Abstract
Background/Aim: Breast cancer (BC) is the most prevalent oncological diagnosis worldwide. Molecular subtyping has provided valuable insights for treatment decisions, but challenges remain in adjuvant treatment for hormone receptor (HR)-positive/HER2-negative luminal BC (LBC). Multigene markers like Oncotype DX have emerged to provide more precise prognostic information. This study aimed to evaluate the influence of gene expression panels on fear of cancer recurrence (FCR), quality of life (QoL), and healthcare-related greenhouse emissions. Patients and Methods: A monocentric retrospective analysis was conducted using a prospective database of patients undergoing Oncotype DX. QoL assessments were performed using the Short Breast Health Perception Questionnaire (BHPQ) and Life Satisfaction Questionnaire (LSQ-32). Reductions in hospital visits and travel distance were analyzed. Results: Twenty-eight patients underwent Oncotype DX testing. Of these, 17.85% received adjuvant chemotherapy based on the recurrence score (RS). The implementation of Oncotype DX resulted in a significant reduction in hospital visits, travel distance, and healthcare-related greenhouse gas emissions. QoL assessments using BHPQ and LSQ-32 showed lower levels of FCR and improved QoL in various domains for patients who received hormone therapy (HT) alone. Conclusion: The implementation of Oncotype DX in clinical practice has the potential to reduce overtreatment, decrease healthcare-related greenhouse gas emissions, and improve QoL. Lower levels of FCR and improved QoL were observed in patients who received HT-only based on the RS score.
Breast cancer (BC) remains the most prevalent oncological diagnosis worldwide, with an annual incidence exceeding 2.3 million cases (1). During the past century, the approach to BC treatment has evolved from a singular surgical procedure to a multidisciplinary treatment strategy that takes into account both tumor and patient-related characteristics, including comorbidities and preferences (2-4).
In the past decade, the classification of BC molecular subtypes has emerged as a significant breakthrough in tumor assessment and management, providing clinicians with a valuable tool to shift adjuvant treatment decisions from relying solely on statistical risk to incorporating predictive biomarker assessment (5). BC distant disease spread is the result of a not fully understood complex interplay between biological processes, including tumor circulation, proliferation, angiogenesis, and the microenvironment of the target tissue (6-8). Although progress has been made, many questions remain unsolved in this area (9-11).
The issue of adjuvant treatment in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative, luminal BC (LBC) continues to pose challenges. This subtype accounts for nearly 70% of all BC cases (12), and current guidelines recommend adjuvant chemotherapy for patients with more than 3 metastatic lymph nodes (LNs) following upfront surgery in addition to endocrine therapy (ET). Adjuvant treatment is also suggested for patients with up to 3 metastatic lymph nodes (LNs) or tumors larger than 5 cm, taking into consideration other prognostic and predictive factors such as age, histology, HR expression, proliferative index (Ki67), histological grade, and lymph vascular invasion (13). However, despite these indications, chemotherapy administration is still recommended for many patients inspite of the limited benefits, leading to overtreatment in a significant number of women (14, 15).
To address this issue, several multigene markers have been developed to provide more precise prognostic information and predict the potential benefits of adjuvant treatments beyond classical clinical-pathological features alone. One such marker, Oncotype DX (Exact Sciences, Madison, WI, USA), is a gene expression panel consisting of 21 genes (16 tumor-associated and 5 reference genes) (16). Normalized Oncotype DX gene expression analysis determines a recurrence score (RS) from 0 to 100 with higher score associated with higher risk of recurrence (17). Traditional categories were set as follows: low-risk (RS <18), intermediate risk (RS 18-30) and high-risk (RS >30) of recurrence (18). This assay has recently been introduced in the Italian National Health Service for localized LBC subset of patients, with the aim of reducing the risk of overtreatment. While de-escalating treatment has shown promise in improving Patients Reported Outcome Measures (PROM), the impact of Oncotype DX on the cost-effectiveness of treatment and the fear of cancer recurrence (FCR) has only been partially evaluated (19-21). Furthermore, the effect of gene expression panels on healthcare-related greenhouse emissions has not yet been assessed. Therefore, the objective of this current analysis was to evaluate the influence of gene expression panels on FCR, QoL, and the reduction of healthcare-related greenhouse emissions.
Patients and Methods
Study design. A retrospective analysis from our prospective updated database was designed to assess the impact of multigene analysis introduction in our clinical practice. Policlinico Tor Vergata Ethical Committee waived the need of informed consent due to the monocentric design and the lack of clinical intervention in our analysis. Prior to their first visit, all our patients routinely sign an informed consent for clinical practice data analysis. Assessment of the patients’ quality of life (QoL) was set as the primary outcome of the study using the Short Breast Health Perception Questionnaire (BHPQ) and Life Satisfaction Questionnaire (LSQ-32) (22, 23). Both questionaries are validated in BC patients and are used to assess patients’ QoL related to the treatment. Secondary outcomes were the evaluation of reduction in both the number of visits to hospital and the distance travelled to reach the hospital. Enrollment periods were set from June 2022 and December 2023, representing the first six months of implementation of the Oncotype DX reimbursement policy in our Institution.
Population and study protocol. Primary inclusion criteria were all patients admitted to the Policlinico Tor Vergata outpatient Breast Center facilities during the study period eligible for Oncotype DX (Exact Sciences) after surgery. According to the Lazio Regional Guideline, Oncotype DX testing proposed to every patient with early LBC (stage I-IIIA) according to AJCC 2018 (Edition VIII) recommendations according to TMN classification (24) when clinical-pathological information was not conclusive to recommend adjuvant chemotherapy (25). Once Oncotype DX was proposed by the multidisciplinary tumor board, patients signed informed consent to undergo chemotherapy if RS showed clear adjuvant treatment benefits according to the Lazio Oncotype DX reimbursement guidelines (26, 27).
Exclusion criteria were patients’ refusal to undergo Oncotype DX or subsequent chemotherapy administration, or patients who were currently in follow-up in other facilities. After the Oncotype DX test, all patients underwent multidisciplinary visit at which they were informed of the test results and the adjuvant treatment proposed. Data regarding adjuvant treatment were included in the analysis. If patients underwent HT-only, blinded re-evaluation without Oncotype RS score was obtained from a clinical oncologist (IP) with more than 15 years of experience in BC care to determine which adjuvant chemotherapy would have been suggested in HT-only patients if a high RS score had been obtained.
At three months from results communication, assessment of patients’ QoL was performed with telephonic follow up during which BHPQ and LSQ-32 were administered (Table I and Table II, respectively). Both questionaries were reported on a Likert scale (Always=1 point; Very often=2 points; Sometimes=3 points; Rarely=4 points; Never=5 points). Sub analysis was performed between patients according to the treatment schedule (Chemotherapy group vs. HT-only group).
English translation of Short Breast Health Perception Questionnaire (BHPQ) (23). All questions were answered on a Likert scale: Always=1 point; Very often=2 points; Sometimes=3 points; Rarely=4 points; Never=5 points.
English translation of Life Satisfaction Questionnaire (LSQ-32) (22). All questions were answered on a Likert scale: Not at all agree=1; Disagree=2; Neither agree nor disagree=3; Somewhat agree=4; Absolutely agree=5.
Data collection and statistical analysis. Retrospective data were collected from a prospectively updated database containing all clinical data including age, personal history, multidisciplinary treatment, and clinicopathological BC variables. Data from pathological examinations such as HR and Ki67 expression are presented as percentage of positive cells in specimens examined using immunohistochemistry. Over-expression of the HER2 gene (HER2 SCORE) was determined using IHC or fluorescence in situ hybridization (FISH), as indicated by the recommendations of the 2018 ASCO/CAP. For continuous variables, means and interquartile range (IQR) were calculated. Statistical analysis was performed using the SPSS statistical package version 23.0 (SPSS Inc., Chicago, IL, USA).
Results
From June 2022 to December 2022, Oncotype DX testing was proposed to a total of 32 patients at our facility that were considered eligible for enrollment. However, four patients were excluded from the analysis: three patients decided to undergo follow up at other clinical centers and one patient refused to undergo adjuvant treatment if suggested by Oncotype DX. Therefore, a total of 28 consecutive cases were included in the final analysis. Table III summarizes demographic and clinical variables. Median population age was 70.59 and 7 (25.00%) of patients were classified as premenopausal women. Mean Oncotype DX RS was 15.47, and in 5 cases (17.85%) adjuvant treatment with chemotherapy was administered due to the RS score. Mean distance travelled to reach the hospital was calculated as 56.34 km in the study group. After obtaining the RS scores, a total of 340 outpatient visits were not performed for chemotherapy administration in women in the HT-only group. This reduced the distance travelled to reach the hospital by 20,694.58 km resulting in a significant reduction in green-house gas emission.
Demographic and clinical characteristics of the study group.
Regarding patients’ QoL, the results from BHPQ and LSQ-32 are summarized in Table IV for the HT-only group. Interestingly, while BHPQ reported intermediate values for questions regarding domains as sexuality, or daily activity, lower values were reported in domains regarding BC awareness and anxiety. Moreover, while LSQ-32 reported higher value in physical symptoms (1-4), lower values were reported in domains assessing sickness impact, quality of everyday activities, socio-economic situation, quality of family relations, and quality of close friend relationship, demonstrating how chemotherapy sparing was associated with less side effects without affecting social and economic domains.
Short Breast Health Perception Questionnaire (BHPQ) and Life Satisfaction Questionnaire (LSQ-32) results in the HR-only group.
Discussion
BC multigene assay brought a revolution in adjuvant BC care, shifting from a classical clinical-pathological risk assessment to a more in-depth intrinsic tumor biology evaluation, reducing the rate of overtreatment in early LBC patients (16, 28). However, while the beneficial role of BC multigene assay on overtreatment risk has been clearly demonstrated in TAILORx and RxPONDER trials (26, 27), in the present study we examined how Oncotype DX implementation in clinical care may result in potential savings for the national health system, reducing the environmental impact of BC without affecting BC patients’ QoL and FCR.
FCR is defined as “fear, worry or concern relating to the possibility that cancer will come back or progress” (29) and represents one of the most unmet psychological needs in BC survivors (30). In fact, while the multidisciplinary approach resulted in a steady reduction in mortality among patients with BC in the last 30 years (31), up to 50% of BC survivors experience during their lifetime moderate to severe FCR, with higher rate among younger women (32, 33). Higher levels of FCR are correlated with decreased QoL and increased levels of anxiety, depression, and psychological distress (34).
FCR often emerges during the vulnerable period after completion of primary treatment and before adjuvant treatment administration (34-36). In this fragile period, communication of the results of multigene assessment such as Oncotype DX may represent a further stressor for patients with BC. Gormley et al. demonstrated that higher Oncotype DX RS score may have an impact on FCR and anxiety, our results demonstrated a lower level of FCR in the HT-only group evaluated with BHPQ and LSQ-32 (20). BHPQ represents a valid instrument designed to evaluate breast health perception in BC survivors, exploring different domains related to the effect of BC recurrence on health perception (23). Additionally, the LSQ-32 test was administered to our patients to explore six different domains such as 1) ‘Quality of family relation’, 2) ‘Physical symptoms’, 3) ‘Socioeconomic situation’, 4) ‘Quality of daily activities’, 5) ‘Sickness impact’ and 6) ‘Quality of close friend relation’ (22).
Additionally, de-escalating adjuvant chemotherapy may represent a benefit in terms of health care costs, social costs, and healthcare related green-house gas emission. In fact, in our preliminary analysis, only 5 (17.85%) patients required adjuvant chemotherapy, determining a net reduction of 340 outpatient visits, and 20,694.58 km of distance travelled. Our results confirm the cost-consequence model designed by de Jongh et al. to determine the economic impact of different gene expression tests in node negative early breast cancer (EBC). The cost-consequence model, including chemotherapy, short- and long-term event costs, productivity loss, genomic profiling testing costs, cost of cancer recurrence, and hospitalization costs, demonstrated that Oncotype DX may result in an average saving of €6,768 (37). This result is mostly achieved by reducing adverse events, sick days, outpatient visits and hospitalization required in patients undergoing HT.
Additionally, the distance travelled by patients was reduced. In fact, green-house gas emission and climate change have a direct impact on global health care and health policy worldwide because they shift health care resources toward extreme weather events, emerging zoonotic infection, and increasing exposure to air pollutant carcinogenic agents (38-40). Amid the COVID-19 pandemic, Health care providers understood that marginal interventions, such as the incorporation of telemedicine, had the potential to raise healthcare accessibility and concurrently mitigate atmospheric pollutants (41-44). Under this perspective, enhanced sustainability of BC care, the most diagnosed neoplasm worldwide, may eventually contribute to a reduction in the detrimental effects of climate change on global health.
We are aware that our preliminary study has some limitations. First, monocentric and retrospective analysis may have introduced biases. Moreover, the lack of comparative group cannot allow the determination of the effect of multigene assay on QoL of patients. In order to overcome these biases, further multicentric studies comparing patients undergoing Oncotype DX and historical series is currently under development to understand the role of multigene assay on patients’ QoL, risk recurrence, health care sustainability, and breast care environment impact.
Despite these limitations, if confirmed in further studies, our study demonstrated that Oncotype DX is an invaluable tool for determining adjuvant treatment in HR positive BC patients without affecting QoL, anxiety, and FCR, while reducing the need for outpatient visits, and thus the carbon footprint of BC care.
Footnotes
Authors’ Contributions
Study conception and design: Vanni Gianluca, Materazzo Marco. Acquisition of data: Pellicciaro Marco, Meacci Arianna, Pizzimenti Anna Roberta; Analysis of data: Portarena Ilaria, Oreste Claudio Buonomo; Interpretation of data: Vanni Gianluca, Materazzo Marco, Oreste Claudio Buonomo; Article draft: Vanni Gianluca, Materazzo Marco; Critical revision: Portarena Ilaria, Pellicciaro Marco, Pizzimenti Anna Roberta; Critical Revision of Literature: Buonomo Oreste Claudio.
Conflicts of Interest
The Authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
- Received July 16, 2023.
- Revision received August 29, 2023.
- Accepted August 30, 2023.
- Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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