Patient characteristics, treatment patterns and healthcare resource utilization of newly diagnosed Triple Negative Breast Cancer Patients: an observational retrospective cohort analysis of real-world data in England (ODR2021_259)

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Objective for processing

The aim of this study is to harness real-world data using cancer registration and secondary care data in England, to characterize the treatment patterns, clinical outcomes and HCRU of locally advanced non-metastatic TNBC patients, in the adult Adelphi Group Ltd and Merck Sharp & Dohme (UK) Limited (Medical Affairs UK) request access to NHS England data for the purpose of the following research project: population. Patient characteristics, treatment patterns and healthcare resource utilization of newly diagnosed Triple Negative Breast Cancer Patients: an observational retrospective cohort analysis of real-world data in England 2.1 Primary Objective(s) & Hypothesis(es) For the purposes of this version (v2) of the Data Sharing Agreement (DSA), Adelphi Group Ltd and Merck Sharp & Dohme (UK) Limited (Medical Affairs UK) have requested a further extension to process the NHS England Data they already hold under this DSA for a further 2 years. The specific primary research objectives for the study are: The following is a summary of the aims of the research project provided by Adelphi Group Ltd: 1. To describe the demographics and clinical characteristics of patients with Triple negative breast cancer (TNBC) is an aggressive form of breast cancer that is typically associated with a poorer prognosis and worse survival outcomes. This study aims to describe the disease characteristics of patients diagnosed with Triple negative breast cancer (TNBC) that has spread to nearby areas (termed locally advanced). The study will describe the treatments patients receive, how effective these treatments are and look at the use and costs associated with the healthcare provided to these patients in England. This study will help inform the use of new treatments that could improve outcomes for patients with Triple negative breast cancer (TNBC). newly diagnosed, locally advanced non-metastatic TNBC. Breast cancer is one of the leading causes of global disease and death in women. A recent estimate found that approximately 2 million breast cancer cases were diagnosed worldwide in 2018, with more than 600,000 deaths. In the UK specifically, breast cancer is the most common cancer accounting for 15% of all new cancer cases, Since the early 1990s, rates of new breast cancer cases have increased by 18% with rates in females increasing by 23% between 2015 and 2017, whilst rates in males have remained relatively stable. 2. To describe the pharmacological and other interventional (i.e. surgery, radiotherapy) treatment utilization patterns of patients with newly Triple negative breast cancer (TNBC) is an aggressive form of breast cancer that is typically associated with a poorer survival rate. It is called triple negative, as the cells that make up the tumour do not contain three types of protein on their outer layers. Around 15% of breast cancer cases are diagnosed as Triple negative breast cancer (TNBC) and it is more commonly found in premenopausal and black females. People with Triple negative breast cancer (TNBC) tend not to survive as long as people with other types of breast cancer. diagnosed locally Standard breast cancer treatments are unsuitable for Triple negative breast cancer (TNBC) as the tumour cells lack the molecules which these treatments target. Furthermore, there are fewer effective therapies available for this type of breast cancer. The effectiveness and patterns of Triple negative breast cancer (TNBC) treatment in the UK is not well understood, and it is believed that Triple negative breast cancer (TNBC) patients may benefit from new therapies. advanced non-metastatic TNBC, including: This study will therefore evaluate how patients in England are being treated for locally advanced Triple negative breast cancer (TNBC), by providing a comprehensive overview of the types of patients prescribed different treatments, outcomes of these treatments and the healthcare use and costs related to this, to identify which patients may benefit from improvements in treatment. o Place in therapy, The Data will be used to provide services to Merck Sharp & Dohme (UK) Limited (Medical Affairs UK) only. Merck act as a joint Controller and Funder under this Data Sharing Agreement. o Number of planned & actual cycles, The Data will be used to provide the following services only: o Dosing, • improvement of health and social care planning. o Real-world time on treatment, (rwToT), The following NHS England Data has been accessed: o Reasons for discontinuation. • NDRS Cancer Registrations 3. To evaluate real-world effectiveness outcomes of patients with newly diagnosed locally advanced non-metastatic TNBC including event-free survival • NDRS Systemic Anti-Cancer Therapy Dataset (SACT) (EFS) and OS, for all patients within this study population and by stage at • NDRS National Radiotherapy Dataset (RTDS) TNBC diagnosis. • NDRS Linked HES APC 4. To describe the all-cause and TNBC-related HCRU and direct medical costs, prior to and following a new diagnosis of locally advanced, non-metastatic TNBC. • NDRS Linked HES Outpatient 2.2 Exploratory Objective(s) & Hypothesis(es) • NDRS Linked HES AE 1. To evaluate disease progression following a diagnosis of locally advanced non-metastatic TNBC, including pCR, time to locoregional progression (LR/P) and time to recurrent/distant metastases (R/DM). • NDRS Linked Cancer Waiting Times (Treatments only) 2. To describe the treatment landscape, including pharmacological and other interventional (i.e. surgery, radiotherapy) treatments by stage of TNBC proregression (PCR, LR/P and R/DM). • NDRS Linked DIDs 3. To describe the all-cause and TNBC-related HCRU and direct medical costs by stage of TNBC progression (pCR, LR/P and R/DM). • NDRS Cancer Pathway All data is necessary to characterize the treatment patterns, clinical outcomes and HCRU of locally advanced non-metastatic Triple negative breast cancer (TNBC) patients, in the adult population. The level of the Data continues to be: • Pseudonymised The Data is minimised as follows: • Limited to a study cohort identified by NHS England (previously PHE) as – Adults (≥18 years old) in England with a first diagnosis of locally advanced non-metastatic TNBC within the indexing period. Patients who are diagnosed with early stage disease and progress to the locally advanced non-metastatic stage are of interest as well as newly diagnosed patients at the locally advanced non-metastatic stage. • Patients diagnosed with breast cancer between 01/01/2015 and 31/12/2018. • Limited to conditions relevant to the study identified by specific ICD code (ICD-10 C50x) • Limited to the following geographic areas: England Adelphi Group Limited (AGL); otherwise known as Adelphi Real World (ARW); is a joint Controller. Merck Sharp & Dohme (UK) Limited (Medical Affairs UK) act as a joint Controller and Funder under this application. Merck has commissioned Adelphi Group Limited to undertake this work and has determined the purpose of processing but will not process the data nor direct Adelphi Group Limited in the processing of these data. The lawful basis for processing personal data under the UK GDPR is: Article 6(1)(f) - processing is necessary for the purposes of the legitimate interests pursued by the controller or by a third party. Adelphi Group Limited has determined the processing is necessary for its legitimate interests in being able to describe the current treatment patterns and outcomes for the patient group to increase general understanding and increase awareness for multiple scientific and public groups including clinicians, researchers, the patient community, and the public. The lawful basis for processing special category data under the UK GDPR is: Article 9(2)(j) - processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89(1) based on Union or Member State law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject. This processing is in the public interest because it adheres to the UK Policy Framework for Health and Social Care Research, which protects and promotes the interests of patients, service users and the public, and aims to produce generalisable and publicly available information to inform future decisions over patients’ treatments or care. The funding is provided by Merck Sharp & Dohme (UK) Limited (Medical Affairs UK). The funding is specifically for the project described. Funding to continue the work described will be sought on an ongoing basis. The funder will have no ability to suppress or otherwise limit the publication of findings. Box.com is a processor acting under the instructions of Adelphi Group Ltd. Box.com provides cloud storage services to Adelphi Group Ltd and will store the Data as contracted by Adelphi Group Ltd.

Processing activities

The population of interest for this study will be adult patients (≥18 years)in England with a first diagnosis of locally advanced non-metastatic TNBC within the indexing period. Patients who are diagnosed with early stage disease and progress to the locally advanced non-metastatic stage are of interest as well as newly diagnosed patients at the locally advanced non-metastatic stage. Specific eligibility criteria are detailed in the subsequent section. Public Health England (PHE) dissolved in October 2021, and the National Disease Registration Service (NDRS) migrated to NHS England. Inclusion Criteria 1.Patient has a diagnosis of primary breast cancer (ICD-10 codes C50) recorded within the Cancer Registry at any time.2.Patient has a confirmed hormone receptor status of TNBC recorded within the Cancer Registry for the primary breast tumour (or presumed TNBC for a sensitivity analysis). 3.Patient has a record of locally advanced non-metastatic disease of the primary TNBC tumour within the indexing period defined as: a.TNM staging criteriai.T1c, N1-N2, M0ii.T2, N0-N2, M0iii.T3, N0-N2, M0iv.T4a-d, N0-N2, M0b.Staging derived from imaging: Stage II -IIIb4.Patient is aged ≥18 years on the date of the first record of locally advanced non-metastatic TNBC. 5.Patient has data linkage to HES datasets(necessary for deriving full assessment of treatment patterns, and associated HCRU /costs).3.4 No data will flow to NHS England for the purposes of this Data Sharing Agreement (DSA). Exclusion Criteria PHE provided the relevant records from the Cancer Registry, Systemic Anti-Cancer Therapy Dataset (SACT), National Radiotherapy Dataset (RTDS), HES Admitted Care, HES Outpatient, HES Accident and Emergency, Cancer Waiting Times (CWT), Diagnostic Imaging Dataset (DIDs) and the Cancer Pathway datasets to Adelphi Group Ltd. 1.Patient has a record of newly diagnosed primary TNBC at the metastatic stage(Stage IV; TNM: M1).2.Patient is diagnosed with and/or receiving treatment for other primary malignancies registered within the Cancer Registry prior to, including or during the index and/or follow up period.3.Patient is enrolled in a clinical trial for any line of systemic anti-cancer therapy treatment relating to their TNBC diagnosis, identified by the clinical trial indicator in the SACT dataset(or any other of the NCRAS datasets). The Data held contains no direct identifying data items. The Data is pseudonymised and individuals cannot be reidentified through linkage with other data in the possession of the recipient. Stratification Adelphi Group Ltd will extract a subset of the Data comprised of aggregated data and make this available to Merck. Where possible and if sample size allows, all analyses will be stratified according to the following factors:1)Socio-demographics: age, gender, ethnicity, Index of Multiple Deprivation (IMD)quintile2)Stage at diagnosis: Stage II, Stage III3)Hormone receptor status: True TNBC vs ‘presumed/likely’TNBC Adelphi Group Ltd stores Data on the Cloud provided by Box.com. Data Sources The Data will not leave the UK at any time. NCRAS is the population-based cancer registry for England. It is responsible for collecting, quality assuring and analysing data on all patients who have been diagnosed with a primary tumour (ICD 10 C00-97, D00-48) in England. NCRAS employs an event-based registration model, with data on each primary tumour being sent from multiple sources to NCRAS, and either registered as a new cancer or linked to an existing cancer registration as a new event. Finalised cancer registrations are processed within an environment called the Cancer Analysis System (CAS). CAS is comprised of a number of relational datasets, outlined in the sections below. NCRAS data sets are maintained and managed by Public Health England (PHE) and NHS England. The individual data sets are linked by pseudonymized Patient ID numbers to ensure patient anonymity. A single data application, currently via PHE, is required to provide access to the linked data sets with no limitation on the number of linkages that can be requested. The suggested data sets for use in this study are detailed below. The core dataset will only be accessed by employees or agents of Adelphi Group Ltd. They will produce subsets of the Data that will be accessed by Merck. PHE NCRAS data sets All personnel accessing the Data have been appropriately trained in data protection and confidentiality. Cancer Registry Data linkage was conducted by NHS England’s predecessor (PHE). The Cancer Registry is a population-based registry which collects data on cancer patients in England, including diagnosis information, tumour information and treatment events. Patients are entered into the registry on their first cancer diagnosis(multiple primary cancers are recorded). Various validation and quality control steps are applied to each registry input, ensuring the collection and release of consistent and fully processed data. The registry has complete national coverage of cancer patients in England, receiving data from all NHS providers (~98-99% of hospital activity). Data is received from a variety of sources, including: ‘multidisciplinary team meetings, pathology reports, molecular testing results, treatment records, hospital activity records, hospital Patient Administration Systems, and operational standards such as cancer waiting times’[41]. Tumour site and morphology is coded using the International Classification of Diseases for Oncology version 2 (ICD-O2) classification and ICD-10 coding. Patients diagnosed with registerable tumours in the calendar years 1995 to 2018are currently available within the dataset. Patient data collected includes socio-demographics including age and ethnicity. Comorbidities via the Charlson Comorbidity Index (CCI) is captured using data from HES. Vital status information (including date and cause) is reported using data from the Office for National Statistics (ONS). Cancer/tumour specific details captured include: diagnosis date, cancer site, morphology, stage at diagnosis (TNM), hormone receptor status for specific tumour types, and cancer treatment data (procedure codes) [41]. Registry records can be deterministically linked to the SACT data set which provides additional comprehensive chemotherapy-specific treatment data. There will be no requirement and no attempt to reidentify individuals when using the Data. Systemic Anti-Cancer Therapy (SACT) Data Set Analysts from Adelphi Group Ltd will analyse the Data for the purposes described above. The SACT data set collects data on both adult and paediatric patients receiving chemotherapy for cancer, in or funded by the NHS. This includes inpatient, outpatient, day case and community delivered chemotherapy occurrences, as well as chemotherapy provided in clinical trials[42].The SACT data set contains granular and comprehensive data for all anti-cancer chemotherapy occurrences allowing for a detailed assessment of the treatment landscape, including regimen specifics (e.g. start date and decision to treat date); cycle details (e.g. start date and cycle number); drug details (e.g. regimen, drug types and dosages) and outcomes (e.g. regimen modifications and overall outcome summary). Basic patient demographics are also captured, along with tumour information such as primary diagnosis, morphology and TNM stage at the start of each treatment regimen[42].Like the cancer registry, the ICD-10 coding system is used for diagnoses. Tumour information is coded using ICD-O2(histology) and ICD-10 (topography) coding systems. Some treatment procedure information is coded using the UK Office of Population, Census and Surveys (OPCS) Classification of Interventions and Procedures system[42]. Data is available to the last available quarter before the request date, which is approximately 6 months behind the current date. The same time periods for data availability also apply to the RTDS (see Section 3.6.1.3 Radiotherapy Data Set (RTDS). PHE applies restrictions on data related to treatment using drugs funded through the Cancer Drug Fund (CDF) [43]. As a result, data on patients receiving such treatments may not be available (see Section7.2.2Limitations. It is anticipated that this limitation will have minimal impact on the study since all therapies for TNBC (regardless of disease stage), are currently funded via routine commissioning. Radiotherapy Data Set (RTDS) The RTDS captures clinical information on patients treated with radiotherapy in or funded by the NHS in England. Detailed radiotherapy information is collected including comprehensive treatment dates, regimen details, exposure details and dosages. Diagnoses (ICD-10) are also captured. RTDS data will allow radiotherapy-related interventions to be observed for the study. NHS England Data sets Hospital Episode Statistics (HES) secondary care data The PHE data sets will be linked to the HES Admitted Care (AC), Outpatient (OP) and Accident & Emergency (A&E) datasets. HES contains details on all inpatient admissions (AC), outpatient appointments (OP) and A&E attendances (A&E) to an NHS funded centre in England and was established to monitor hospital activity. HES linkage will enable an extensive assessment of HCRU in relation to TNBC patients and allow for derivation and identification of key events in the patient pathway. HES data is available up to 4-7 months prior to the current date/date of request and can be linked up to 12-months prior to patient registration in the cancer registry, enabling baseline data to be gathered. HES AC data includes basic patient demographics, date and method of hospital admission (elective/non-elective) and discharge, diagnoses (including primary diagnosis), specialists seen, and procedures undertaken. Data is coded using the ICD-10 coding frame as well as procedure information being coded using the OPCS version 4.6 Classification of Interventions and Procedures system. HES OP contains records of outpatient appointments in England including dates, specialty, clinical diagnoses and procedures. The HES A&E dataset consists of individual records of patient attendances in A&E in England, including diagnoses and investigations and attendance outcomes. A Healthcare Resource Group (HRG) can be derived for each inpatient admission and outpatient attendance, whereby HRGs are standard groupings of clinically similar treatments / events which use common levels of healthcare resource. The HRG4+ Local Payment Grouper can be used to derive HRGs and was developed to be used in line with the National Reimbursement System as produced by NHS England and NHS Improvement[44]. The derivation of HRGs in the inpatient setting incorporates patient demographics, source / method of admission, destination / method of discharge, durations of episodes, specialties treated under, diagnoses and procedures undertaken. Derivation of HRGs in the outpatient setting incorporates only patient demographics, specialties treated under, sequence of attendances and procedures undertaken. Unit cost data The following elements of HCRU can be transformed into direct healthcare costs using appropriate unit cost data:•Systemic anti-cancer therapy, For branded systemic anticancer therapies, the following two sources may be used to estimate costs associated with each treatment: ▪Monthly Index of Medical Specialities (MIMS)[45] Or British National formulary (BNF) aka Medicines Complete[46] For chemotherapies the Drugs and pharmaceutical electronic market information tool (eMIT)may be used to estimate costs associated with each treatment[47].Systemic anti-cancer treatment cost calculations will take into account the time on treatment and drug doses administered. Diagnostic Imaging Data set (DID) The DID collects detailed diagnostic imaging data for NHS patients, which is extracted from radiology information systems. The DID captures information about referrals for diagnostic imaging (e.g. the source), imaging details (type and body site), dates of imaging (including request dates and reporting dates). It also captures patient demographics. National Interim Clinical Imaging Procedure (NICIP) codes and Systematized Nomenclature of Medicine Clinical Terms (SNOMED-CT) codes are used to inform on test modality and body site of tests. Due to limitations in data availability (data only available to end of 2018) DID data for the baseline clinical characteristics only will be assessed, using this dataset. Cancer Pathway Data set The cancer pathway data set describes significant clinical or administrative patient events occurring in the process between diagnosis to treatment and into follow up. Such events are summarized using data from the Cancer Registry, SACT, RTDS, HES, DID and CWT. Events may include, CWT referrals, diagnoses, A&E attendances, major surgery or various treatment events, each of which are recorded as a single event. Disease progression may be inferred using patient pathway events using this dataset. National Cancer Waiting Times (CWT) The National CWT Monitoring Data Set supports the continued management and monitoring of English NHS cancer waiting times standards. Data is available for all cancer treatments recorded in the CWT database that are linked to a registerable tumour from the cancer registry data. Approximately 80% of tumours (ICD-10 C00-C97, D05 exc. C44) are linked to at least one treatment record in the National CWT database. The CWT captures information about the patient’s referral process, diagnosis including tumour characteristics as well as treatment events.

Expected output

A final study report is in development, describing the methods, results, and interpretation of results. A manuscript will be developed and submitted to a relevant peer-reviewed journal (such as the Journal of Clinical Oncology, Frontiers in Oncology or Annals of Oncology (to be decided) as well as an abstract and poster to be submitted to an appropriate congress (such as the European Society for Medical Oncology [ESMO] or American Society of Clinical Oncology [ASCO], (to be decided). Manuscript development, submission and review is planned to be completed by the end of 2023. These outputs will enable both the scientific community and general public to be informed of and benefit from the results of this study, with the aim of encouraging discussion between academics and clinicians on potential areas for improvement within the patient treatment pathway. The outputs will only be aggregated data with small number suppression applied where necessary (both primary and secondary suppression). The study is not looking at specific treatments and direct outcomes and no safety data will be generated as a result of this study. The expected outputs of the processing will be: Results to the public domain in the form of abstracts, posters, presentations and/or manuscripts for submission to scientific congresses and journals will be aggregated outputs of the results only, with both primary and secondary small number suppression where required. Additionally, published findings of this study will be disseminated to the public and patient community to improve patient information / understanding and patient engagement. • Submissions to peer reviewed journals (such as the Journal of Clinical Oncology, Frontiers in Oncology or Annals of Oncology) HRGs derived for secondary care activity.oThe HRG4+ Local Payment Grouper will be used to derive HRGs for care provided in the inpatient, outpatient and A&E settings. The monetary amount a provider is reimbursed for a particular HRG code will be taken from the national prices and national tariff workbook compiled and provided by NHS Improvement and NHS England [48]. The workbook outlines national prices for each HRG code, which are dependent upon the care setting (inpatient or outpatient), method of admission (elective, non-elective, day case etc.) and length of stay.For all sources of unit cost data, the most recent source document available at the time of analysis will be used with the version noted and detailed in the final study report. If the most current documentation is one or more years outdated at the time of analysis, inflation adjustments for costs will be applied with full details to be documented in the SAP.Previous unit cost data may be used ifdata from recentsource documents lacks costing information for specific HRG costs. • Presentations to an appropriate congress (e.g. European Society for Medical Oncology [ESMO] or American Society of Clinical Oncology [ASCO]) • Presentation at ESMO 2022. The outputs will not contain NHS England Data and will only contain aggregated information with small numbers suppressed as appropriate in line with the relevant disclosure rules for the dataset(s) from which the information was derived. The outputs will be communicated to relevant recipients through the following dissemination channels: • Journals • Press/media engagement • Public promotion of the research • Reports aimed at the public and patient community The DSA extension is required to complete the analyses for the purpose of manuscript publication, to further demonstrate the burden of the disease, inform ongoing standard of care improvement strategies in the use of new and emerging treatments. Furthermore, following manuscript submission, Adelphi Group Ltd would benefit from having the dataset available, in case feedback from journals require further minor amendments to analyses conducted.

Expected measurable benefits

Triple negative breast cancer (TNBC) is an aggressive form of breast cancer [10 words unchanged] of breast cancer cases are diagnosed as TNBC; approximately 7500 cases of TNBC Triple negative breast cancer (TNBC) are diagnosed within England and Wales each year. The prognosis of TNBC Triple negative breast cancer (TNBC) is considered poor due to the lack of effective therapies and its [12 words unchanged] that the study results could help highlight gaps in the care of TNBC Triple negative breast cancer (TNBC) patients and improve the lives of these patients. [1 paragraph unchanged] - A better understanding of the clinical characteristics of patients with locally advanced [LA] (stage II-IIIB) TNBC Triple negative breast cancer (TNBC) - Treatment patterns and observed pathways for patients diagnosed with LA TNBC locally advanced Triple negative breast cancer (TNBC) - An understanding of gaps in the treatment of LA TNBC, locally advanced Triple negative breast cancer (TNBC), and highlight where the introduction of immunotherapy and other medical strategies may benefit patient outcomes and improve survival rates - An understanding of the burden of LA TNBC locally advanced Triple negative breast cancer (TNBC) on both patients and the NHS by assessing the real-world effectiveness outcomes [5 words unchanged] as well as healthcare resource use and costs incurred to the NHS The dissemination strategy will provide evidence to support clinicians in the treatment of LA TNBC, locally advanced Triple negative breast cancer (TNBC), inform ongoing standard of care improvement strategies in the use of new [9 words unchanged] clinical trials in line with the overall aim to improve patient outcomes. This study is not in support of a PhD/post-graduate research study. Data will not be used for sales and marketing purposes.

Benefits reported

N/A The results from this study have been published in an online abstract for the American Society of Clinical Oncology (ASCO) 2023. This abstract demonstrated the real-word treatment patterns and burden of early-stage/locally advanced Triple negative breast cancer (TNBC) in relation to survival outcomes.