Dr Roy on Limitations of the Pathway Trial Evaluating PGS and Survival in Breast Cancer

Arya Mariam Roy, MBBS, fellow, Hematology/Oncology, Roswell Park Comprehensive Cancer Center, discusses limitations of the Pathway trial evaluating the association between polygenic scores (PGS) and survival outcomes in patients with breast cancer, and explains ways investigators plan to address these limitations.

Pathway was a prospective cohort study that gathered genome-wide genotype data from 3995 patients with breast cancer who were enrolled from 2006 to 2013. Investigators used data to calculate four different PGS: PGS313, PGS4k, PGS5k, and PGS6m. These PGSs were then evaluated for their association with different survival outcomes, including recurrence, contralateral second primary breast cancer, other second primary cancers, and death.

, showed that patients who had a PGS of PGS313 were associated with a higher risk of recurrence, total breast cancer and invasive breast cancer events, and death. These outcomes were worse in patients with medium (T2) PGS313 and high (T3) PGS313 scores vs those with low (T1) PGS313 scores. However, no increased risks of these outcomes were observed among other PGS variants analyzed during the study.

Roy notes that a significant limitation of Pathway was the low enrollment of patients from minority populations. Of the patients evaluated, 7% were Black, 12% of patients were Asian, and 11% of patients were Hispanic. Roy explains that in the future, extended collaboration between institutions could help expand the minority patient population in this study, which could help identify other potential racial and ethnic disparities.

She says that another limitation of the study was the use of polygenic risk models developed from European ancestry populations. She notes that the efficacy of PGS models in patient populations with non-European ancestry has yet to be independently validated. Roy and colleagues are hope to extrapolate these data to see if we adjustments can be made to account for ancestry, she concludes.

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Arya Mariam Roy, MBBS discusses limitations of the Pathway trial evaluating the association between polygenic scores and survival outcomes in patients with breast cancer.



Dr Roy on Polygenic Scores and the Risk of Recurrence in Breast Cancer

Arya Mariam Roy, MBBS, fellow, Hematology/Oncology, Roswell Park Comprehensive Cancer Center, discusses findings from the Pathway trial—a prospective cohort study—evaluating the association between polygenic scores (PGS) and survival outcomes in patients with breast cancer.

The study utilized genome-wide genotype data from 3995 patients, enrolled from 2006 to 2013, to calculate four different PGS: PGS313, PGS4k, PGS5k, and PGS6m), and evaluated their associations with various survival outcomes, including recurrence, contralateral second primary breast cancer, other second primary cancers, and death.

Findings presented at the 2024 ASCO Annual Meeting showed that at a median follow-up of 10.5 years (range, 0.2-14.2), 504 patients experienced disease recurrence, 146 had contralateral second primary breast cancer, 237 had non-breast second primary cancers, and 762 patients died, including 352 with breast cancer–specific deaths.

Data demonstrated that compared with patients with low (T1) PGS313, patients with medium (T2) PGS313 risk scores were associated with a higher risk of recurrence (HR, 1.28; 95% CI, 1.02-1.61; 

 = .04), all-cause death (HR, 1.12; 95% CI, 0.96-1.31; 

 = .03), total breast cancer events (HR, 1.27; 95% CI, 1.04-1.54; 

 = .02), and invasive disease (HR, 1.33; 95% CI, 1.09-1.63; 

 = .006). Patients with high (T3) PGS313 scores also had worse outcomes vs patients with T1 scores in regards to recurrence (HR, 1.29; 95% CI, 1.02-1.61; 

 = .04), all-cause death (HR, 1.28; 95% CI, 0.96-1.31; 

 = .03), total breast cancer events (HR, 1.29; 95% CI, 1.04-1.54; 

 = .02), and invasive disease (HR, 1.34; 95% CI, 1.09-1.63; 

 = .006). However, these increased risks were not observed with the other PGS variants assessed in the study.

Previously, it was known the PGS was associated with the risk of developing breast cancer, Roy explains. Findings from this study help further that understanding by showing the PGS313 scores are linked to worse survival outcomes and a higher risk of recurrence in patients who have already developed breast cancer, she concludes.

Arya Mariam Roy, MBBS, discusses the role of polygenic scores in predicting the risk of recurrence and survival outcomes in breast cancer.

Addressing socioeconomic health disparities has been a crucial objective of health policy in the United States. The relationship between cancer incidence and mortality and socioeconomic status varies across malignancies.

Risk factors associated with the development and progression of cancer, such as smoking, alcohol use, dietary habits, obesity, lifestyle choices, environmental pollution, and occupational exposure, are directly and indirectly influenced by an individual’s socioeconomic status and where they live. Although existing data indicate a higher incidence of breast cancer among those with higher socioeconomic status, limited information is available regarding the clinical outcomes of breast cancer based on neighborhood socioeconomic status.

Our research group at Roswell Park Comprehensive Cancer Center sought to clarify these possible connections. What we have found from our analysis of nationwide data underscores how imperative it is for clinicians to examine the relationship between neighborhood socioeconomic status and morbidity and mortality rates of specific malignancies.

Socioeconomic inequalities in cancer mortality are a global concern. Insufficient resources in areas with lower socioeconomic status contribute to delayed cancer diagnoses and inadequate treatment options, resulting in significant mortality and morbidity.

 Social factors, including income, educational and job opportunities, housing, social support, transportation barriers, and racial disparities also play a significant role in cancer-related mortality. These disparities are particularly pronounced in low- and middle-income countries where access to care and financial toxicity pose challenges for the majority of patients. Because of disparities in socioeconomic factors and developmental infrastructure, areas characterized by low individual and neighborhood socioeconomic status may be associated with poorer prognosis for certain malignancies.

Breast cancer is the most prevalent form of malignancy among women worldwide.

 Survival rates for patients with breast cancer are influenced by demographic, clinical, and pathologic factors. Additionally, racial and ethnic backgrounds as well as socioeconomic factors have been shown to effect clinical outcomes in breast cancer.

Using information compiled through the national cancer database, we conducted an analysis to explore the effect of neighborhood deprivation on clinical outcomes in breast cancer. Our findings were based on data from 88,572 patients throughout the US and revealed a higher prevalence of racial and ethnic minorities, particularly among individuals identifying as Black/African American or as Hispanic/Latinx, in areas characterized by greater deprivation compared with those not characterized as deprived. Likewise, the most deprived areas had a higher proportion of uninsured patients.

We observed predominant levels of aggressive subtypes of breast cancer, including HER2-positive and triple-negative breast cancer, as well as advanced disease stages, in the most deprived neighborhoods. Our analyses demonstrate that patients with early-stage breast cancer from areas with greater neighborhood deprivation experienced inferior overall and breast cancer-specific survival rates,

 after adjustment for common confounders effecting survival. Our findings were presented as a Poster Spotlight Discussion at the 2022 San Antonio Breast Cancer Symposium.

The identification of higher breast cancer stages in areas with the highest levels of deprivation raises concerns about delayed access to screening, insufficient insurance support, and inadequate education and awareness regarding general health among individuals residing in socioeconomically disadvantaged areas. Early detection of breast cancer is associated with improved prognosis, provided that appropriate care is delivered. Although our study results revealed a higher proportion of individuals representing racial and ethnic minorities in economically deprived neighborhoods, the disparity in survival rates persisted even after adjusting for patients’ race, ethnicity, and clinicopathological features. This highlights the significant role that both patients’ socioeconomic status and neighborhood characteristics play in determining breast cancer outcomes.

Our study findings have elucidated the critical effect of neighborhood deprivation on survival outcomes of patients with breast cancer. The cumulative impact of various neighborhood factors, such as infrastructure (eg, schools and hospitals), accessibility to nearby health care facilities, availability of healthy food and water, and neighborhood hygiene contributes to this phenomenon. Factors such as prolonged exposure to water and air pollution in underresourced neighborhoods can induce changes in the tumor microenvironment of individuals residing in those areas, potentially leading to the development of aggressive forms of breast cancer.

Unfavorable neighborhood conditions also can contribute to the emergence of chronic medical comorbidities, fostering an immunosuppressive tumor microenvironment that facilitates the development and progression of breast cancer.

Our work outlines strategies that can be implemented to effectively address these disparities as follows:

Enhance coordination among social workers and case managers at hospitals to identify and address barriers preventing patients from underresourced neighborhoods from accessing necessary care.

Implement government policies aimed at improving basic infrastructure in underresourced neighborhoods.

Deploy mobile mammography units to reach neighborhoods with limited access to health care, facilitating proper disease screening.

Provide free transportation services for patients residing in underresourced neighborhoods, ensuring their ability to attend regular appointments, receive treatment, and undergo necessary scans or radiation therapy.

Provide financial aid and support to patients with breast cancer from the most deprived neighborhoods and their families.

Implement community-based education and awareness programs in underresourced neighborhoods, focusing on breast cancer prevention, early detection, and the importance of regular screenings. These programs can be conducted in collaboration with local community organizations, schools, and health care providers to ensure widespread dissemination of information and empower individuals with knowledge to make informed decisions about their health.

Establish partnerships with local businesses and organizations to provide financial incentives and resources for breast cancer screenings and treatment in underresourced neighborhoods. Collaborating with community stakeholders, such as pharmacies, clinics, and charitable organizations, can help alleviate the financial burden associated with screenings and treatments. Such measures can involve offering discounted or subsidized mammograms, treatment medications, and supportive care services, as well as facilitating access to patient assistance programs or grants for individuals from disadvantaged backgrounds.

It is crucial for cancer clinicians to identify patients seeking breast cancer treatment from areas characterized by higher deprivation indices. This key step enables the implementation of strategies aimed at overcoming barriers related to financial status and transportation, thereby facilitating patients’ access to essential care, regular appointments, and vital diagnostic procedures, treatments, and follow-ups. These interventions hold significant potential to improve the clinical outcomes for patients with breast cancer.

Singh GK, Jemal A. Socioeconomic and racial/ethnic disparities in cancer mortality, incidence, and survival in the United States, 1950-2014: over six decades of changing patterns and widening inequalities. 

2017;2017:2819372. doi:10.1155/2017/2819372

Vaccarella S, Georges D, Bray F, et al. Socioeconomic inequalities in cancer mortality between and within countries in Europe: a population-based study. 

2023;25:100551. doi:10.1016/j.lanepe.2022.100551

Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. 

Goel N, Hernandez A, Thompson C, et al. Neighborhood disadvantage and breast cancer-specific survival. 

2023;6(4):e238908. doi:10.1001/jamanetworkopen.2023.8908

Roy AM, George A, Attwood K, et al. Effect of neighborhood deprivation index on breast cancer survival in the United States. 

. Preprint posted online April 7, 2023. doi:10.21203/rs.3.rs-2763010/v1

Roy AM, George A, Attwood K, Gandhi S. Neighborhood deprivation index and survival in breast cancer in the United States. 

. 2023;83(suppl 5):PD1-04. doi:10.1158/1538-7445.SABCS22-PD1-04

Gearhart-Serna LM, Hoffman K, Devi GR. Environmental quality and invasive breast cancer. 

2020;29(10):1920-1928. doi:10.1158/1055-9965.EPI-19-1497

Saini G, Ogden A, McCullough LE, Torres M, Rida P, Aneja R. Disadvantaged neighborhoods and racial disparity in breast cancer outcomes: the biological link. 

2019;30(7):677-686. doi:10.1007/s10552-019-01180-4

Articles

Neighborhood Plays an Important Role in Clinical Outcomes for Patients With Breast Cancer

Arya Mariam Roy, MBBS, a hematology fellow at the Roswell Park Comprehensive Cancer Center, discusses the effect of neoadjuvant chemotherapy on overall survival (OS) in patients with sarcomatoid muscle-invasive bladder cancer.

In a retrospective database study examining the impact of neoadjuvant chemotherapy on pathological stage and survival in sarcomatoid bladder cancer, findings showed that patients treated with neoadjuvant chemotherapy experienced a median OS of 40.8 months vs 19.4 months for those who were not treated with neoadjuvant chemotherapy (log-rank 

 = .003). Additionally, 24.5% of patients who were administered neoadjuvant chemotherapy underwent downstaging to pT0-1N0 at the time of radical cystectomy, compared with 6.8% of patients who did not receive neoadjuvant chemotherapy (

Sarcomatoid bladder cancer is a rare and aggressive histological variant that is associated with a poor prognosis; however, investigators identified and analyzed 573 patients with sarcomatoid bladder cancer. Twenty-five percent of these patients received neoadjuvant chemotherapy. Prior to this study, investigators did not have data pointing to the survival benefit for the use of neoadjuvant chemotherapy in this patient population, Roy says.

Since the median age of patients who received neoadjuvant chemotherapy was 65 years, compared with 71 years for those who did not receive neoadjuvant chemotherapy, investigators also adjusted the analysis in order to account for the confounding factors that could affect the study results, including age, race, gender, socioeconomic status, and where a patient received treatment, such as at an academic institution or a community center, Roy says.

After adjusting for these confounding factors, the survival statistics were better in the neoadjuvant chemotherapy group compared with the non–neoadjuvant chemotherapy group. Both the pathological downstaging (HR, 0.5; 95% CI, 0.3-0.8; 

 < .001) and the use of neoadjuvant chemotherapy (HR, 0.73; 95% CI, 0.56-0.91; 

 = .02) were independent predictors of survival in sarcomatoid bladder cancer, Roy concludes.

Arya Mariam Roy, MBBS, discusses the effect of neoadjuvant chemotherapy on overall survival in patients with sarcomatoid muscle-invasive bladder cancer. 

Arya Mariam Roy, MBBS

Articles

Dr Roy on Limitations of the Pathway Trial Evaluating PGS and Survival in Breast Cancer

Dr Roy on Polygenic Scores and the Risk of Recurrence in Breast Cancer

Neighborhood Plays an Important Role in Clinical Outcomes for Patients With Breast Cancer

Dr. Roy on the Effect of Neoadjuvant Chemotherapy on OS in Sarcomatoid Bladder Cancer