA 3140 A&amp;gt;G and ERBB combination pathway had a large area under the curve (AUC), with AUC of 0.789, and 0.734 respectively. Conclusions: Using NGS in ctDNA, we found that the PIK3CA 3140A&amp;gt;G mutation was more frequent in HER2+ disease, and was the only mutation associated with shorter PFS on multivariate analysis. The presence of a TP53 mutation was associated with worse OS. Evaluation of ctDNA is feasible in a general breast cancer population and has prognostic impact; further correlation of these findings with tumor samples is ongoing. Citation Format: Li H, Wang J, Rugo HS, Zhang Y, Yang L, Liu X, Shao B, Xu Y, Yang L, Zhang R, Ran R, Chang L. Biomarker analysis by next generation circulating tumor DNA (ctDNA) sequencing in patients with advanced breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-02-06.