Understanding key symptoms, side effects, and impacts of HR+/HER2- advanced breast cancer: qualitative study findings

Background Patients with breast cancer experience a variety of disease symptoms and treatment-related side effects that can adversely affect functioning. The breast cancer experience may differ across disease stages and biomarker subtypes. This study identified relevant disease symptoms, treatment-related side effects, and physical functioning impacts in women with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. Methods One-on-one concept elicitation interviews were conducted with 15 patients with HR+/HER2- advanced breast cancer. Open-ended questions about patient experience with breast cancer and its treatment were drawn from a semi-structured interview guide. All interviews were audio-recorded and transcribed verbatim, and codes were used to document and organize patient descriptions of their experiences. Coded concepts were defined, supported by exemplary patient quotes, and analyzed for frequency of mention and saturation. Five interviews with experienced oncologists were conducted to supplement the concept elicitation interviews. Results The average age of the patients was 66 years. Most (53%) self-identified as White/Caucasian; 40%, as Black/African American. Patients were reported to have metastases to bone (87%), liver (20%), lung (13%), skin (7%), and lymph nodes (7%). The most frequently reported disease-related concepts were fatigue and lump in breast (47% each) and pain (40%), while the most frequently reported treatment-related side effects were hair loss (67%), fatigue/tiredness (47%), and nausea (40%). Patients identified 10 concepts associated with both breast cancer and its treatment, including fatigue/tiredness, shortness of breath, weakness, and nausea. The most frequently reported impacts on physical function included working around home (73%), walking (73%), and cooking (53%). The most frequently reported symptoms and side effects from the expert perspective included fatigue, pain, and hot flashes (n = 5 each, 100%), while the ability to work (n = 5, 100%) and walk (n = 3, 60%) were reported impacts, aligning with those concepts reported by patients. The resulting concepts were organized into a patient-based conceptual model. Conclusions Patients have varied experiences due to HR+/HER2- advanced breast cancer and its treatment, and commonly experience fatigue/tiredness, hair loss, general pain, lump in breast, and nausea, as well as impacts to physical functioning (specifically, activities of daily living and mobility). Electronic supplementary material The online version of this article (10.1186/s41687-019-0098-1) contains supplementary material, which is available to authorized users.


Background
For patients with hormone receptor positive (HR+)/human epidermal growth factor receptor-2 negative (HER2-) advanced (i.e., metastatic, locally advanced, or stage III or IV) breast cancer, standard treatments include endocrine monotherapy or targeted therapy with an anti-estrogen in patients with non-visceral or asymptomatic visceral tumors [1]. Disease process and associated treatments can give rise to numerous symptoms, typically differing based on site of metastasis and disease course, and adverse effects that negatively impact patients' day-to-day lives [1]. Treatment goals for this patient population are to increase overall survival, delay disease progression, and improve or maintain quality of life [2].
Because treatment for HR+/HER2-advanced breast cancer is rarely curative, understanding the most relevant disease-related symptoms, treatment-related side effects, and impacts, particularly those on physical functioning, is essential for promoting and maintaining high levels of quality of care in this patient population. In order to evaluate treatment benefits from the patient perspective, it is necessary to understand the most important and relevant aspects of the HR+/HER2-advanced breast cancer experience.
In its 2009 Patient-Reported Outcome (PRO) Guidance to Industry, the United States Food and Drug Administration (FDA) acknowledged the value of the patient perspective in evaluating drug efficacy to support labelling claims [3]. In oncology specifically, the FDA has encouraged the evaluation of patient symptoms and functioning in addition to more traditional biomarkers such as tumor response and progression-free survival [4,5]. This acknowledges that the impact of disease-related symptoms and adverse events resulting from drug therapies plays a role in patient functioning, particularly in regard to physical functioning [6]. From a measurement strategy perspective, prior work suggests that core contributors to patient health-related quality of life (HRQoL) include diseaserelated symptoms, treatment-related side effects, and physical functioning, and that each core contributor should be articulated and measured separately in order to best assess patient-reported effects of therapy [6]. Given the plethora of disease-related symptoms and potential treatment-related side effects in oncology, the inclusion of PRO measures assessing drug effects is an important and necessary step in incorporating meaningful patient perspectives and better understanding the outcomes of these clinical trials.
To direct and inform the research described in this paper, a targeted review of the scientific literature was first conducted to identify and describe the patient experience of advanced breast cancer from the perspective of the peer-reviewed literature. The literature review identified several qualitative studies that sought to provide findings on the relevant and important disease-related symptoms, treatment-related side effects, and impacts of breast cancer from the patient perspective. For example, two semi-structured interview studies and one study that involved essay writing all identified pain and lack of energy (fatigue) as key symptoms or side effects among women with metastatic breast cancer [7][8][9]. Other symptoms and side effects that women in these studies described included muscle weakness, nausea, vomiting, infections, hot flashes, and sexual dysfunction. Study participants also reported a number of breast-cancer related impacts, such as the ability to enjoy life, worry that the condition will get worse, concerns about appearance, and the ability to work and care for family. Further, another exploratory study of the psychosocial aspects of metastatic breast cancer endorsed similar impacts [10].
Although patient experiences with advanced breast cancer have been researched, there is a need to understand patient experiences across biomarkers, which can differ substantially due to various sites of metastases, disease history, and treatment options [7,11]. Understanding experiences across biomarkers can inform selection of tools that reflect concerns specific to each population. The purpose of this article is to identify relevant disease symptoms, treatment-related side effects, and physical functioning impacts in women with HR +/HER2-advanced breast cancer specifically from the perspective of patients, as well as experienced oncologists, in order to inform patient-centered measurement strategies of drug efficacy and adverse events in this patient population.

Methods
Qualitative concept elicitation interviews were conducted with patients with HR+/HER2-advanced (i.e., metastatic, locally advanced, or stage III or IV) breast cancer. Interviews with experienced oncologists were also conducted to supplement findings from the patient perspective.

Qualitative patient interviews
Concept elicitation interviews were conducted to collect and document information about the important and relevant disease-related symptoms, treatment-related side effects, and physical functioning impacts from the perspective of patients with HR+/HER2-advanced breast cancer. Patients were also administered selected PRO measures to evaluate their understanding of the content; results of that activity are beyond the scope of the present paper and will be published elsewhere.
Approval to execute the study was received from Quorum Independent Review Board on 27 June 2016. All patients completed and signed statements of informed consent prior to their participation and, once enrolled, completed a Demographic Health and Information Form. A clinician-completed Subject Clinical Screener was used to collect clinical data about patients enrolled in the study.

Patient recruitment
Patients were recruited in person by clinicians at four different clinical sites in the United States (US) from June 2016 to December 2016. Clinicians reviewed patient charts and communicated with a third-party recruitment agency regarding patient eligibility. Patients were considered eligible for participation if they had clinical confirmation of HR+/HER2-advanced breast cancer not amenable to curative treatment by surgery or radiotherapy and were willing and able to participate in a 90-min interview. Additional clinical targets were identified (i.e., menopausal status, treatment experience, and metastatic site) to align the qualitative study population with clinical trials, as recommended by the FDA's 2009 PRO guidance [3]. Recruitment targeted approximately 20 patient participants based on predictions about the number of participants required to achieve saturation (i.e., the point at which no new or relevant information is gained from additional interviews [12,13]).

Conduct of patient interviews
One-on-one patient interviews were conducted in person or over the telephone. The interviews were approximately 90 min long, and the concept elicitation portion lasted approximately 45 min. Trained interviewers followed a semi-structured interview guide developed to solicit spontaneous responses through open-ended questions about the topics of disease-related symptoms, treatment-related side effects, and physical functioning impacts experienced by patients. The interview guide contained questions designed to allow patients to provide detailed descriptions of these topics, such as:

Data management, analysis, and presentation
Interviews were audio-recorded, transcribed, anonymized (i.e., identifying information was removed), and imported into ATLAS.ti, a computerized qualitative data analysis package (ATLAS.ti Scientific Software Development GmbH, Berlin, Germany) [14], to facilitate the storing, coding, and retrieval of qualitative data using Boolean operators [15]. Coding consisted of a researcher or "coder" identifying transcript text where a patient expressed a unique breast cancer-related symptom, treatment-related side effect, or physical functioning impact (i.e., a concept), highlighting that text, and then assigning the text to a code from the codebook, or developing a new code, that best characterized the concept. All three coders coded and then reviewed the first transcript together, and subsequently met to review each coded transcript to ensure consistency across the study sample. This process was ongoing until harmonization of the use of all codes within all transcripts was reached.
To evaluate saturation, disease-related symptom, treatment-related side-effect, and physical functioning impact concept emergence was documented across sets of successive interviews. The first 25% of interviews were compared with the next 25% of interviews to see what, if any, new concepts emerged, followed by comparing the third 25% against the first 50%, and the final 25% against the first 75% [16][17][18]. Saturation was considered reached when no new relevant data was expected to emerge from additional interviews (i.e., when ≥90% of sign, symptom, and treatment-related side-effect concepts had emerged in the first 75% of interviews).
To organize and catalog patients' descriptions of their HR+/HER2-advanced breast cancer experience, concepts were analyzed qualitatively by examining specific words and phrases used by the patient regarding relevant characteristics of each concept (e.g., description of sensation, duration, location, severity, frequency, and attribution of the concept to disease and/or its treatment) and quantitatively by overall frequency of report (i.e., the number of patients who reported a concept as being relevant). The frequency with which a concept was reported by patients as most bothersome or occurring most frequently was also analyzed quantitatively. This approach allowed for the concepts that are important and relevant to the patients' HR+/HER2-advanced breast cancer experience to emerge by observing and examining the patient voice. Data collected from the interviews were organized into concept description tables and were used to construct an HR+/HER2-advanced breast cancer conceptual model.

Interviews with experienced oncologists
Concept elicitation interviews with five oncologists experienced in the area of advanced breast cancer were conducted to support the patient interview findings by defining and describing disease-related symptom concepts, treatment-related side-effect concepts, and impact concepts from the perspective of therapeutic area experts. Experienced oncologists were identified by study sponsor-employed clinicians. The interviews were conducted over the telephone by trained interviewers, followed a semi-structured interview guide, and were approximately 60 min in length. The interviews were audio-recorded, transcribed, anonymized, and analyzed using semi-quantitative and qualitative data analytic methods via ATLAS.ti Version 7.5 or later [14]. Concepts reported by at least three oncologists were considered to be the most frequently reported.

Qualitative patient interviews Study sample
A total of 15 patients participated in the interviews. Patients' ages ranged from 45 to 87 years, with a mean age of 66 years (standard deviation = 12.4). Six patients (40%) self-identified as black or African American, eight (53%) self-identified as white/Caucasian, and one (7%) selected "Other" in response to race. The majority of patients reported completing some college or beyond (n = 13, 87%) and reported their overall health status as "good" or "fair" (n = 13, 87%) ( Table 1).

Disease-related symptom and treatment-related side-effect concepts
A total of 50 sign, symptom, and treatment-related side-effect concepts were elicited spontaneously from patients during the qualitative interviews. Patients identified 14 unique concepts that they attributed to be disease-related signs or symptoms; fatigue and lump in breast (n = 7 each, 47%) and pain (n = 6, 40%) were the three most frequently reported. Patients also identified 43 concepts that they attributed to be treatment-related side effects. The three most frequently reported treatment-related side effects were hair loss (n = 10, 67%), fatigue/tiredness (n = 7, 47%), and nausea (n = 6, 40%). Fatigue/tiredness, general pain, nausea, shortness of breath, weakness, diarrhea, lymphedema, weight loss, neck swelling, and cough were identified as both disease-and treatment-related experiences. Due to some overlap in patients' attribution of disease-and treatment-related concepts, analyses were performed to identify the most frequently reported concepts overall, which included fatigue/tiredness (n = 12, 80%), hair loss (n = 10, 67%), and general pain and lump in breast (n = 7 each, 47%). The overall most frequently reported concepts are reported with exemplary patient quotes in Table 3.
Eleven of the 50 sign, symptom, and treatment-related side effect concepts were reported by patients as the "most frequent" (i.e., occurring often) characteristic of their disease, with general pain reported by the greatest number of patients as occurring frequently (n = 3, 20%). The disease-related symptoms or treatment-related side effects that patients reported to be "most bothersome" were varied; shortness of breath (n = 3, 20%), followed by fatigue/tiredness, general pain, and vomiting (n = 2 each, 13%) were mentioned as "most bothersome" by more than one patient each. All of the "most frequent" concepts were also reported by patients as the most bothersome, with the exception of vomiting (Note: The "vomiting" concept is not included in Table 3, as it was reported by fewer than 20% of patients).

Impact concepts
The majority of the 36 total impact concepts reported by patients were related to the impact of HR+/HER2advanced breast cancer on patients' ability to function physically (n = 26, 72%). Most frequently, patients reported that their condition affected concepts within the activities of daily living domain (including their ability to do housework [n = 11, 73%] and ability to cook [n = 8, 53%]) and the general physical functioning domain (ability to walk [n = 11, 73%]) ( Table 4). Patients spontaneously reported on other types of impacts aside from physical functioning, which were noted during analysis. For instance, more than a quarter of subjects described the impact their condition had on the domains of leisure activities (e.g., bowling) (n = 10, 67%), relationships (e.g., ability to maintain relationships) (n = 7, 47%), work (e.g., having to transition from full-time to part-time work) (n = 4, 27%), and sleep (e.g., difficulty sleeping due to pain or discomfort) (n = 4, 27%) (Additional file: 1 Table S3).
The 50 sign, symptom, and side effect concepts and 36 impact concepts reported by subjects during the concept elicitation portion of the interviews were organized into a patient-based conceptual model (Fig. 1).

Saturation
Of the 50 sign, symptom, and treatment-related side-effect concepts that were elicited spontaneously from subjects during the qualitative interviews, 48 (96%) were elicited in the first 75% of interviews. A total of 26 physical function impacts were elicited from subjects, 23 (88%) of which were elicited in the first 75% of interviews. Based on these saturation results, it was determined that an adequate number of interviews had been conducted.

Overall results
A concept tracking matrix was developed to evaluate the extent to which patients' most frequently reported HR  +/HER2-advanced breast cancer-related concepts were also endorsed by experienced oncologists (Table 6). In summary, all of the sign, symptom, and side effect concepts frequently reported by patients were also reported by the oncologists: fatigue/tiredness, hair loss, general pain, lump in breast, nausea, shortness of breath, and weakness. Additionally, fatigue/tiredness, general pain, nausea, and shortness of breath were identified as both disease-and treatment-related by patients and oncologists. Hair loss was reported by both sources as a treatment-related side effect only. Oncologists defined "weakness" as specifically a disease-related symptom, whereas the patients attributed weakness to both the disease and its treatment (Table 7). Of the three physical functioning impacts most frequently reported by patients, two were supported by the oncologists: ability to walk and ability to do housework. The third impact, patients' ability to cook, was reported by approximately half of the patients (53.3%), but was not reported by the oncologists.

Discussion
The intent of the present research was to identify the important and relevant disease-related symptoms, treatment-related side effects, and physical functioning impacts from the perspective of patients with HR +/HER2-advanced breast cancer, supported by the perspective of experienced oncologists. The present study suggests, similar to other research [7][8][9], that pain and fatigue were the most relevant symptoms. Further, these symptoms affect important areas of functioning [7]. The importance of fatigue specifically is consistent with findings in general advanced cancer populations. In a study by Butt et al. (2008) of symptoms in advanced cancer patients who had received chemotherapy for advanced bladder, brain, breast, colorectal, head and neck, hepatobiliary/pancreatic, kidney, lung, ovarian, or prostate cancer or lymphoma (N = 534), patients reported fatigue as either the first or second most important symptom or concern to monitor [19]. Garcia et al. also found fatigue  Frequency is presented as the total count for each concept reported at least once by at least one-third of patients; all signs, symptoms, and side effects were spontaneously reported by the patient without prior mention by the interviewer. The following concepts were reported by fewer than one-third of patients: diarrhea, lymphedema, neuropathy, skin burn, altered taste, constipation, feeling unwell, injection site reaction, joint pain, loss of appetite, vomiting, bone pain, dizziness, headache, hot flashes, indent in breast, memory loss, mouth sores, nail issues, neck swelling, stiffness, stomach pain, acid reflux, allergic reaction, bleeding, bloating, breast size decrease, chemotherapy brain, cough, flu-like symptoms, lung fluid build-up, flushing, gout, itching, lack of balance, lymph node inflammation, runny nose, skin peeling, sore throat, vaginal bleeding, weight gain (Additional file: 2 Table S1) c Frequency is presented as the total count for each concept reported as most bothersome by the patients d Frequency is presented as the total count for each concept reported as most frequent by the patients e Frequency is presented as the total count for each concept reported as disease-related, treatment-related, and/or unsure attribution; frequency counts for concept attribution are not mutually exclusive to be the most important symptom experienced by advanced breast cancer patients [7]. Similarly, in Siefert's 2010 study of outpatient chemotherapy patients (breast, colorectal, lung, and lymphoma; N = 70), fatigue was the most commonly reported symptom and most important to patients [20].
The present study also found that patients attributed many concepts to both the condition and its treatment, and in some cases, patients were unable to attribute a particular concept specifically to their disease or its treatment. The challenges of distinguishing between diseaseand treatment-related symptoms were not unique to the Frequency is presented as the total count for each concept reported at least once by at least one third of patients; all impacts were spontaneously reported by the patient without prior mention by the interviewer. The following physical functioning impact concepts were reported by less than one-third of patients: toileting, bathing, ability to drive, ability to lift, ability to climb stairs, ability to exercise, ability to lie down, ability to sit, ability to stand, fine motor skills, ability to bend, ability to get in and out of car, ability to move at normal pace, ability to stand from seated position, dancing, gardening, bowling, crocheting/knitting, ability to care for pets, ability to play pool, lack of interest in hobbies, and ability to sleep (Additional file: 3 Table S2) c Frequency is presented as the total count for each concept associated with a disease-related sign or symptom and/or treatment-related side effect current study or to breast cancer. Indeed, prior research by Cleeland et al. (2010) has noted that cancer-related disease and treatment symptoms do not occur in isolation, but instead occur simultaneously, and that this should be taken into consideration when trying to measure the patient experience [21]. Rosenberg and colleagues (2012) conducted a study that aimed to describe symptom burden and symptom attribution patterns in a large sample of breast cancer survivors taking endocrine therapy [22]. They found that more than half of women (53%) misattributed at least one symptom to their endocrine therapy.
The results of the current research were combined into a concept tracking matrix (Table 6), which demonstrates the extent to which patients' most frequently reported disease-experience concepts overlapped with those from the experienced oncologists. The value of this table is that these results may help to guide future PRO instrument development for this specific patient population. While FDA PRO guidance places primacy on the patient perspective [3], understanding and evaluating the commonalities in report across the two data sources provides additional insight into which concepts may be the most important and relevant for future measurement.
Limitations of this study include several challenges in generalizing findings to the wider advanced breast cancer population. Although saturation was determined to have been achieved for symptoms/side effects, Fig. 1 Patient-centric conceptual model of HR+/HER2-advanced breast cancer. Concepts that are shown in bold were reported by subjects patients to be related to both the disease and its treatment. Disease-related, treatment-related, and unknown cause concepts are ordered by frequency with which subjects patients reported concept attribution.*The following treatment-related side effects were reported by one subject patient each: acid reflux, allergic reaction, bleeding, bloating, breast size decrease, chemotherapy brain, cough, flu-like symptoms, flushing, gout, itching, lack of balance, neck swelling, runny nose, skin peeling, sore throat, stiffness, stomach pain, weight gain, weight loss suggesting that these concepts are the key features of the HR+/HER2-advanced breast cancer experience, there is a possibility that because of the specific breast cancer subtype and treatments received, these results may not be generalizable to the wider advanced breast cancer population. Treatment-related concepts may vary based on treatment regimen, dose, sequence, and schedule [6]. Furthermore, it is not known the extent to which molecular subtype or solid tumor type affect the experience of disease-related symptoms. For example, it is not clearly understood whether HR-/ HER2+ status or tumor location distinguish one patient population from another. However, a greater understanding of these differences and similarities will allow researchers to more confidently draw conclusions about generalizability.
Another potential limitation of the current study was the sole focus on physical functioning-type impacts during the patient interviews. Although other types of impacts were spontaneously elicited and reported in the findings, these were not explored in as much depth, given time limitations and the focus of this study. The focus on physical functioning was driven from a PRO measurement perspective; previous literature indicated that it is a core contributor to patient HRQoL, and less susceptible to confounding sources other than the disease or its treatment [6], thus taking precedence over other impacts in terms of measuring drug efficacy.
Documenting and describing the relevant sign, symptoms, and impacts from the patient perspective contributes to a deeper understanding of the specific patient experience of HR+/HER2-advanced breast cancer and Table 5 Oncologist-reported HR+/HER2-advanced breast cancer concepts (N = 5)

Concept
Disease symptom oncologist report n (%) Treatment side effect oncologist report n (%)  can provide avenues to identify and target the measurement of treatment outcomes. Recent emphasis on PROs from the FDA, particularly in oncology [4,5], highlights the continued need to encourage and affirm the patient voice in drug development. Future research is necessary to both confirm the findings of this study and assess their applicability to the general advanced breast cancer population.