Percent Of Breast Cancer Patients Research Articles

‘I presumed the pain would eventually get better by itself’; challenges with access to rehabilitation for upper limb dysfunction after breast cancer treatment - Descriptive and qualitative findings from a cross-sectional survey

PurposeSixty percent of breast cancer patients develop persistent upper limb pain and dysfunction, but only limited knowledge exists about how these symptoms relate to rehabilitation access. MethodsA postal survey was sent to patients treated at a London University Teaching Hospital (2018–2020). Data were collected on pain (Pain Detect), shoulder function (Disability of Shoulder Arm and Hand (DASH)), quality-of-life (QoL) (EQ-5D-5L), and clinical characteristics, including treatment and access to rehabilitation. The free-text section invited patients’ comments on upper limb symptoms and management strategies, which were analysed thematically. Quantitative data were analysed descriptively, and the medians were examined with Mann-Whitley U-Tests or Kruskal-Wallis Test. ResultsOf 511 patients surveyed, 162 (32 %) questionnaires were returned and analysed. Respondents’ mean age was 62 years (SD 11.3). The majority had Sentinel Node Biopsy 71 % (116/162) and mastectomy 61 % (99/162). 73 % (119/162) reported pain. Mean (SD) Pain Detect and DASH Score were respectively 11.07 (7) and 21.7 (21.5), with 51 % recording significant shoulder dysfunction, and only 28 % reporting access to rehabilitation. Individuals with neuropathic pain had significantly higher median (range) DASH score 60.8 (35.8, 75.0) p = 0.000. Median DASH score for sedentary individuals was significantly higher 22.9 (7.9, 31.8) p = 0.0009.Free-text analysis revealed persistent, progressive symptoms, mixed attitudes towards exercise and variations in access to rehabilitation and support. ConclusionTwo years following surgery many patients reported significant upper limb symptoms which adversely impact on QoL. However, approximately two thirds did not access potentially beneficial rehabilitation treatments. There is a need to improve pathways of care.

Impact of Breast Cancer Treatments on the Occupation of Sleep Among Breast Cancer Survivors: A Mixed-Methods Study

Abstract Date Presented 03/22/24 Eighty percent of breast cancer patients report sleep disturbances while undergoing treatment. The purpose of this mixed-methods research was to understand the impact of various breast cancer treatments on the occupation of sleep among breast cancer survivors. Primary Author and Speaker: Manisha Sheth Additional Authors and Speakers: Thea Aliman, Anne Camille Almazora, Kayla Francisco, Chris Ghadimi, Nicole Tafolla

The prevalence of mild cognitive impairment in breast cancer patients receiving chemotherapy according to the criteria of the National Institute on Aging-Alzheimer's Association (NIA-AA).

Breast cancer patients receiving chemotherapy can develop cognitive impairment. There is no gold standard for defining cognitive impairment. We applied the National Institute on Aging-Alzheimer's Association (NIA-AA) criteria for mild cognitive impairment (MCI) to determine its prevalence in breast cancer patients receiving adjuvant chemotherapy and examine differences between patients with and without MCI. We used pre-existing cognitive data on 5 neuropsychological test outcomes (verbal memory, processing speed, executive functioning, and verbal fluency) gathered from 240 breast cancer patients who received adjuvant conventional (n = 154) or high-dose chemotherapy (n = 86). Assessments occurred 6 or 12months post-chemotherapy and results were compared with data from 66 women without cancer. MCI was defined by the following: (i) presence of concern regarding a change in cognition, (ii) impairment in one or more cognitive tests (1.5 standard deviation below a normative mean), (iii) preservation of independence in functional abilities, and (iv) the absence of dementia. Twenty percent (n = 49) of breast cancer patients who received chemotherapy (conventional therapy n = 29 (12%), high-dose therapy = 20 (8.3%)) met the criteria for MCI, compared with 7.6% (n = 5) of controls. Prevalence was significantly different between patients and controls (P = 0.020, and corrected for IQ P < 0.001). Patients with MCI had significant lower education levels (P < 0.002) and premorbid IQ (P = 0.001) compared with patients without MCI. Twenty percent of breast cancer patients treated with chemotherapy met NIA-AA criteria for MCI, compared with 7.6% of the controls. These criteria, which include formal test performance as well as a person's symptoms and functional status, can be useful in clinical practice and scientific research.

CTIM-02. PHASE 2 TRIAL OF PEMBROLIZUMAB FOR PATIENTS WITH BRAIN METASTASES OF DIVERSE HISTOLOGIES

Abstract BACKGROUND Patients with brain metastases have limited treatment options.The PD-L1/PD-1 pathway is an immune suppressive mechanism in brain metastases. METHODS This was a single-arm phase 2 clinical trial evaluating the intracranial efficacy of pembrolizumab, a PD-1 inhibitor, in patients with brain metastases. The target accrual was 58 patients to achieve at least 52 evaluable patients. The primary endpoint was intracranial benefit (complete response, partial response, or stable disease by modified RANO criteria). The study design compared a null intracranial benefit rate of 10% against an alternative of 24%. If at least 8 patients among 52 had intracranial benefit, the primary efficacy endpoint would be met and pembrolizumab would be considered worthy of further study (type-I error of 10%, power of 89%). RESULTS In 57 evaluable patients, median age was 53 (range 28-80). Tumor histologies included breast (n = 35), NSCLC (n = 7), melanoma (n = 2), small-cell lung cancer (n = 2), sarcoma (n = 2), and other (n = 9). For patients with breast cancer, 16 patients had HER-2 positive, 17 had hormone-receptor positive and 11 patients had triple-negative disease. The study met its primary endpoint and achieved an intracranial benefit rate of 42.1% (90% confidence interval [CI]: 31-54%). Thirty-seven percent of breast cancer patients (90% CI: 24–52%) and 43% of NSCLC patients (90% CI: 13–77%) had intracranial benefit. All four breast cancer subtypes derived efficacy from pembrolizumab. Seven patients, who had either breast cancer, melanoma or sarcoma, had overall survival &amp;gt;2 years. The extracranial benefit rate in patients with evaluable extracranial disease based on RECIST 1.1 criteria was 45% (90% CI: 31-59%). Median overall survival was 8.0 months (90% CI: 5.5-8.7 months). Grade 4 toxicities at least possibly related to treatment were observed in 2 patients: cerebral edema. CONCLUSIONS Our study of pembrolizumab met overall primary endpoint for intracranial benefit in patients with brain metastases across diverse histologies.

The Impact of Chemotherapy on Female Breast Cancer Survivors &amp; the Occupation of Sleep: A Mixed-Methods Study

Abstract Date Presented 04/22/2023 Eighty percent of breast cancer patients report sleep disturbances while undergoing treatment. The purpose of this mixed-methods research presentation is to understand the impact of chemotherapy on the occupation of sleep among breast cancer survivors. Primary Author and Speaker: Manisha Sheth Additional Authors and Speakers: Nicole Pisano, Antonia Hillman, Tiffany De Guzman, Monica Ribeiro, Rileigh Rodriguez

P11.61.B Capecitabine treatment of CNS metastases from breast cancer: intracranial response and survival

Abstract Background 20-30% of breast cancer patients develop brain metastases (BM) and 5% leptomeningeal metastases (LM). Incidence of BM and/or LM is dependent on breast cancer subtype. Treatment of BM consists of local treatment (resection and/or radiotherapy) and if possible systemic therapy. LM can be treated with radiotherapy of the symptomatic location of the nervous system and/or systemic therapy. Capecitabin is effective for both systemic metastases and BM of HER2-positive breast cancer. The effect of capecitabine in the non-HER2-positive breast cancers and in the LM group is largely unknown. The goal of this study is to determine the intracranial response of capecitabine and survival in HM and/or LM of the various breast cancer subtypes. Material and Methods breast cancer patients with HM and/or LM treated with capecitabine were selected retrospectively from a breast cancer patient cohort treated at the Netherlands Cancer Institute - Antoni van Leeuwenhoek between 2005 and 2020. Follow-up MRI scans of the brains were performed in all patients. The primary endpoints were intracranial response, intracranial progression-free survival (PFS) and overall survival (OS). Subgroup analyses for breast cancer subtypes and BM and LM patient groups were done. Results 93 of 381 patients treated for CNS metastases of breast cancer fulfilled the inclusion criteria. Sixty-one patients (66%) had HM only, 13 (14%) had LM only and 19 patients (20%) had both HM and LM. Forty-six percent of patients had HER2-positive breast cancer, 26% had hormone receptor-positive breast cancer and 28% of patients had a triple negative subtype. After three months of capecitabine treatment intracranial response was 53%. Median OS in the patient group with intracranial response was 16.5 months versus 4.5 months in the non-response group. The hazard ratio (HR) for the median OS, corrected for radiotherapy and concurrently administered, other systemic therapy was 0.33 (95% CI: 0.17-0.67). Median intracranial PFS was 7.3 months in the response group versus 1.4 months in the non-response group (p&amp;lt;0.001).The corrected HR for median intracranial PFS 0.13 (95% CI 0.06-0.27). The HER2-positive subtype group showed the longest median OS (22 months) as compared to the other subtypes (OS in hormone-receptor positive and triple negative subtype both 12 months) Conclusion Fifty-three percent of breast cancer patients with HM and/or LM treated with capecitabine demonstrate an intracranial response after three months of treatment. HER2+ breast cancer patients with HM and/or LM have a longer survival than patients with hormone receptor-positive or triple negative breast cancer subtypes.

Overlap of high-risk individuals predicted by family history, and genetic and non-genetic breast cancer risk prediction models: implications for risk stratification

BackgroundFamily history, and genetic and non-genetic risk factors can stratify women according to their individual risk of developing breast cancer. The extent of overlap between these risk predictors is not clear.MethodsIn this case-only analysis involving 7600 Asian breast cancer patients diagnosed between age 30 and 75 years, we examined identification of high-risk patients based on positive family history, the Gail model 5-year absolute risk [5yAR] above 1.3%, breast cancer predisposition genes (protein-truncating variants [PTV] in ATM, BRCA1, BRCA2, CHEK2, PALB2, BARD1, RAD51C, RAD51D, or TP53), and polygenic risk score (PRS) 5yAR above 1.3%.ResultsCorrelation between 5yAR (at age of diagnosis) predicted by PRS and the Gail model was low (r=0.27). Fifty-three percent of breast cancer patients (n=4041) were considered high risk by one or more classification criteria. Positive family history, PTV carriership, PRS, or the Gail model identified 1247 (16%), 385 (5%), 2774 (36%), and 1592 (21%) patients who were considered at high risk, respectively. In a subset of 3227 women aged below 50 years, the four models studied identified 470 (15%), 213 (7%), 769 (24%), and 325 (10%) unique patients who were considered at high risk, respectively. For younger women, PRS and PTVs together identified 745 (59% of 1276) high-risk individuals who were not identified by the Gail model or family history.ConclusionsFamily history and genetic and non-genetic risk stratification tools have the potential to complement one another to identify women at high risk.

Abstract PD4-07: Targeting latent residual HER2+ breast cancer brain metastatic cells

Abstract Approximately fifty percent of breast cancer patients with brain metastasis are positive for human epidermal growth factor receptor 2 (HER2+). Systemically effective cytotoxic drugs, and HER2 targeted therapies are ineffective on brain metastases. Current understanding of HER2 brain metastatic disease is limited as biopsying brain metastatic lesions and detecting micro-metastasis from asymptomatic patients with residual disease remains a challenge. Therefore, to isolate disseminated tumor cells that stay latent in the brain, while retaining their metastasis-initiating capabilities, we performed a phenotypic screen in mouse employing human breast cancer cell lines. Using this approach, we isolated isogenic latent residual cells (Lat) and metachronous brain metastatic outbreaks (M-BM). Phenotypically stable latent cells display stem cell-like characteristics, downregulate immune activating sensors and survive in equilibrium with innate immune surveillance, while M-BM escape and metastasize. Brain-tropic Lat and M-BM cells are resistant to HER2 targeted therapies - lapatinib, neratinib and tucatinib. Transcriptomic analysis identified AXL, a receptor tyrosine kinase from the TAM receptor family, to be highly enriched in brain-tropic Lat and M-BM. Moreover, AXL is over expressed in metachronous brain metastasis samples compared to matched primary tumors from HER2+ breast cancer patients. AXL activation and overexpression has been associated with chemoresitance mechanisms, dormancy maintenance, invasion, tumor angiogenesis, immune regulation, metastasis and poor prognosis in cancer patients. Therefore, we hypothesized AXL promotes residual/latent breast cancer survival and brain metastatic relapse in HER2+ breast cancer. shRNA depletion of AXL in Lat and M-BM resulted in reduced oncosphere formation, an assay used to measure tumor or metastasis initiating capacity. Brain metastatic incidence was significantly attenuated in mice bearing AXL depleted M-BM compared to their controls. Bemcentinib, an AXL inhibitor currently in clinical trials for non-small cell lung cancer, triple negative breast cancer, pancreatic cancer and melanoma, alone or in combination with lapatinib, neratinib or tucatinib, reduced oncosphere formation in HER2 therapy resistant Lat and M-BM cells. Ongoing experiments are designed to assess the impact of bemcentinib on brain metastasis in vivo and to mechanistically define how AXL promotes survival of latent residual and brain metastatic HER2+ breast cancer cells. Citation Format: Mauricio Marquez-Palencia, Srinivas Malladi. Targeting latent residual HER2+ breast cancer brain metastatic cells [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD4-07.

Abstract P3-12-30: Impact of medicaid expansion on breast cancer stage at diagnosis: Exploring the mechanisms at play

Abstract Background: Prior studies have shown significant improvements in earlier breast cancer stage at diagnosis following Medicaid expansion. However, the mechanisms behind this finding have not been explored. The timing of Medicaid enrollment among cancer patients has been shown to be associated with cancer stage at diagnosis, with significantly higher percentages of women with late-stage breast cancer enrolling in Medicaid shortly before or after cancer diagnosis (hereafter referred to as the Peri-dx group), compared to those continuously enrolled in Medicaid at least 4 months prior to cancer diagnosis (Pre-dx group). Hence, we conducted a causal mediation study based on a logistic regression model to determine whether the observed improvements in breast cancer stage at diagnosis from Pre- to Post-expansion can be attributed to a decreasing percentage of women in the Peri-dx group, and a corresponding increase in the Pre-dx group. Methods: We used the linked Ohio Cancer Incidence Surveillance System and Medicaid data, and identified women in Ohio age younger than 66 years, diagnosed with incident invasive breast cancer during the period May 2011-December 2017, and enrolled in Medicaid at the time of cancer diagnosis (n=5,880, excluding those with unstaged/unknown-stage cancer). We defined the years 2011-2013 and 2014-2017 as the Pre- and Post-expansion periods, and Month 0 as the month of cancer diagnosis. We identified women enrolled in Medicaid in the -3 to +3-month window in the Peri-dx group, and those continuously enrolled in Medicaid at least 4 months prior to cancer diagnosis in the Pre-dx group. We conducted a causal mediation analysis to estimate the direct, indirect, and total effect of Medicaid expansion on being diagnosed with local-stage disease versus late- (regional- and distant-) stage disease, with the mediator variable being a patient in the Pre-dx group (versus in the Peri-dx group), adjusting for patient- and area-level covariates. Results: The median age of our study population was 53 years; 75.0% were non-Hispanic White. The percent of breast cancer patients diagnosed with late-stage disease was 43.5% and 53.4% in the Pre- and Peri-dx groups, respectively. We observed a clear shift in the distribution of breast cancer patients from the Peri- to the Pre-dx group over time, with an increase in the percentage of women in the Pre-dx group (from 55.2% to 74.2% from the Pre- to Post-Expansion period), and a corresponding decrease in the Peri-dx group (from 44.8% to 25.8%). Findings from our causal mediation analysis, based on a risk difference scale, showed that while the direct effect of Medicaid expansion on being diagnosed with local-stage disease was not significant (coefficient: 0.037, (p=0.297)), both the indirect and total effects were highly significant (0.049 (p &amp;lt; 0.001), and 0.086 (p=0.015)). Conclusion: Our results indicate that the improvements in breast cancer stage at diagnosis from Pre- to Post-Expansion can be attributed to a decrease in the Peri-dx group, and a corresponding increase in the Pre-dx group, which improves access to screening, increases the likelihood of breast cancer patients being engaged with Medicaid providers, and reduces delays in enrollment logistics prior to treatment initiation. Citation Format: Siran M. Koroukian, Weichuan Dong, Jeffrey Albert, Uriel Kim, Johnie Rose, Cynthia Owusu, Kristine Zanotti, Gregory Cooper, Jennifer Tsui. Impact of medicaid expansion on breast cancer stage at diagnosis: Exploring the mechanisms at play [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-12-30.

Awareness, perceptions, and usage of whole person integrative oncology practices: Similarities and differences between breast cancer patients and oncologists.

e24123 Background: The use of Complementary and Lifestyle (C&amp;L) approaches in conjunction with medical treatments is known as Integrative Oncology. While Integrative Oncology practices have been steadily rising in the past few decades, there are still awareness and education gaps that medical professionals can help address for their patients. Methods: Survey-based data collection and analysis was used to assess awareness, perceptions, and usage of Integrative Oncology. Patients were randomly sampled among breast cancer patients diagnosed within 2 years and included all stages (0-IV) and all US regions (NE, South, Midwest, West). Physicians were sampled from a panel of community and academic practices across the US, with the requirement they treat at least 10 breast cancer patients in a typical 3-month period and have been in practice for at least 6 years since residency or fellowship. Results: Survey invitations were sent to 1,901 patients and 2,758 Oncologists; 164 breast cancer patients and 115 Oncologists completed the surveys. Approximately two-thirds of Oncologists and patients agree that C&amp;L approaches contribute to improved quality of life and well-being for patients (table row 1, 2). However, significantly more patients than Oncologists believe that Integrative Oncology also leads to better treatment outcome and survival (row 3). In addition, Oncologists are significantly more aware of C&amp;L practices than are patients (row 4). When asked what percent of breast cancer patients they discuss C&amp;L methods with, Oncologists report 55% average (CI: 50-60%). However, when asked how they became aware of C&amp;L, only 28% of patients (CI: 21-35%) mention their Oncologist/cancer care team or the institution where they were treated (not in table). Ideally, patients desire information about C&amp;L to come directly from Oncologists, but that is not the predominant model (row 5). Conclusions: Many breast cancer patients believe an Integrative approach will improve their treatment outcomes and prefer their providers to discuss this with them.[Table: see text]

Abstract P6-11-06: The association of health literacy with internet usage for breast cancer patient education

Abstract Introduction: As more breast cancer educational resources are transitioned from printed materials to online formats, it is important to identify the patients that are at risk for low health literacy and who still need access to printed materials. The purpose of this study is to evaluate breast cancer patient health literacy and internet access in the South Texas region and to establish how they prefer to learn about their condition and surgical options. Methods: A 15-item questionnaire was given to patients with newly diagnosed breast cancer at the University Texas Health San Antonio Mays Cancer Center including a validated 3-question health question health literacy assessment, defining patients with high (HHL) or low health literacy (LHL). Patients enrolled in the study were 21 years old or older and planning to undergo mastectomy or lumpectomy for ductal carcinoma in situ, stage I, II, III, or prophylaxis (n=112). Patients who had cancers other than breast cancer were not eligible to participate. Questionnaires were included in the analysis if they were greater than 90% completed. Relationships between demographics, and type of media use were assessed. Results: English was the preferred language for 79.5% of the patients followed by Spanish for 17.9%. Seventy nine percent of breast cancer patients had high health literacy while 21% had low healthy literacy. LHL was associated with high school level education (High school: 83%, College: 17%, p=0.001) and patients with LHL were less likely to access the Internet for healthcare information, (LHL: 28%, HHL 69%, p&amp;lt; 0.001). After adjusting for differences: language, education, age, and cancer stage, possession of a smartphone and access to Internet at home was not associated with Internet use for healthcare information. Regardless of level of education, patients preferred receiving information via printed materials (High school: 60.2%, College: 71%, p=0.581). Neither groups preferred using supplemental videos (High school: 79% and College: 89%, p=0.58). There was no correlation between the level of education and the number of resources patients used to gain knowledge about their breast cancer and reconstructive options (Spearman correlation = 0.111). Conclusion: The majority of South Texas breast cancer patients do have access to the internet but still prefer written materials over online resources. This preference was not driven by patients’ language, educational level, or access to the internet or a smartphone. However, patients that had low health literacy were less likely to use the internet for health related information. As more healthcare information is being digitized, access to printed materials and traditional methods of education should still be available to avoid disparities in health education delivery. Further study will be done to determine the reason for preference of written over online educational materials and the utility of implementing interventions such as courses to teach patients about utilization of online resources. Citation Format: Bao-Quynh Julian, Efstathios Karamanos, Kari Eugenia Smith, Maryam Elmi, Amita Rashmikant Shah. The association of health literacy with internet usage for breast cancer patient education [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 P6-11-06.

Mutation signature of patients with ER+ metastatic breast cancer who received endocrine therapy.

1057Background: Approximately eighty percent of breast cancer patients are estrogen receptor alpha (ER-α) positive. Although women initially respond well to endocrine therapies, resistance often em...

Abstract P3-05-13: The neo-epitope landscape of breast cancer: Implications for immunotherapy

Abstract Introduction: Immune checkpoint blockade is an effective immunotherapy for multiple cancers, including a subset of TNBCs. The clinical response to checkpoint blockade correlates with high tumor mutational burden. Cancer-induced mutations are predicted to generate new HLA-binding epitopes (neo-epitopes), which are potential targets of T cells. To determine the neo-epitope load in breast cancer, we developed a rapid bioinformatics pipeline and filtering strategy, EpitopeHunter, to identify and prioritize clinically relevant neo-epitopes from the landscape of somatic mutations. Here, we determined the specificity and frequency of neo-epitopes from the TCGA dataset of invasive breast cancers. Methods: We analyzed 842 tumor and normal breast cancer exome sequencing from the TCGA dataset. Subgroup analysis was performed based on the IHC status of ER, PR and HER2: (i) TNBC (n=98); (ii) ER and/or PR(+), Her2(-) (n=604); and (iii) ER and PR(+/-), Her-2(+) (n=140). Cancer specific mutations were called uniformly for the aligned tumor and normal pairs using VarScan2. For each annotated non-synonymous mutation, we generated all possible neo-epitopes (up to 11-mers) including the mutant amino acid. HLA typing of A, B and C MHC class I genes of each patient was determined using the POLYSOLVER algorithm. We selected high affinity binding epitopes using the IEDB prediction algorithm based on the known epitopes to identify likely binding of each neo-epitope within the suite of patient-specific HLA alleles (IEDB score &amp;lt; 500). We then filtered the epitopes based on tumor transcript abundance using RNAseq expression for 837/842 patients. An expression value of FPKM &amp;gt; 2 was used as a cut-off for the expressed neo-epitopes. Results: Total mutational burden was highest for TNBC (median=53, range: 2-1162); followed by ER and PR(+/-), Her-2(+) (median=40, range: 6-4983); and lowest for ER and/or PR (+), Her-2(-) (median=30, range: 0-5515). About 15% of the nonsynonymous mutations led to the generation of neo-epitopes. The neo-epitope load (high affinity neo-epitopes with IEDB score &amp;lt;500) is highly correlated with the mutational burden (R2= 0.8-0.9). Number of patients with at least one neo-epitope expressed in each category was: TNBC (n= 79/97, 81%); ER and/or PR(+), Her2(-) (n=478/600, 79%); and ER and PR(+/-), Her-2(+) (n=115/140, 82%). Overall, 672/837 patients have at least one predicted high affinity neo-epitope expressed, with an average of 14.7 (1-525) neo-epitopes expressed per patient. Conclusions: We have developed a rapid bioinformatics pipeline, EpitopeHunter, for the identification of neo-epitopes from tumor sequencing data. Eighty percent of breast cancer patients have at least one expressed neo-epitope, which may serve as candidates for targeted immunotherapy. Citation Format: Narang P, Chen M, Sharma AA, Anderson KS, Wilson Sayres MA. The neo-epitope landscape of breast cancer: Implications for immunotherapy [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 P3-05-13.

Abstract P3-05-18: The complex landscape of breast cancer immune evasion and its implications to personalized and combined immunotherapy

Abstract Cancer immunotherapy activates the patient's immune system to recognize and kill cancer cells. The efficacy of immunotherapy in human breast cancer (BRCA) is hindered by the poor understanding of the immune system's anti-tumor response and tumor evasive mechanisms, and the lack of optimized treatment regimens for each BRCA patient. There are 6 known evasion mechanisms (M) by which tumors can escape immune surveillance. M1: immunosuppression via interleukin 10 (IL-10) and tumor growth factor beta (TGF-β); M2: induction of tolerance by cytotoxic T-lymphocyte associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1) and its ligands (PD-L1/PD-L2), and interferon gamma (IFN-γ); M3: apoptosis resistance via the expression of anti-apoptotic molecules, namely baculoviral IAP repeat-containing protein 3 (BIRC3), TNF receptor associated factor 1 (TRAF1), and TNF alpha induced protein 3 (TNFAIP3); M4: counterattack via decoy death receptors; M5: impaired antigen presentation by decreasing beta 2 microglobulin (B2M) and human leukocyte antigens A and B expression (HLA-A and HLA-B); and M6: ignorance caused by the absence of a danger signal or an antigen. Yet, which mechanisms or combination of mechanisms BRCA tumors utilize is unknown. Moreover, the currently used biomarkers for the choice of immunotherapy are not ideal, as for example, not all PD-L1+ patients respond to anti-PD-L1 treatment, and certain PD-L1- patients respond. Thus, there is a need for more precise biomarkers. Using the sequential biclustering method on the RNA-sequenced data of BRCA from The Cancer Genome Atlas (TCGA), eighty-one percent of BRCA patients were grouped into 7 different clusters (CL) of immune evasion subtypes. We found that the majority of breast cancer tumors utilize multiple immune evasion mechanisms. Tumors may use from 1 up to 4 combinatorial mechanisms simultaneously. We also identified classifier genes that would help sort patients based on their evasion mechanisms, and guide the choice of immunotherapy. This is especially important since the immune evasion molecules may not be the ideal biomarkers for the best choice of immunotherapy. Moreover, we showed that triple negative breast cancer (TNBC) patients were significantly associated with CL2 (M5). Citation Format: Bou-Dargham MJ, Liu Y, Sang Q-XA, Zhang J. The complex landscape of breast cancer immune evasion and its implications to personalized and combined immunotherapy [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 P3-05-18.

Abstract PD6-01: Analysis of breast cancer in young women in the department of defense (DOD) database

Abstract Background: Women under the age of 40 account for approximately 7% percent of breast cancer patients. Breast tumors from young women are often ER-negative, occur in African-American patients, and have other indicators of high risk: yet, multivariate analyses demonstrated that young age is an independent predictor of poor outcome. Due to the unique nature of the patient population served by DOD, a disproportionate number of breast cancer cases in young women are seen. We compare the characteristics, treatment, and outcomes of young patients diagnosed with breast cancer with those of older patients. Methods: The databases of the Military Health System Repository and the DOD Central Registration were used to identify female breast cancer patients treated at DOD facilities between 1998 and 2007. Information on demographics, breast cancer stage at diagnosis, definitive surgical treatments, systemic treatment, recurrence rate and overall survival was analyzed by age groups at the time of diagnosis (less than 40 years old, 40 to 49 years, and 50 years or older) using X2 testing with significance defined as p&amp;lt; 0.05. Results: We identified 10,066 women who were diagnosed with invasive breast cancer at DOD facilities between 1998 and 2007, of which 11.3% (1139) were less than 40 years old at diagnosis. 53% of this young cohort were white, 25% were African-American and 8% were Hispanic (14% undisclosed). The percentage of breast cancer among African-American women in the young cohort was higher than in the older cohorts (19.3% in 40-49yo and 10.6% in ≥50yo). High-grade tumors were significantly more frequent in the younger cohort when compared to the older group (49.5% vs 34.7% and 25.2%, p&amp;lt;0.001). &amp;lt;40yo most commonly presented with Stage II disease (45.3%) at diagnosis, while older groups were mostly diagnosed with Stage I disease (41.6% and 52.4%). The most common subtype of breast cancer across ages was ER+ disease, however, &amp;lt;40yo group had proportionally less ER+ (49% vs 61% and 67.3%, P&amp;lt;0.001). There was a higher rate of bilateral mastectomies among the young women (18.4% vs 9.1% and 5.0%, p&amp;lt;0.0001). Independently of the stage of disease, chemotherapy was given significantly more frequently to &amp;lt;40y (90.43%) and 40-49yo (81.44%) than ≥50yo (53.71%). The 10-year overall survival of younger women was similar to the ≥50yo cohort, despite intensive treatment. Discussion: This study is one of the largest retrospective studies of women under 40 years old with breast cancer. Younger women with invasive breast cancer had more aggressive tumors presenting at higher stages. In this group with good access to healthcare, younger women still had a similar overall survival rate to older women despite receiving more aggressive treatment and potentially having fewer comorbidities than the older group. Citation Format: Zimmer AS, Gatti-Mays M, Soltani S, Lipkowitz S, Steeg PS, Zhu K, Perkins JG, Hu H, Shao S, Brown D, Shriver CD. Analysis of breast cancer in young women in the department of defense (DOD) database [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PD6-01.

Abstract 3776: Mechanistic evaluation of AG311 - an OXPHOS inhibitor - as a potential treatment for breast cancer

Abstract About fifty percent of breast cancer patients receiving a combination of surgery, radiation and systemic therapy will not remain cancer-free. Most solid tumors, including breast tumors, have hypoxic regions that can contribute to chemoresistance, radioresistance, and poor differentiation in tumors resulting in a poor clinical outcome in patients with advanced disease. It has been reported that mitochondrial respiration remains active in these hypoxic microenvironments. Complex I of the mitochondrial electron transport chain (ETC) has been shown to switch to a de-active catalytic state under hypoxic conditions. The purpose of this study was to investigate the potential anticancer action of a novel compound with antimitochondrial activity under hypoxic conditions. AG311 (5-[(4-Methylphenyl)thio]-9H-pyrimido[4,5-b]indole-2,4-diamine) is a small molecular weight compound shown to inhibit complex I activity in vitro and to drastically reduce mitochondrial oxygen consumption rate by 62.9% at 7.5 μM in breast cancer cells (p&amp;lt;0.001). In two triple negative breast cancer mouse models (MDA-MB-435 and 4T1), AG311 significantly reduced tumor volume by 85% and 81%, respectively (p&amp;lt;0.001 for both). In this current study, the effect of the microenvironment on AG311 mitochondrial inhibition was examined. First, it was shown that AG311 inhibited complex I activity not only in vitro, but also in breast cancer cells (54% inhibition, p&amp;lt;0.001) and tumor homogenate (50% inhibition, p = 0.01). AG311 induced greater cytotoxicity in cells (MDA-MB-435) cultured in glucose-depleted media (IC50 15.5 μM vs 20.0 μM, p&amp;lt;0.01), a condition favoring mitochondrial ATP production, as compared to normal glucose concentrations. Further, co-treatment of AG311 with dichloroacetate, a pyruvate dehydrogenase kinase inhibitor and stimulator of oxidative phosphorylation, showed a synergistic effect on cell kill (CI = 0.7 at 20 μM). Importantly, hypoxic conditions (1% O2) significantly sensitized cancer cells to AG311-induced cell death (from 43.3% to 30.1%, p = 0.019). Further, the effect of AG311 on the deactive form of complex I, which is promoted under hypoxic conditions was assessed by measuring NADH oxidation rate. The switch to the de-active state was thermally-induced in mitochondrial homogenates and once in this state, complex I activity was sensitized to AG311 inhibition (from 45.4% to 65.0% inhibition, p = 0.04). Thus, a mitochondrial inhibitor that preferentially inhibits the de-active state of complex I in hypoxic tumor regions could potentially provide a therapeutic benefit. Citation Format: Anja Bastian, Satoshi Matsuzaki, Kenneth M. Humphries, Lora C. Bailey-Downs, Aleem Gangjee, Michael A. Ihnat. Mechanistic evaluation of AG311 - an OXPHOS inhibitor - as a potential treatment for breast cancer. [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 3776.

204. HER2-Specific Chimeric Antigen Receptor T Cells for the Treatment of Breast-to-Brain Metastasis

Adoptive transfer of chimeric antigen receptor (CAR)-engineered T cells has demonstrated robust and durable clinical efficacy in patients with CD19+ B-cell malignancies. Broader application of this approach to brain and other advanced solid tumors is an immediate goal for the field and is presently under intense investigation. In 2014, 40,000 individuals in the U. S. alone succumbed to breast cancer, primarily as a result of metastatic disease. Approximately 30 percent of breast cancer patients carry an amplification of the HER2 gene and/or HER2 over-expression, which confers a particularly poor prognosis. Among the most common sites of HER2-positive breast cancer metastases is the brain. For patients with breast cancer that has metastasized to the brain, the 1-year survival rate is a dismal 20 percent. Despite clinical successes in both preventing relapse and treating systemic disease with HER2-targeted therapies, the currently available agents are only modestly effective in managing brain metastasis. Our group has demonstrated safety and transient anti-tumor responses in two U. S. FDA-authorized phase I clinical trials evaluating local intracranial adoptive transfer of CAR T cells in glioma patients.Our current project builds on this clinical experience with locally administered CAR T cells that specifically target HER2 for the treatment of breast-to-brain metastasis. Our lab has initiated design and testing of CAR T cell therapy targeting HER2 based on an scFv derived from trastuzumab. We anticipate that local intracranial delivery will enhance therapeutic response, while reducing the likelihood of off-tumor systemic toxicities as previously observed. Importantly, HER2 expression in normal brain tissue is limited, supporting HER2 as a therapeutic target in brain metastasis. Our innovative CAR T cell platform focuses on engineering central memory T cells (Tcm) for therapeutic application, with the intent of improving persistence of T cells after infusion, a critical parameter correlated with ultimate therapeutic success. Herein, we have evaluated several HER2-CAR constructs incorporating either the CD28 or 4-1BB co-stimulatory domain using both in vitro T cell functional assays as well as orthotopic patient-derived xenograft models of breast-to-brain metastasis. While HER2-28ζ and HER2-BBζ CAR T cells similarly kill HER2+ breast cancer cells in vitro, BBζ CARs demonstrate lower induction of the exhaustion marker PD-1 and proliferate better compare with 28ζ CARs. Both HER2-CARs similarly lead to tumor eradication and prolonged survival. Based on these data, we have successfully developed HER2-specific CAR T cells, and plan to clinically develop these CARs for the treatment of HER2+ metastatic disease.

Abstract IA15: Immune control of breast cancer metastasis

Abstract Twenty to thirty percent of breast cancer patients eventually develop metastasis despite receiving state-of-the-art therapies. Clearly, identifying better ways to eliminate micro-metastatic tumor cells is paramount to eradicating death from breast cancer. We now know that every tumor is unique and that each tumor is heterogenous. Tumors hijack multiple, redundant pathways to survive and grow, and evolve resistance under selective pressure from therapy. Moreover, micro-metastatic cancer cells may be dormant and resistant to therapy. Thus, traditional approaches to treat cancer and prevent metastatic recurrences don't work for everyone. Stimulating the immune system to kill cancer cells (known as immunotherapy) carries strong appeal: the response can be individualized; the immune system is effective against diverse pathogens (in this case, tumor antigens); and immunity can evolve and retain memory for long-term control of disease. The challenge is that by the time tumors are clinically detectable they are already ‘invisible’ to the immune system due to a number of factors: (1) natural selection for tumor cells that can escape immune control; (2) immune tolerance to self- and tumor-antigens; and (3) the strongly immunosuppressive environment in tumors, which renders effector cells inactive. A better understanding of how tumors achieve immune evasion will allow development of strategies to promote more effective anti-tumor immunity. We have determined that Ron protein kinase activity in the host immune system is a major contributor to metastasis. This finding was unanticipated; the expected result was that blocking Ron signaling in tumor cells would inhibit tumor progression, which was the basis for development of Ron inhibitors by the pharmaceutical industry. Our work now shows that Ron inhibitors reduce metastasis through dual effects on tumor cells and on the immune system: Approximately 40% of human breast tumors upregulate the Ron ligand, which is secreted from the tumor, activates Ron on macrophages, and polarizes them to an immune suppressive state. Inhibiting Ron, either genetically or with drugs, blocks metastasis by activating an anti-tumor immune response mediated by CD8+ cytotoxic T lymphocytes (CTLs). Thus, inhibition of Ron boosts anti-tumor immunity and prevents metastasis. These data suggest that inhibition of Ron in the tumor microenvironment might provide a new, complementary strategy to ongoing immunotherapy. Thus, Ron inhibitors might serve as macrophage ‘checkpoint inhibitors’ to complement checkpoint inhibition in T-cells. Citation Format: Alana L. Welm. Immune control of breast cancer metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr IA15.

Systematic development of a a breast cancer survivorship program at a small independent oncology practice.

52 Background: It is widely accepted that providing survivorship care plans leads to improvements in outcomes for cancer survivors. Treatment summaries are now part of ASCO and NCCN survivorship guidelines. We faced a unique challenge of implementing the survivorship care plan at the Jones Clinic as a small independent practice. The Jones Clinic consists of three full time physicians and two full time nurse practitioners. We see approximately 850 new patients per year. Methods: As a part of ASCO’s quality training program, we focused on the stage I – III (early stage) breast cancer patients who completed their initial therapy. We formed a team, identified the barriers, created a flow diagram of the process, assigned roles for each individual member and finally implemented the process. Results: The major issues identified were lack of provision in the electronic medical record (EMR) system for survivorship and lack of standardized data entry process. We created a system in the EMR for survivorship data entry and extraction of such data in a document. Since July 2015, one hundred percent of breast cancer patients completing adjuvant therapy at the Jones Clinic have received a survivorship treatment summary and a plan of care. The care plan is also shared with their primary care provider. Importantly, creating a survivorship document required less than 10 minutes of the provider’s time. Conclusions: We are now able to provide our patients with a survivorship care plan and address survivorship issues within thirty days of completion of therapy. Creating the care plan requires minimal time from the providers. Our new process meets ASCO guidelines for survivorship care plans and no additional staffing was needed. We now plan to provide a survivorship care plan to all oncology patients treated with curative intent.

Development of HER2-specific chimeric antigen receptor T cells for the treatment of breast-to-brain metastasis

Adoptive transfer of chimeric antigen receptor (CAR)-engineered T cells has demonstrated robust and durable clinical efficacy in patients with CD19+ B cell malignancies. Broader application of this approach to brain and other advanced solid tumors is an immediate goal for the field and is presently under intense investigation. In 2014, 40,000 individuals in the U.S. alone succumbed to breast cancer, primarily as a result of metastatic disease. Approximately 30 percent of breast cancer patients carry an amplification of the HER2 gene and/or HER2 over-expression, which confers a particularly poor prognosis. Among the most common sites of HER2-positive breast cancer metastases is the brain. For patients with breast cancer that has metastasized to the brain, the 1-year survival rate is a dismal 20 percent. Despite clinical successes in both preventing relapse and treating systemic disease with HER2-targeted therapies, the currently available agents are only modestly effective in managing brain metastasis. Our group has demonstrated safety and transient anti-tumor responses in two U.S. FDA-authorized Phase I clinical trials evaluating local intracranial adoptive transfer of CAR T cells in glioma patients. Our current project builds on this clinical experience with locally administered CAR T cells that specifically target HER2 for the treatment of breast-to-brain metastasis. Our lab has initiated design and testing of CAR T cell therapy targeting HER2 based on an scFv derived from trastuzumab. We anticipate that local intracranial delivery will enhance therapeutic response, while reducing the likelihood of off-tumor systemic toxicities as previously observed. Importantly, HER2 expression in normal brain tissue is limited, supporting HER2 as a therapeutic target in brain metastasis. Our innovative CAR T cell platform focuses on engineering central memory T cells (Tcm) for therapeutic application, with the intent of improving persistence of T cells after infusion, a critical parameter correlated with ultimate therapeutic success. Herein, we have evaluated several HER2-CAR constructs incorporating either the CD28 or 4-1BB co-stimulatory domain using both in vitro T cell functional assays as well as orthotopic patient-derived xenograft models of breast-to-brain metastasis. While HER2-28z and HER2-BBz CAR T cells similarly kill HER2+ breast cancer cells in vitro, BBz CARs demonstrate lower induction of the exhaustion marker PD-1 and proliferate better compare with 28z CARs. Both HER2-CARs similarly lead to tumor eradication and prolonged survival. Based on these data, we have successfully developed HER2-specific CAR T cells, and plan to clinically develop these CARs for the treatment of HER2+ metastatic disease.