Significance of Patient-Reported Outcomes for Metastatic Breast Cancer Patients

Breast cancer is the most common malignancy among women worldwide (24.5%) with an incidence of more than 2 million new cases and a mortality of 6.9% in 2020. It is the fourth leading cause of cancer-related deaths (all genders) and the leading cause of cancer-related deaths in women [1]. Depending on tumor stage, 5-year survival rates vary from up to 99% for localized breast cancer and 86% for node-positive breast cancer to 28% in women with metastatic disease (MBC) [2]. Although there have been some improvements in treatment, therapy options in the incurable metastatic disease stage focus primarily on reducing symptom burden, delaying disease progression, and prolonging overall survival (OS) [3, 4].

Compared to other tumor entities like lung, pancreatic, or prostate cancer, breast cancer patients are initially diagnosed in about 90% in an earlier stage (stage I–III) with reduced tumor symptoms and a good prognosis [5]. In contrast, only about 30% of lung cancer and 25% of pancreatic cancer patients are diagnosed at an early stage and often present with more severe symptoms and a worse prognosis due to advanced disease [5]. Although breast cancer patients are confronted with tumor- and treatment-associated symptoms, clinical experience shows that these patients, on average, have a more positive attitude as well as mental and motivational status than patients with other cancers. Especially in early stages, breast cancer patients are generally younger and well-motivated. For younger patients with cancer, career and/or caring for family or family planning and young children are the biggest motivational aspects to fight the disease and continue with their normal life at all costs, taking into account treatment-associated side effects. Older breast cancer patients, however, have set their focus more on maintaining good quality of life (QoL), especially in the presence of metastatic disease [6]. Breast cancer patients are usually willing to contribute to their systemic therapy by additional physical activity, better nutrition, psychological support, and participation in support groups [7].

Patient-reported outcomes (PROs) in breast cancer studies are assessed with validated questionnaires to better evaluate new treatment strategies, which might be similar in efficacy but different in treatment-associated side effects, and to improve medical care. PROs are a valuable and important outcome parameter, specifically for patients with metastatic disease. In MBC, the primary intent of therapy is not curative but focusses on the best possible QoL, balancing this with the toxicity of systemic therapies [8, 9]. The most commonly used PRO questionnaires in MBC trials are the Functional Assessment of Cancer Therapy – Breast Subscale (FACT-B), the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), often complemented by the EORTC QLQ – Breast Cancer Module (EORTC-QLQ-BR23), and the Euro Quol – 5 Dimensions (EQ5D) Questionnaire [8, 9]. As endpoints, QoL in general is used as the most common endpoint of the PRO measurement concepts, followed by symptoms, and global or overall health status, health-related QoL, and depression [9]. The heterogenous use of types of questionnaires and QoL endpoints in MBC trials results in disaggregated data. That way, answers to research questions and hypotheses are not well comparable between studies [10, 11]. Therefore, a standardized form of PROs might improve their interpretation in clinical trials as well as in routine clinical practice. This would increase even more the value and significance of PROs as an endpoint, also for the consideration in drug approval processes [8].

In early stages of breast cancer, the disease is often detected during routine screening or becomes initially noticeable with only a few symptoms that are focused locally in, on, or around the breast, including palpable nodes or lumps as well as changing and retraction of the skin above the tumor (peau d’orange), and swollen lymph nodes in the axillary region. Metastatic disease initially may present with unspecific symptoms (e.g., fatigue) and obvious metastases, e.g., in the bone, lung and liver which can be detected during follow-up of patients. However, the metastatic disease can also present with common general symptoms including weight loss. Reduction in performance and general health condition become noticeable which might cause the patient to see a physician if local symptoms have not been detected yet. Additionally, metastatic disease can also lead to patients suffering from symptoms resulting from distant disease, including, dyspnea, cough, pain (bone, joints/muscle), appetite-, and weight loss, liver insufficiency, weakness, and fatigue [12]. Besides these symptoms, almost 50% of breast cancer patients experience depression or anxiety even after completion of therapy, and most patients report a decrease in overall QoL [13, 14].

Although tumor symptom burden of MBC and depression can influence the QoL, especially in the metastatic stage, treatment-associated side effects of systemic therapies have an additional large impact on patients and their QoL, affecting physical mobility, family life, social-, and psychological well-being, and possibly the course of treatment with discontinuation of the treatment plan [8]. The most frequently reported treatment-associated side effects to chemotherapy include nausea, vomiting, diarrhea, fatigue, hair loss, and joint/muscle pain. Although modern systemic therapies (endocrine therapy, antibodies and antibody drug conjugates, CDK4/6 inhibitors, and immunotherapies) generally entail less severe toxicities, these still do exist. Treatment-associated side effects to endocrine therapy include toxicity of the nervous system, vascular disease (e.g., hot flashes), toxicities of the gastrointestinal tract, skin, and subcutaneous tissue, as well as bone and connective tissue. For antibodies and antibody drug conjugates the main toxicities include cardiotoxicity, changes in blood counts, as well as diarrhea and nausea. Cell cycle inhibitors often present with changes in blood counts and gastrointestinal toxicities (e.g., nausea, diarrhea). Immunotherapeutic drugs often come along with diarrhea and rashes. Delayed organ toxicities (e.g., hepatitis, pneumonitis) can occur, which are rare but need to be taken seriously [15, 16]. These symptoms are particularly disturbing, impacting the patient’s everyday life and hence their QoL, if no effective management is available and they are long-lasting [17]. However, every MBC patient experiences symptoms and treatment-associated side effects differently. Additionally, there may also be discrepancies of the weighting of side effects between patients and their physicians. While patients are more concerned about side effects that might influence their everyday life and self-esteem, e.g., hair loss, gastrointestinal disorders, and rashes, from a physician’s point of view, e.g., changes in blood values are of greater importance [17]. Therefore, PROs give a direction on what affects patients most.

A considerable number of systemic therapies have been approved for metastatic breast cancer. Depending on the subtype of cancer, a range of endocrine treatments or drugs targeting numerous signaling pathways or interactions (e.g., HER2, CDK4/6, PD-L1) can be used. Finding a balance between the intensity of a systemic treatment for optimal tumor control and the severity of side effects to maintain a good QoL is a considerable challenge for physicians. Milder, less intense therapies, e.g., mono-chemotherapies, endocrine treatments, and targeted therapies, often cause fewer and less severe side effects and therefore preserve a good QoL which is beneficial for everyday life. In contrast, intensified therapy regimens, e.g., combination chemotherapies, also go along with higher toxicity, worse symptom burden, and worse QoL [18]. It has been shown that the survival benefit is not influenced by mild or intensified therapy regimens [19]. Generally, guidelines recommend treatment of MBC with non-chemo monotherapies or targeted therapies with only one chemotherapy throughout almost all subtypes. A polychemotherapy regimen is applied in rare cases only, e.g., when acute symptoms of distant disease impair the patient’s QoL [15]. It has been shown that endocrine therapies and targeted therapies (anti-Her2 and PD-L1) are able to decrease symptoms and can improve overall QoL. Chemotherapy is effective in relieving tumor-associated symptoms and improve disease control but has a negative impact on the development of QoL, especially if the patient had a poor health-related QoL at the beginning of therapy [8, 18]. The decision on which treatment with the lowest toxicity is the right one for the patient should be an individual, patients-based decision, especially if OS is comparable between different treatments. PRO surveys can help to identify patient preferences regarding the type of treatment and side effects an individual patient is willing to accept.

Besides tumor parameters, all patient characteristics, including constitution (e.g., age, comorbidities), social support and situation (e.g., family- and social situation, marital status, children), and therapeutic experience (relapses or metastasis, hormone sensitivity status) should be considered when making a treatment choice for MBC patients. Communication with the patient, listening to their fears, concerns and preference is essential for good decision making and an individualized treatment plan [20]. It has been shown that the contribution of patients to treatment decision making and self-management improves and stabilizes adherence to therapy, especially oral therapy, as well as long-term disease control, disease-related outcomes, and QoL [21, 22]. Studies have shown that the most important aspects during anti-cancer treatments for patients is to maintain their physical agility and motility, followed by achieving an improved OS and progression-free survival (PFS). PFS was more important than OS since it is more apprehensible for patients in their everyday life and has a direct impact on their situation [17]. As long as OS and PFS can be prolonged and the QoL can be maintained on a desirable level, treatment-related side effects are not as important for patients and they are willing to accept the consequences of anticancer treatments [17]. It has been reported that patients and their QoL are more impaired by symptom burden, and treatment-related side effects that are not controllable. Additionally, patients are burdened by the constant fear of worsening of the disease and the lack of response to therapy. Therefore, QoL, OS, and PFS should be considered equally for treatment decision making [17]. Other studies have shown that the most important aspect is survival, despite the risk of toxic side effects from systemic therapy [23]. Following OS, side effects including fatigue, neutropenia, worsening of the general condition, and hair loss, are of great importance to the patient, influencing the daily life [24]. However, if there is an improvement in OS, patients are willing to accept the additional risks from treatment-associated side effects if they are not too severe [20, 23]. Therefore, communication with the individual patient about their preferences should be an important factor and established in treatment decision making in routine clinical practice.

As described above, outcome parameters (OS and PFS) are important factors for patient’s treatment decision making. However, regulatory authorities often neglect disease progression parameters during the approval processes of new drugs as being relevant for the patient because progression might not directly be associated with morbidity. Furthermore, a longer PFS is not always associated with longer OS. However, besides these aspects, disease progression can be associated with a distinct deterioration in health-related QoL among MBC patients, emphasizing the importance and relevance of PFS from a patient’s perspective, which has been shown by a number of studies [25‒27].

In clinical studies, the primary and relevant source of adverse event reporting used to come from the physician’s point of view only, which was crucial for authorities and drug approval. Progressively, PROs became more relevant and routinely used in clinical studies but also in clinical routine care. This is an important step since in routine clinical care, patient’s symptoms often go undetected by the physician and could be missed, resulting in inadequate management of symptoms, treatment interruptions, and unnecessary hospital visits [28, 29]. The self-reporting of symptoms via PRO is a critical step towards a good symptom control and management. Reporting by the patient itself is mostly earlier, more frequent, and symptoms are reported to be more severe compared to the physician’s point of view, reflecting the actual daily health status of the patient [30‒34]. PROs contribute to a better understanding and characterization of this complex disease, on an individual basis and without the interpretation of someone else [9]. However, physicians’ reporting better predicts unfavorable clinical events including death and hospitalization [29]. Therefore, a patient’s and physician’s perspective of adverse symptoms seem to complement each other, providing a complete picture of the toxic effects of anti-cancer treatments [29]. PROs contribute to a better communication between patient and physician, and to patient satisfaction, because their opinion is taken into consideration, and patient well-being which might improve OS [35‒39]. The form of patient self-reporting can vary from web-based symptom reporting, tablets, or paper-based questionnaires. In web-based applications, the advantage lies in the possibility of automated e-mail alerts send to the physicians and the possibility for the physician or nurse to react promptly to the deterioration of symptoms via telephone counseling, medication changes, and or hospital referrals, improving symptom management in routine clinical care [40]. Furthermore, it was shown that the integration of PROs in routine clinical care of metastatic cancer patients was associated with increased survival compared with usual routine clinical care [41]. Due to good symptom management, patients are able and willing to endure systemic therapies longer, which results in a beneficial outcome or prolonged survival [41]. In clinical trials, however, PROs are almost never evaluated as primary endpoints but are almost always degraded to be evaluated as secondary or exploratory endpoints. Therefore, it is of great importance to assess PROs in routine clinical practice. Good examples for implementation are non-interventional studies and tumor registries, mirroring real-world PROs and QoL [9, 25]. Hence it is of great relevance to integrate PROs in routine oncology practice [41]. Efforts are already being made to put this into practice in several countries like the UK (eRAPID reporting system), Canada (Canada Cancer Care Ontario PRO Program), or in the USA (PRO Program and PRO implementation Research at Dartmouth, Memorial Sloan Kettering Cancer Center, and the University of North Carolina). Patient self-reporting and reactive action of physicians and nurses toward possible changes is still a nascent field that is progressing and feasible to implement in clinical routine practice [42].

The implication of PROs in clinical trials, non-interventional studies, and tumor registries becomes more frequent and has gained insight into important information for routine clinical practice on QoL of MBC patients being treated with different anticancer therapies (e.g., intensified, less intensified). PROs provide information on patient preferences concerning therapy choices, important aspects that matter most to patients concerning their therapies as well as on the interplay between QoL, symptom burden and control, and disease progression. The gained information indicates that a direct communication between physician and patient in daily routine can positively influence clinical routine practice, by individualized treatment choices and adequate symptom management and control outside of clinical trials, thereby positively impacting the QoL and hence the course of the disease. Therefore, a systematic integration of PROs in clinical trials and clinical routine practice is of relevant value for patients and physicians and is urgently recommended.

We thank Martina Jänicke for providing input to and critical review of the manuscript. She was not compensated beyond her salary as employee of iOMEDICO AG.

N. Marschner reported receiving personal fees from Roche, Novartis, Celgene, TEVA, Amgen, Lilly, AstraZeneca, MSD, and Böhringer Ingelheim and remuneration for the documentation of patient data from iOMEDICO outside the submitted work; Dr. Marschner also is a chief executive officer and shareholder of iOMEDICO AG. U. Söling is a shareholder of iOMEDICO AG. No further conflicts of interest are to be declared.

iOMEDICO AG.

Drafting of the manuscript: L.E. Hillebrand. Critical revision of the manuscript for important intellectual content: L.E. Hillebrand, U. Söling, and N. Marschner.