Physical and mental health of breast cancer patients and survivors before and during successive SARS-CoV-2-infection waves

The World Health Organization declared the coronavirus disease 2019 (COVID-19) outbreak a pandemic on March 11, 2020 [1, 2]. Due to the immediate high burden on healthcare systems, adapted cancer treatment protocols were implemented rapidly [3‐11]. A subsequent temporary disruption in breast cancer screening programs[12, 13], changed referral patterns and changed attitudes toward health care consumption [3, 4, 14] contributed to a sharp decrease in breast cancer diagnoses in 2020 [12, 15]. In response to the dropping cancer diagnoses and abrupt changes in cancer care, increased concerns and anxiety about the consequences of delay and discontinuation of screening, diagnosis, and treatment were observed among cancer patients [2, 14, 16‐18].

The unpredictable course of the viral spread still provides an uncertain prospect toward the future for patients [19, 20]. Despite governmental efforts, including social restrictions and rapid development of COVID-19 vaccines, the global pandemic continues to affect daily life through mutant variants of the virus [21]. It is estimated that the current pandemic is likely to last for years, and that social restrictions should not be discarded completely before 2024 due to possible resurgence in contagion [22].

Regardless of a pandemic, patients with currently active or a history of breast cancer have an increased risk of impaired mental health compared to individuals without cancer [23, 24]. As long-term consequences of adverse mental health among breast cancer patients may result in poorer treatment adherence, impaired prognosis and survival, and higher barriers to returning to work [25‐29], the pandemic could result in unforeseen long-term adverse effects [30].

During the first months of the COVID-19 pandemic, a deterioration in emotional well-being and an increased need for mental health care were already observed among breast cancer patients [3, 4, 8, 31]. In our previous study [3], conducted amidst the first SARS-CoV-2-infection wave, we observed a substantial drop in emotional and social functioning among breast cancer survivors, and one in two experienced loneliness. However, initial emotional response could stabilize or diminish after patients adjust to a certain situation [32]. As previously described during the 2009 H1N1 pandemic, psychological effects of a viral pandemic can last until 30 months after its onset [33]. Therefore, it is important to understand and monitor the long-term effects of the lingering COVID-19 pandemic on physical and mental health in patients with breast cancer [3, 32, 34].

The aim of this follow-up study was to assess patient-reported quality of life (QoL), physical functioning, and psychosocial well-being in a large prospective cohort of breast cancer patients during the second SARS-CoV-2-infection wave. For context, we compared patient-reported outcomes (PROs) measuring QoL, physical functioning, and psychosocial well-being during the second SARS-CoV-2-infection wave to (1) PROs of the same population during the first SARS-CoV-2-infection wave, (2) PROs of a similar non-cancer reference population, and (3) their own pre-COVID-19 PROs.

Between October 2013 and April 2020, 3239 patients were enrolled in UMBRELLA (Fig. 1). Of those, 1595 patients were eligible for receiving the COVID-19-specific survey during the first SARS-CoV-2-infection wave. By November 2020, 3364 patients were enrolled in UMBRELLA, of whom 1614 met the inclusion criteria for the second COVID-19-specific survey. Response rates were 69.3% (n = 1106) during the first SARS-CoV-2-infection wave, and 50.9% (n = 822) during the second SARS-CoV-2-infection wave.

In total, 696 patients responded to both COVID-19-specific surveys (Fig. 1). Mean age of responders to both surveys was 56 years (range = 29–79, SD = 9.2) and mean BMI was 26.1 (SD = 4.7, Table 1). Median follow-up was 31 months (range = 1–85). The majority were diagnosed with a pathological T1-stage tumor (n = 401, 57.6%) and treated with breast conserving surgery (n = 555, 79.7%) and (loco)regional radiation therapy (n = 631, 90.7%). Most responders (n = 554, 79.6%) were living with a partner and/or child(ren), and 25.6% (n = 178) had received mental healthcare support since diagnosis. During both waves, baseline characteristics of responders and non-responders were comparable (Supplementary Table 2).

The non-cancer reference population included 241 individuals without currently active or a history of cancer with a mean age of 58 years (range = 31–82, SD = 9.2, Table 1). The majority (n = 190, 78.9%) were living with their partner and/or child(ren). Baseline characteristics of the reference population were similar to the responders of both surveys regarding age, sex, BMI, educational level, and current living situation (Table 1).

The number of responders to the survey during the second SARS-CoV-2-infection wave who had also completed the pre-COVID-19 survey varied per questionnaire and per subdomain, resulting in a population of 664–729 participants depending on the subdomain (Table 4).

This large prospective observational study observed several clinically important and reassuring findings concerning the impact of the ongoing COVID-19 pandemic on patient-reported QoL, physical functioning, and psychosocial well-being among breast cancer patients up to nine months since onset. From the first to the second SARS-CoV-2-infection wave, emotional functioning, and symptoms of anxiety and depression improved, while all other QoL scores remained stable. Also, the proportion of patients experiencing emotional loneliness decreased from 37.6 to 29.9%. However, during the second SARS-CoV-2-infection wave, patients treated or being treated for breast cancer still scored worse on all QoL domains in comparison with a similar non-cancer reference population of similar age, except for financial difficulties. When comparing PROs during the second SARS-CoV-2-infection wave to pre-COVID-19 PROs, outcomes were largely similar.

In accordance with our findings, previous studies observed a worldwide increase in anxiety and depression among breast cancer patients and survivors during the first months of the pandemic [31, 34, 58‐60]. Fortunately, we observed no further clinically meaningful deterioration on all QoL-subdomains, anxiety or depression among breast cancer patients nine months after the onset of the pandemic. Moreover, the proportion of patients with clinically relevant impairment on the different QoL-subdomains did not change statistically significantly from the first to the second SARS-CoV-2-infection wave.

Emotional functioning and emotional loneliness improved between the first and second SARS-CoV-2-infection wave, and lower levels of anxiety and depression were observed. Independent of a pandemic, gradual increases in physical functioning and psychosocial well-being and QoL are generally observed over time during the first years after diagnosis among patients treated or being treated for breast cancer [3, 61]. However, as mean follow-up of our study population was 31 months, our cohort was likely to have reached a plateau in which this improvement in mental well-being has naturally stabilized [62‐64]. Moreover, whether emotional functioning (MD = 3.0) improved to a clinically relevant extent is debatable. A small MID has previously been estimated at MD > 5–10[49, 63, 65]; however, a breast cancer-specific MID for emotional functioning has yet to be established [47, 48].

Similar to our findings, Rentscher and colleagues [66] found an increase in loneliness among breast cancer survivors during the first months of the pandemic in comparison with pre-COVID-19, and no difference in loneliness compared to matched controls. Likewise, a Dutch study [24] observed increased loneliness among cancer patients and their family members during the first SARS-CoV-2-infection wave. From the first to the second SARS-CoV-2-infection wave, we observed a decrease in the proportion of patients reporting moderate to severe overall loneliness from 47.7 to 42.0%, which was also comparable to our non-cancer reference population. Nonetheless, these proportions are still substantially higher than the previously published 34% of individuals experiencing loneliness in a general Dutch population of comparable age in 2019, pre-COVID-19 [67].

COVID-19 has an especially large impact on the mental health of individuals with currently active or a history of cancer when compared to similar and non-cancer reference individuals [68]. A large American study showed that, shortly after the COVID-19 outbreak, cancer survivors were more likely to feel anxious, depressed and lonely than adults without cancer [69]. Nine months after the onset of the pandemic patients still scored worse than the non-cancer reference population on all QoL-subdomains, however, we did not observe differences in anxiety, depression, and loneliness. Based on known MIDs [47, 48], the observed differences for patient-reported QoL, financial difficulties, social, role, and physical functioning would be considered clinically trivial, and differences for emotional and cognitive functioning, dyspnea and insomnia of small clinical relevance [47, 48]. No breast cancer-specific MID has been established yet for the subdomain future perspectives [47, 48], but based on the established MID for future perspectives among multiple myeloma patients, an MD < 10 would not be considered clinically meaningful [70]. Several pre-COVID-19 studies showed that, regardless of a pandemic, breast cancer patients have a higher risk of worse mental health and cognitive issues than non-cancer individuals [23, 71]. Therefore, the observed differences with small clinical relevance are most likely explained by the treatment of the disease and/or the disease itself rather than the COVID-19 pandemic.

When compared to pre-COVID-19, PROs during the second SARS-CoV-2-infection wave provided reassuring perspective, as all observed differences in EORTC-QLQ-C30/BR23 scores between pre-COVID-19 and the second wave were estimated clinically trivial [47, 49, 70]. No breast cancer-specific MIDs for the HADS have been established yet [55], however, based on the MIDs for the HADS among patients with chronic obstructive pulmonary disease[72], the differences in HADS scores would also not be considered clinically meaningful. Thus, the previously observed deterioration in psychosocial well-being during the first SARS-CoV-2-infection [3] wave could likely have reflected a temporal effect of the pandemic, as most QoL domains seemed to return to pre-COVID-19 levels during the second SARS-CoV-2-infection wave. As such, it seems that participants adjusted to the new situation and learned to live through a pandemic.

To date, herd immunity, effectiveness of vaccines and SARS-CoV-2-infection control measures have improved, resulting in dropping hospitalization and mortality rates due to SARS-CoV-2-infection [73, 74]. While this has likely reduced levels of anxiety toward contracting SARS-CoV-2-infection, the pandemic continues to cause concerns about its long-term effects. For example, the effectiveness of vaccines beyond six months is still unclear [73], and it has been reported that women older than 20 years, and thus, the vast majority of breast cancer patients are more likely to develop at least one out of the three ‘Long COVID’ symptoms, including persistent fatigue with bodily pain or mood swings, ongoing respiratory problems, or cognitive problems [75].

Since the start of the pandemic, there has been extra attention for the mental health of breast cancer patients through the implementation of various e-mental-health projects [76‐78]. Although improved over time, emotional functioning of breast cancer patients was still lower during the second wave than pre-COVID-19 and lower when compared to non-cancer individuals. Consequences of decreased emotional functioning should not be underestimated. Impaired mental health in breast cancer patients is associated with poorer treatment compliance and might thereby negatively affect survival [29, 34, 79]. As such, long-term effects of the current COVID-19 pandemic on mental health of breast cancer patients should continue to be monitored to minimize adverse effects of the pandemic in the future [16, 68, 79, 80]. Moreover, previous studies have shown that social isolation and the lack of emotional support from family and friends are associated with higher risk of mortality [81, 82]. For current clinical practice and beyond an apparent end of the pandemic, it is therefore strongly advised to (further) develop and implement e-mental health applications and psychosocial interventions, aiming to improve mental health of this vulnerable population that is reported to be uniquely at risk for experiencing emotional distress [2, 31].

This study has some limitations. First, although baseline characteristics of responders and non-responders were comparable during both infection waves, an under- or overestimation of the results due to selective (non-)response could not be ruled out as the reasons for non-response were unclear. Second, only participants who had opted to complete online surveys were eligible for this study. Participants who opted for paper surveys were excluded, possibly resulting in some degree of selection bias. Third, although baseline characteristics, and thus, socio-economic status, of the reference population were similar to our UMBRELLA participants, the reference population might still have been subject to some degree of selection bias, as all reference individuals were directly or indirectly faced with the impact of breast cancer diagnosis and treatment through the related UMBRELLA-participant. Last, the results of this study represent PROs during the first and second SARS-CoV-2-infection peaks in the Netherlands and might therefore be subject to fluctuations that follow the severity of the infection peaks. An important strength of this study is that this is the first longitudinal study to evaluate the course of PROs in patients treated or being treated for breast cancer from pre-COVID-19 until the second SARS-CoV-2-infection wave. The ongoing collection of clinical data and PROs within UMBRELLA allows for future analyses with successive PROs during and after consecutive SARS-CoV-2-infection waves to monitor the impact of the pandemic and its subsequent social measures on physical functioning and psychosocial well-being of breast cancer patients and survivors, aiming to support nationwide preventive and curative mental health care programs.

Despite the lingering COVID-19 pandemic, patient-reported QoL, physical functioning and psychosocial well-being in individuals treated or being treated for breast cancer did not deteriorate between the first and second SARS-CoV-2-infection waves. Emotional functioning, anxiety, and depression slightly improved, and the proportion of patients experiencing emotional loneliness decreased. Compared to a similar and non-cancer reference population, individuals treated or being treated for breast cancer still scored clinically meaningfully worse for patient-reported physical, emotional, and cognitive functioning, future perspectives, dyspnea, and insomnia nine months after the COVID-19 outbreak. However, in comparison with pre-COVID-19, no clinically meaningful differences were found during the second SARS-CoV-2-infection wave.