Young Breast Cancer Patients Research Articles

Deep learning-based breast cancer grading and survival analysis on whole-slide histopathology images

Breast cancer tumor grade is strongly associated with patient survival. In current clinical practice, pathologists assign tumor grade after visual analysis of tissue specimens. However, different studies show significant inter-observer variation in breast cancer grading. Computer-based breast cancer grading methods have been proposed but only work on specifically selected tissue areas and/or require labor-intensive annotations to be applied to new datasets. In this study, we trained and evaluated a deep learning-based breast cancer grading model that works on whole-slide histopathology images. The model was developed using whole-slide images from 706 young (< 40 years) invasive breast cancer patients with corresponding tumor grade (low/intermediate vs. high), and its constituents nuclear grade, tubule formation and mitotic rate. The performance of the model was evaluated using Cohen’s kappa on an independent test set of 686 patients using annotations by expert pathologists as ground truth. The predicted low/intermediate (n = 327) and high (n = 359) grade groups were used to perform survival analysis. The deep learning system distinguished low/intermediate versus high tumor grade with a Cohen’s Kappa of 0.59 (80% accuracy) compared to expert pathologists. In subsequent survival analysis the two groups predicted by the system were found to have a significantly different overall survival (OS) and disease/recurrence-free survival (DRFS/RFS) (p < 0.05). Univariate Cox hazard regression analysis showed statistically significant hazard ratios (p < 0.05). After adjusting for clinicopathologic features and stratifying for molecular subtype the hazard ratios showed a trend but lost statistical significance for all endpoints. In conclusion, we developed a deep learning-based model for automated grading of breast cancer on whole-slide images. The model distinguishes between low/intermediate and high grade tumors and finds a trend in the survival of the two predicted groups.

P03.04.B Garcin syndrome and hippocampal-sparing WBRT: successful resolution of a rare case

Abstract Background first case of a rare Garcin syndrome resolution in a young metastatic breast cancer(BC) patient treated with a hippocampal-sparing approach. Material and Methods we report a case of a 49-year-old caucasian female. The medical record review was relevant for BC diagnoses in 1997, when she was 26yo; complicated by bone and liver metastasis appeared in 2008. In March 2020, she was referred to our department complaining about increasingly worsening left otalgia with initial hearing loss, left facial numbness, and homolateral decreased facial sensitivity, left increased lacrimation, and tingling tongue. Clinical presentation was suggestive for a Guillain-Alajouanine-Garcin Syndrome (Garcin Syndrome), caused by a lytic lesion in the left sphenoid wing. A contrast MRI (02/04/2020) of the brain demonstrated a lytic lesions in the left sphenoid wing, that was noted to infiltrate surrounding bone of the sphenoid sinus wall, including clivus, left pterygoid process and petrous bone; two parietal and occipital bone lesions were identified with a partial leptomeningeal involvement. According to the good PS, she underwent to a hippocampal-sparing WBRT VMAT plus a sequential boost on sphenoid lesion. PTV and OARs were delineated according to a fused planning MRI/CT image. Bilateral hippocampal contours were generated on the set according to RTOG 0933 contouring atlas. After that, a hippocampal avoidance(HA) region was created by expanding the hippocampal contours by 5 mm in all directions according to Brown et al.The PTV-HA was defined as the WB parenchyma, meninges and skull, excluding the HA-region, dose prescription 30Gy/10fx; the PTV-Boost was defined as the sphenoidal metastases, dose prescription of sequential boost was 12Gy/4fx. VMAT was used to deliver the conformal RT plan. Planning priorities that should be followed were:Hippocampus, OpticChiasm, OpticNerve_L or OpticNerve_R, Lens_L or Lens_R. Results The neurological symptoms improved after the end of RT with a complete resolution two months later. At the last MRI, a year and a half from the end of RT, there was no evidence of brain lesion, and no neurological symptoms were referred. These are our results of plan sum: for PTV-HA D2%=43.43 Gy, D98%=26.36 Gy, V30=94.96%; for Hippocampus D100%=8.78 Gy, Dmax=17.24 Gy; for Left OpticNerve Dmax=33.51%; for Right OpticNerve Dmax=29.25%; for OpticChiasm Dmax=35.93%. Conclusion To our knowledge, this is the first described case using the VMAT technique to spare the hippocampus plus a boost in a rare case of Garcin Syndrome. Prevention of neurocognitive sequelae by hippocampal avoidance has shown promise in several studies as in this case. Sequential boost demonstrated to be feasible and effective.Advanced RT techniques may be used to customize a treatment that allows preserving cognitive impairment achieving good clinical results in the long-term survival of metastatic patients.

Association of socioeconomic status with the clinical management and outcomes in young patients (≤35 years) diagnosed with breast cancer: A retrospective analysis

BackgroundVery young breast cancer at 35 years or younger is rare and tends to be aggressive. The management of very young breast cancer should be equally aggressive, and early diagnosis is critical. We hypothesized that socioeconomic status (SES) is associated with how very young breast cancer (VYBC) patients are diagnosed and treated in our community. MethodsWe retrospectively analyzed a database for invasive breast cancer or ductal carcinoma in-situ (DCIS) diagnosed ≤35 years old (VYBC) from both a government-run county hospital (CH) and a neighboring private hospital (PH) for 82 months. Inclusion criteria composed of female patients diagnosed with invasive breast cancer and DCIS at ≤35 years of age at diagnosis were examined in our analysis. Patient diagnoses and severity, treatment, and outcomes were compared between the two facilities. The methods are consistent with the STROCSS guidelines. ResultsThe incidence of VYBC was a significantly higher percentage of new breast cancers diagnosed in the CH at 5.4% as compared to the PH at 1.9% (OR: 2.94; p < 0.001). CH had a significantly higher proportion of Medicaid payers (73% CH vs. 21% PH, p < 0.001). Mean time from patient's initial symptoms until a tissue diagnosis was significantly longer at the county hospital at 9.6 months vs 2.1 months at the private hospital (p < 0.01). Stage I tumors were only found in 13% of county hospital patients versus 67% at the private hospital (p < 0.001). Approximately 63% of the patients at the government-run county facility had a relative delay in diagnosis, contributing to higher stage at presentation. The rate of mastectomy surgery was high at both institutions: CH 83% vs. PH 76% (p = NS). DiscussionThe results of our study suggest a significant healthcare difference between county and private hospital systems among very young breast cancer patients. Patients at the county hospital system had a longer delay to diagnosis leading to worse outcomes. This difference may be a reflection of barriers in health literacy or access to medical care.

A novel germline mutation of the &lt;i&gt;PALB&lt;/i&gt; gene in a young Yakut breast cancer woman

Background. Breast cancer (BC) is the most common female malignancy worldwide. partner and localizer of BRCA2 gene (PALB2) is directly involved in DNA damage response. germline mutation in PALB2 has been identified in breast cancer and familial pancreatic cancer cases, accounting for approximately 1–2% and 3–4%, respectively. the goal of this report was to describe new PALB2 mutation in a young Yakut breast cancer patient with family history of cancer. Material and methods. Genomic DNA were isolated from blood samples and used to prepare libraries using a capture-based target enrichment kit, Hereditary Cancer Solution™ (SOPHIA GENETICS, Switzerland), covering 27 genes (ATM, APC, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, FAM175A, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, PALB2, PIK3CA, PMS2, PMS2CL, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53 and XRCC2). paired-end sequencing (2 × 150 bp) was conducted using NextSeq 500 system (Illumina, USA). Results. Here we describe a case of a never-before-reported mutation in the PALB gene that led to the early onset breast cancer. We report the case of a 39-year-old breast cancer Yakut woman with a family history of pancreatic cancer. Bioinformatics analysis of the NGS data revealed the presence of the new PALB2 gene germinal frameshift deletion (NM_024675:exon1:c.47dela:p.K16fs). in accordance with dbPubMed ClinVar, new mutation is located in codon of the PALB2 gene, where the likely pathogenic donor splice site mutation (NM_024675.3:c.48+1delG) associated with hereditary cancer-predisposing syndrome has been earlier described. Conclusion. We found a new never-before-reported mutation in PALB2 gene, which probably associated with early onset breast cancer in Yakut indigenous women with a family history of pancreatic cancer.

Correlation analysis of body image level and female sexual dysfunction in young patients with postoperative breast cancer

To determine the relationship between female body image and female sexual dysfunction (FSD) in young patients (20-40 years) with postoperative breast cancer. Using the convenient sampling method, we identified 276 young patients with postoperative breast cancer from June 2017 to 2019 in the Department of Oncology and Radiotherapy of the First Affiliated Hospital of Anhui Medical University to be included in the study. A general situation questionnaire for body image scale (BIS) and female sexual function index (FSFI) scale was used to evaluate the correlation between body image level and the prevalence of FSD in young patients with postoperative breast cancer. The total score for BIS was 10.98 ± 7.19, indicating that patients were moderately dissatisfied with their body image The total prevalence of FSD was 63.41%. Pearson correlation analysis showed a negative correlation between the total score, each dimension score of BIS, total FSD, and the incidence of each dimension disorder (range, r: -0.414 to -0.717, all P values <0.05). There is a negative correlation between the body image level and the prevalence of FSD in young patients with postoperative breast cancer. This suggests that clinical medical workers should develop an intervention plan to improve the body image level of postoperative young breast cancer patients according to the unique physiological and psychological characteristics of these patients while also reducing the prevalence of FSD.

Efficacy and safety of controlled ovarian hyperstimulation with or without letrozole for fertility preservation in breast cancer patients: A multicenter retrospective study

IntroductionFertility preservation (FP) is recommended in young breast cancer (BC) patients before (neo)adjuvant treatment. Letrozole-associated controlled ovarian hyperstimulation (LetCOH) is used worldwide to collect mature oocytes for FP, but its efficacy and safety compared to conventional protocols (cCOH) are still debated. AimsTo compare efficacy and safety of FP procedure using LetCOH or cCOH in BC patients in terms of oocyte maturation rate and disease-free survival rates after at least two years of follow-up. MethodsThis multicenter retrospective study compared outcomes of 107 cycles in 97 non-metastatic BC patients aged ≤40 years who underwent cCOH (n = 56) or LetCOH (n = 41) for FP in CHU-Lille and Erasme Hospital, respectively, between December 2012 and January 2017. ResultsPatients and oncological characteristics were similar except for tumor size and HER2 status which were less favorable in the LetCOH group. Patients underwent adjuvant chemotherapy in 96.4% and 48.8% of the cases in cCOH and LetCOH groups, respectively. Hence, 51.2% of LetCOH patients underwent neoadjuvant chemotherapy (p < 0.001). Estradiol peak at ovulation trigger was lower in LetCOH compared to cCOH group while oocyte maturation rates were significantly higher (p < 0.001), without impacting the final number of mature oocytes collected. Seven and four patients relapsed in LetCOH and cCOH groups, respectively, and one patient died in each group after a median follow-up of four years. ConclusionLetCOH is as effective as cCOH for FP. At this time point, there were no safety concerns regarding cCOH in the adjuvant setting but a longer follow-up is warranted.

A cholesterogenic gene signature for predicting the prognosis of young breast cancer patients.

PurposeWe aimed to establish a cholesterogenic gene signature to predict the prognosis of young breast cancer (BC) patients and then verified it using cell line experiments.MethodsIn the bioinformatic section, transcriptional data and corresponding clinical data of young BC patients (age ≤ 45 years) were downloaded from The Cancer Genome Atlas (TCGA) database for training set. Differentially expressed genes (DEGs) were compared between tumour tissue (n = 183) and normal tissue (n = 30). By using univariate Cox regression and multi COX regression, a five-cholesterogenic-gene signature was established to predict prognosis. Subgroup analysis and external validations of GSE131769 from the Gene Expression Omnibus (GEO) were performed to verify the signature. Subsequently, in experiment part, cell experiments were performed to further verify the biological roles of the five cholesterogenic genes in BC.ResultsIn the bioinformatic section, a total of 97 upregulated genes and 124 downregulated cholesterogenic genes were screened as DEGs in the TCGA for training the model. A risk scoring signature contained five cholesterogenic genes (risk score = −1.169 × GRAMD1C −0.992 × NFKBIA + 0.432 × INHBA + 0.261 × CD24 −0.839 × ACSS2) was established, which could differentiate the prognosis of young BC patients between high-risk and low-risk group (<0.001). The prediction value of chelesterogenic gene signature in excellent with AUC was 0.810 in TCGA dataset. Then the prediction value of the signature was verified in GSE131769 with P = 0.033. In experiment part, although the downregulation of CD24, GRAMD1C and ACSS2 did not significantly affect cell viability, NFKBIA downregulation promoted the viability, colony forming ability and invasion capability of BC cells, while INHBA downregulation had the opposite effects.ConclusionThe five-cholesterogenic-gene signature had independent prognostic value and robust reliability in predicting the prognosis of young BC patients. The cell experiment results suggested that NFKBIA played a protective role, while INHBA played the pro-cancer role in breast cancer.

EP-573 Does type of surgery influence recurrence of breast cancer in younger patients?

Abstract It is well established that young age is a risk factor for outcome of breast cancer, and younger women are more likely to have adverse prognostic factors. Our aim was to investigate whether type of surgery (wide local excision vs mastectomy) had any effect on local or distant recurrence in women under the age of 35. All women with breast cancer under the age of 35 treated between 1st January 2010 and 31st December 2020 were included. Data including age at diagnosis, comorbidities, type of surgery, neoadjuvant/adjuvant treatment, histology, lymph node positivity, expression of receptors, local/distant recurrence was collected. There were 34 patients included, age range 21–34. Ten patients had a wide local excision (WLE) while the rest had a mastectomy. Four patients had local recurrence while nine patients had distal recurrence. In WLE group 1 out of 10 had local recurrence and 2 out of 10 had distant metastasis (one of these patients had both). In mastectomy group 2 out of 24 had local recurrence and 7 out of 24 had distant metastasis (two patients had both). The average recurrence time was 1.7 years after initial diagnosis. Using a Chi-square test, there was no significant difference found for local, distant or overall recurrence between patients having wide local excision or mastectomy (p=0.719, p=0.554, p=0.462 respectively). Type of surgery did not affect the local or distant recurrence rate. The sample size is small, and a larger series is required to determine whether it is equally safer to offer WLE to younger women.

Clinical features and prognostic factors of breast cancer in young women: a retrospective single-center study.

This research aims to characterize the differences in clinical features and prognostic factors between younger and older breast cancer (BC) patients in China. All patients who were recently diagnosed with BC between January 1, 2015 and December 31, 2016 at Shanxi Province Cancer Hospital were recruited. We collected the epidemiological and clinical data as well as the follow-up information. Out of the 1968 BC patients who met the criteria for analysis, 227 (11.53%) were under 40years of age with a median age of 34years at diagnosis. All patients were classified into the age < 40, age 40-59, and age ≥ 60 groups. There were significant differences in the histology, tumor size, T stage, grade, and human epidermal growth factor receptor-2 (HER-2) levels among the three groups (all P < 0.05). The 5-year overall survival (OS) rates were 86.34%, 89.58%, and 84.84% for the age < 40, age 40-59, and age ≥ 60 groups, respectively. The TNM stage was the only predictor of clinical outcome in all BC patients. The prognostic value of intrinsic subtypes for OS was different among the three groups. Our study helped identify an age-related prognostic indicator of adverse events in BC patients and showed that young women with BC exhibited more aggressive clinical and pathological features. Our findings may facilitate clinical management and therapeutic interventions in young BC patients, especially in young women with a history of exposure to risk factors and age < 40years.

Comparisons of Metastatic Patterns, Survival Outcomes and Tumor Immune Microenvironment Between Young and Non-Young Breast Cancer Patients.

Background: Metastases are the main cause of breast cancer-related deaths. Breast cancer has a more aggressive phenotype and less favorable prognosis in young females than in older females. In this study, we aimed to compare the metastatic patterns, survival outcomes and tumor immune microenvironment of young and non-young breast cancer patients. Methods: Patients with a diagnosis of breast cancer were identified from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2015. The significance of young age (≤40 years) in the metastatic profile and prognosis of breast cancer was investigated. The transciptome expression data were acquired from The Cancer Genome Atlas (TCGA) database. And the differentially expressed genes (DEGs) and primarily enriched function pathways were identified by comparing between young and non-young breast cancer samples, and tumor immune infiltrating cell types in the tumor microenvironment were compared. Results: A total of 281,829 female breast cancer patients were included in SEER: 18,331 young (6.5%) and 263,498 non-young (93.5%) women. The metastatic rates of bone, liver and distant lymph nodes (DLNs) in the young cohort were significantly higher than those in the non-young cohort. The most frequent two-site metastatic combination was bone and liver (0.61%) in the young cohort, whereas it was bone and lung (0.32%) in the non-young cohort. Breast cancer-specific survival (BCSS) was significantly shortened among those in the young cohort compared with those in the non-young cohort (p < 0.001). Young age was associated with significantly shorter BCSS only among patients with HR+/HER2- tumors (p < 0.001). The enriched biological pathways based on DEGs between two cohorts were related to the regulation of immune response and several metabolic processes. M2 macrophages were significantly abundant in non-young breast cancer than young breast cancer. Conclusion: Young and non-young breast cancer patients present with different metastatic patterns. Young age is a negative prognostic factor, particularly for HR+/HER2- breast cancer. The differences in metastatic patterns between young and non-young cohorts should be taken into account in the clinical management of metastatic breast cancer. The young breast cancer patients may gain better response to immunotherapy due to immune activated TME than non-young breast cancer.

The Clinicopathological Profile of Breast Cancer in Young Women from a Tertiary Care Center

Abstract Background Increasing number of young breast cancer patients are seen in India and many of these young breast cancer patients are considered to have more aggressive disease biology. Aim The aim of this article was to study the clinicopathological profile of breast cancer patients in the young and older patients to understand the difference between these two groups. Methods This was a retrospective study conducted on 421 breast cancer patients. Results Total of 421 breast cancer patients were studied, out of which 158 patients were less than or equal to 40 years age group and 263 patients were in more than or equal to 50 years age group. Commonest T stage on presentation was T2, which was seen 56.32% of young breast cancer patients and in 64.64% of older patients. Higher nodal spread was seen in younger patients when compared with older patients (p-value = 0.00001). Older group patients had significant decline from anatomical to pathological prognostic stage group compared with younger group (29 vs. 13.29%; p-value = 0.00001). Grade 3 tumors were seen in 58.23% of younger patients and 22.05% of older patients (p-value = 0.00001). Triple-negative breast cancer was seen more commonly in younger group compared with older group (p-value = 0.0088). Conclusions Significant number of breast cancer patients present in younger age group in India. Younger breast cancer patients tend to have higher grade tumors and triple-negative breast cancer is common in younger age groups. Pathological prognostic stage grouping appears clinically more relevant than anatomical stage groups.

Fertility Counseling in BRCA1/2-Mutated Women with Breast Cancer and Healthy Individuals.

Breast cancer is the most commonly diagnosed cancer worldwide and the fifth leading cause of cancer death. In 2020, there were 2.3 million new cases, and 685,000 women died from it. Breast cancer among young women under 40 years of age accounts for 5% to 10% of all cases of this cancer. The greater availability of multi-gene sequence analysis by next-generation sequencing has improved diagnosis and, consequently, the possibility of using appropriate therapeutic approaches in BRCA1/2 gene mutation carriers. Treatment of young breast cancer patients affects their reproductive potential by reducing ovarian reserve. It can lead to reversible or permanent premature menopause, decreased libido, and other symptoms of sex hormone deficiency. This requires that, in addition to oncological treatment, patients are offered genetic counseling, oncofertility, psychological assistance, and sexological counseling. Given the number of BRCA1/2 gene mutation carriers among young breast cancer patients, but also thanks to growing public awareness, among their healthy family members planning offspring, the possibility of benefiting from preimplantation testing and performing cancer-risk-reduction procedures: RRM (risk-reducing mastectomy) and RRSO (risk-reducing salpingo-oophorectomy) significantly increase the chance of a genetically burdened person living a healthy life and giving birth to a child not burdened by the parent’s germline mutation. The goal of this paper is to show methods and examples of fertility counselling for BRCA1/2 gene mutation carriers, including both patients already affected by cancer and healthy individuals.

Evaluation of the Long-Term Survival in Non-Metastatic Young Breast Cancer Patients in South of Iran

Evaluation of the Long-Term Survival in Non-Metastatic Young Breast Cancer Patients in South of Iran

Prognostic factors for relapse in young breast cancer patients

Objective. Breast cancer is the leading cause of cancer mortality in women. Most deaths from breast cancer are due to recurrences or metastatic disease. The purpose of this study is to determine the impact of age in treatment strategy correlated with clinicopathological features. Methodology: In this retrospective study, 60 female patients with histologically-confirmed primary breast cancer were included. The women were treated in the Oncofort Hospital Bucharest, Romania between 2018 and 2020. The estrogen receptor (ER), progesterone receptor (PR) and HER2 status were determined using immunohistochemistry. Results. The mean age was 34.14 years (range = 24 – 40 years). Invasive ductal carcinoma of no specific type was seen in 84.1% of patients. The rates of grade I, II and III carcinomas were 6.7%, 28,3% and 65%, respectively. Among all patients, 33.3% had estrogen receptor, progesterone receptor positive tumors and 66.66% had estrogen receptor, progesterone receptor negative tumors. The proportion of patients overexpressing oncoprotein HER2 was 13.3%. Conclusion. Prognostic value of proliferation index (Ki-67) and hormonal receptors, may vary depending on age.

O-197 Predicting individualised risk of developing amenorrhoea in young breast cancer patients: an international multi-cohort study

Abstract Study question What is the likelihood of developing amenorrhoea after breast cancer treatment in young women with early breast cancer? Summary answer We developed risk prediction model for a web-based tool to provide an individualized risk of developing amenorrhoea of young breast cancer patients at diagnosis. What is known already Young breast cancer survivors have an increased risk of developing premature ovarian insufficiency as a long-term adverse effect of chemotherapy. The potential for developing amenorrhoea is a high priority for these young patients, with some choosing less optimal cancer treatments to minimise the impact on fertility and/or unnecessarily taking on the physical and financial burden of fertility preservation. A key component in good-quality decision-making is understanding the likelihood of outcomes. Yet, current tools to predict individualised ovarian function after breast cancer treatments are imprecise with minimal applicability for clinical practice. Study design, size, duration The FoRECAsT (Fertility after Cancer Predictor) study is a multi-institutional study of 5-year survivors of breast cancer. A literature review addressing the impact of chemotherapy regimens for breast cancer on developing amenorrhoea was conducted. Authors of identified articles and known data registries were contacted and invited to contribute their data to the FoRECAsT database. The FoRECAsT database contains 7473 individuals sourced from Australia, UK, USA, Hong Kong, France, Denmark, Italy, Belgium and International Trial Groups. Participants/materials, setting, methods FoRECAsT cohort includes premenopausal women diagnosed with primary breast cancer, reported history of two or more predictors of developing amenorrhoea and menstrual history information after chemotherapy. Patients with bilateral salpingo-oophorectomy were excluded. Primary outcomes were likelihood of developing amenorrhea at 12 and 24 months. Cross imputation was used to manage missing values. Logistic regression was used to develop risk prediction models and prediction performance was evaluated internally using area under the receiver operating curve (AUC). Main results and the role of chance Out of 7473 individual records from FoRECAsT database, 2833 participants (37.91%) reported menstrual history information at 12 months and 2118 participants (28.34%) reported menstrual history information at 24 months and, thus were included in the analysis. In multivariate logistic regression analyses, common predictors for amenorrhea at 12 and 24 months were older age at diagnosis, lower body mass index, chemotherapy regimens, endocrine therapy and pre-treatment follicle stimulating hormone. In addition, history of smoking and alcohol consumption were also predictors for developing amenorrhea at 12-months. Receiver–operator characteristic analysis produced an estimated AUC of 0.88, sensitivity of 95.75% and specificity of 58.52% for amenorrhoea at 12 months and AUC of 0.92, sensitivity of 94.09% and specificity of 53.58% for amenorrhoea at 24 months. Internal validation with 1000 bootstrap resampling showed good discrimination for both models, C-index of 0·88 (95% CI 0·84–0·91) for amenorrhoea at 12 month and C-index of 0·93 (95% CI 0.90 − 0.94) amenorrhoea at 24 months. Based on these models, a web-based calculator that predicts individualised ovarian function is under development for implementing in clinical practice worldwide. Limitations, reasons for caution The limitations including reliance on self-reported menstrual history, heterogeneity in collecting data in different countries could result in bias and insufficiency. These models require external validation. However, excellent prediction performance of the models and good precision in the estimate of accuracy in internal validation provides reassurance. Wider implications of the findings The model and the associated web application could help clinical discussions and decision-making regarding fertility preservation before chemotherapy when appropriate and to optimise adjuvant endocrine therapy in young women with early breast cancer. Additionally, this tool could be adapted to newer breast cancer treatments and for other cancer treatments. Trial registration number N/A

P-481 Characterization of the gene expression profile of breast cancer tumours in patients undergoing ovarian stimulation for fertility preservation purposes

Abstract Study question Could controlled ovarian stimulation (COS) protocols with letrozole supplementation induce changes in the molecular footprints of estrogen receptor-positive (ER+) breast cancer (BC) women? Summary answer Ovarian stimulation with letrozole and gonadotropins does not change the gene expression profile of estrogen receptor-positive (ER+) breast malignant tumours as compared to non-stimulated patients. What is known already Fertility preservation (FP) strategies in ER+ BC patients involve modifications of the classical COS protocols to minimise the impact of estrogen levels during ovarian stimulation. The most common approaches are using the aromatase inhibitor letrozole to block the conversion of testosterone into estradiol in the granulosa cells or the use of tamoxifen to block the ER in the breast tissue. Although retrospective studies suggest that these strategies will have no impact on patient’s survival and disease progression, little is known regarding the effect of the ovarian stimulation on the genomic fingerprints of the exposed cancerous tissue. Study design, size, duration Retrospective, non-randomized, comparative study. Gene expression profiles were compared in biopsies at diagnosis and during excision surgery in two groups of ER+ BC patients: Patients undergoing COS for FP before surgery (COS group, n = 10) and patients not undergoing any type of COS (Control group, n = 11). The former received letrozole (5mg/day) supplements during COS. The latter included 7 patients not doing FP and 4 undergoing ovarian cortex cryopreservation. Patients were recruited between 2009 and 2021. Participants/materials, setting, methods Single 5-µm sections of formalin-fixed, paraffin-embedded (FFPE) needle core biopsy (NCB) and breast surgery (BS) tumour samples were obtained prior to starting gonadotoxic therapies. Differential gene expression and gene set analysis (GSA) was performed in tumour samples before (NCB-sample) and after COS (BS-sample). Simultaneous, quantitative detection of 2549 genes associated with tumour biology was performed with the HTG EdgeSeq Oncology Biomarker Panel. Tumour cell proliferation was also assessed by Ki67 staining. Main results and the role of chance Patients were younger in the COS group (COS: 30.2±3.4 vs Control: 34.5±2.3; p = 0.004). None of the patients experienced any relapse during the observation period. The length of COS was 11.5±3.5 days and 10.6±6.8 MII oocytes were vitrified. The exploratory analysis using principal component analysis revealed no relationships between the two BC biopsy samples and gene expression levels in the experimental groups. The differential expression analysis just revealed 6 genes significantly over-expressed after ovarian stimulation (DUSP1, FOS, EGFR1, NR4A1, JUN and CYR61). From these, DUSP1, FOS, and NR4A1 were also significantly upregulated in the unstimulated group. The GSA showed the cytochrome P450 pathway was significantly enriched after COS. No pathways related to cell proliferation were differentially expressed between groups. However, in unstimulated patients, 6 KEGG pathways were upregulated, with the cytokine-cytokine receptor interaction and the Jak-STAT signalling pathway being the most enriched. Ki67 immunostaining showed no differences in cell proliferation after COS (22.8±7.2 vs 24.0±6.9, p = 0.723). The rate of cell proliferation also remained constant in unstimulated patients (22.9±8.4 vs 25.1±8.1, p = 0.560). Limitations, reasons for caution The main limitations of the present study are the retrospective design and the associated risk of bias, although the population is very homogeneous when it comes to clinical characteristics; and the fact that molecular footprints are only interim markers of survival/response to the treatment. Wider implications of the findings The present study provides molecular evidence supporting the safety of COS using letrozole for oocyte vitrification in young BC patients undergoing ovarian stimulation. This information is crucial to support patient guidance during discussions about fertility preservation. Trial registration number Not applicable

ASO Author Reflections: Simplified Nomogram Predictive of Survival for Young Breast Cancer Patients.

ASO Author Reflections: Simplified Nomogram Predictive of Survival for Young Breast Cancer Patients.

Abstract 5772: Differences in clinical actionability by comparing mutational landscape of young and old breast cancer patients

Abstract Background: Early-onset breast cancer (BC) is associated with poor prognosis, which is also characterized by high recurrence risk, distant metastases and advanced stages at the time of diagnosis. While germline mutations in BRCA1/2 are known to underlie a subset of early-onset BC cases, the clinical and genetic characteristics in other young BC patients remain to be explored. Method: We profiled primary lesions from 440 Chinese female BC patients by using a 425-cancer-gene panel. The population was sub-divided into young (≤40 years old) and old (&amp;gt;40 years old) BC patients according to ages at diagnosis. Young and old BC patients were compared for their associations with genomic aberrations, with focus on existing BC targetable alterations, including those in the ERBB2 gene and PI3K and homologous recombination repair (HRR) pathways. Results: 137 (31.1%) patients presented with BC at a young age (median age=35 [18-40]) and 303 (68.9%) with BC diagnosed at an older age (median age=53 [41-82]) in our study cohort. TP53 (young, 61.3%; old, 67%), PIK3CA (33.6% and 41.3%), and GATA3 (9.5% and 8.3%) were among the top frequently altered genes in both subgroups. A total of 70 patients carried pathogenic germline mutations. Of these, 57.3% were alterations in the HRR pathway genes, including BRCA1/2, WRN, BLM, and PALB2, etc, with comparable frequencies in young and old patients. Germline BRCA1/2 mutations were detected in nine (6.6%) and 23 (7.6%) of the young and old patients, respectively. Somatic BRCA1/2 mutational frequencies were also comparable between young (8.8%) and old (9.9%) patients. Overall, somatic alterations in HRR pathway genes were detected in 32.1% young and 40.6% old BC patients. While similar frequencies of ERBB2 amplification (14.6% vs. 18.2%; P= 0.41) were detected in young and old BC patients, older patients carried more ERBB2 mutations (1.5% vs. 7.3%, P= 0.01). Interestingly, the highest rate of ERBB2 amplification was observed in the 20-30 years age group. Alterations in NF1 (10.6% vs. 3.6%, P=0.02) and PKHD1 (6.9% vs. 2.2%, P=0.04) were more frequent in older patients. Alterations in the PI3K pathway genes were more enriched in the older BC patients with overall mutational frequencies of 55.5% and 68.6% (P=0.01) in young and old subgroups, respectively. Finally, we observed an age-dependent increase in tumor mutational burden. Conclusion: BC in young and old patients exhibited different genomic characteristics that could be taken into consideration for treatment recommendations. Citation Format: Jiaqi Liu, Ziqi Jia, Gang Liu, Xiang Wang, Qi Meng, Sha Wang, Yang Shao. Differences in clinical actionability by comparing mutational landscape of young and old breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5772.

Abstract CT231: Digital phenotyping in young breast cancer patients treated with neoadjuvant chemotherapy

Abstract Introduction: Breast cancer (BC) has particular characteristics in young women, with diagnosis at more advanced stages, a poorer prognosis and highly aggressive tumors. In NeoFit, we will use an activity tracker to identify and describe various digital profiles (heart rate, physical activity, and sleep patterns) in women below the age of 45 years on neoadjuvant chemotherapy for BC.Methods/Analysis: NeoFit is a prospective, national, multicenter, single-arm open-label study. It will include 300 women below the age of 45 years treated with neoadjuvant chemotherapy for BC. Participants will be asked to wear a Withing Steel HR activity tracker round the clock for 12 months. The principal assessments will be performed at baseline, at the end of neoadjuvant chemotherapy and at 12 months. We will evaluate clinical parameters, such as toxicity and the efficacy of chemotherapy, together with quality of life, fatigue, and parameters relating to lifestyle and physical activity. The women will complete REDCap form questionnaires via a secure internet link.Discussion: In this study, the use of an activity tracker will enable us to visualize changes in the lifestyle of young women on neoadjuvant chemotherapy for BC, over the course of a one-year period. This exploratory study will provide crucial insight into the digital phenotypes of young BC patients on neoadjuvant chemotherapy and the relationship between these phenotypes and the toxicity and efficacy of treatment. This trial will pave the way for interventional studies involving sleep and physical activity interventions. Citation Format: Lidia Delrieu, Anne-Sophie Hamy, Florence Coussy, Amyn Kassara, Bernard Asselain, Juliana Antero, Paul De Villèle, Elise Dumas, Nicolas Forstmann, Julien Guérin, Judicael Hotton, Christelle Jouannaud, Maud Milder, Armand Leopold, Adrien Sedeaud, Pauline Soibinet, Jean-François Toussaint, Vincent Vercamer, Enora Laas, Fabien Reyal. Digital phenotyping in young breast cancer patients treated with neoadjuvant chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT231.

The interplay between XPG-Asp1104His polymorphism and reproductive risk factors elevates risk of breast cancer in Tanzanian women: A multiple interaction analysis.

Reproductive history and genetics are well-known risk factors of breast cancer (BC). Little is known about how these factors interact to effect BC. This study investigated the association of ten polymorphisms in DNA repair genes with BC susceptibility in the Tanzanian samples and further analyzed the association between reproductive risk factors and disease risk METHODS: A hospital-based case-control study in 263 histopathological confirmed BC patients and 250 age-matched cancer-free controls was carried out. Allelic, genotypic, and haplotype association analyses were executed. Also, multifactor dimensionality reduction (MDR), and interaction dendrogram approaches were performed. The frequency of genotypic and allelic variants of XRCC1-Arg399Gln (rs25487), XRCC2-Arg188His (rs3218536), XRCC3-Thr241Met (rs861539), XPG-Asp1104His (rs17655), and MSH2-Gly322Asp (rs4987188) were significantly different between the groups (p < 0.05). Moreover, XRCC1-Arg399Gln (rs25487), XRCC3-Thr241Met (rs861539), and XPG-Asp1104His (rs17655) were associated with the increased risk of BC in co-dominant, dominant, recessive, and additive genetic-inheritance models (p < 0.05). XRCC1-Arg/Gln genotype indicated a 3.1-fold increased risk of BC in pre-menopausal patients (p=0.001) while XPG-His/His genotype showed a 1.2-fold increased risk in younger BC patients (<40 years) (p=0.028). Asp/His+His/His genotypes indicated a 1.3-fold increased risk of BC in PR+ patients and a 1.1-fold decreased risk of BC in luminal-A patients (p=0.014, p=0.020, respectively). MDR analysis revealed a positive interaction between BC and the XPG-Asp1104His (rs17655) together with family history of cancer in the first-degree relatives. Dendrogram analysis indicated that the XPG-Asp1104His (rs17655) and family history of cancer in first-degree relatives were significantly synergistic and might be associated with an elevated risk of BC in Tanzania. The XPG-Asp1104His (rs17655) might exert both independent and interactive effects on BC development in the Tanzanian women.