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Breast Cancer Management in the Era of Covid-19; Key Issues, Contemporary Strategies, and Future Implications

Authors Prodhan ASU, Islam DZ , Khandker SS , Jamiruddin MR , Abdullah A, Godman B , Opanga S, Kumar S , Sharma P , Adnan N , Pisana A, Haque M 

Received 23 September 2022

Accepted for publication 19 January 2023

Published 27 January 2023 Volume 2023:15 Pages 51—89

DOI https://doi.org/10.2147/BCTT.S390296

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Professor Harikrishna Nakshatri



AHM Safayet Ullah Prodhan,1 Dewan Zubaer Islam,2 Shahad Saif Khandker,3 Mohd Raeed Jamiruddin,4 Adnan Abdullah,5 Brian Godman,6– 8 Sylvia Opanga,9 Santosh Kumar,10 Paras Sharma,11 Nihad Adnan,2 Alice Pisana,12 Mainul Haque13

1Department of Biochemistry and Molecular Biology, Jahangirnagar University, Dhaka, 1342, Bangladesh; 2Department of Microbiology, Jahangirnagar University, Dhaka, 1342, Bangladesh; 3Department of Biochemistry, Gonoshasthaya Samaj Vittik Medical College, Dhaka, 1344, Bangladesh; 4Department of Pharmacy, BRAC University, Dhaka, 1212, Bangladesh; 5Unit of Occupational Medicine, Faculty of Medicine and Defence Health, Universiti Pertahanan Nasional Malaysia, (National Defence University of Malaysia), Kuala Lumpur, 57000, Malaysia; 6Department of Pharmacoepidemiology, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK; 7Centre of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates; 8Division of Public Health Pharmacy and Management, School of Pharmacy, Sefako Makgatho Health Sciences University, Ga-Rankuwa, South Africa; 9Department of Pharmacy, University of Nairobi, Nairobi, Kenya; 10Department of Periodontology and Implantology, Karnavati School of Dentistry, Karnavati University, Gandhinagar, Gujarat, India; 11Department of Pharmacognosy, BVM College of Pharmacy, Gwalior, Madhya Pradesh, 474006, India; 12Department of Global Public Health, Karolinska Institutet, Stockholm, Sweden; 13The Unit of Pharmacology, Faculty of Medicine and Defence Health, Universiti Pertahanan, Nasional Malaysia (National Defence University of Malaysia), Kuala Lumpur, 57000, Malaysia

Correspondence: Nihad Adnan, Department of Microbiology, Jahangirnagar University, Savar, Dhaka 1342, Bangladesh, Email [email protected]; Mainul Haque, The Unit of Pharmacology, Faculty of Medicine and Defence Health, Universiti Pertahanan, Nasional Malaysia (National Defence University of Malaysia), Kem Perdana Sugai Besi, Kuala Lumpur 57000, Malaysia, Tel +60109265543, Email [email protected]

Abstract: During the COVID-19 pandemic, several priority diseases were not getting sufficient attention. Whilst breast cancer is a fatal disease affecting millions worldwide, identification and management of these patients did not initially attract critical attention to minimize the impact of lockdown, post-lockdown, and other measures. Breast cancer patients’ conditions may not remain stable without proper care, worsening their prognosis. Proper care includes the timely instigation of surgery, systemic therapy, and psychological support. This includes low-and middle-income countries where there are already concerns with available personnel and medicines to adequately identify and treat these patients. Consequently, there was a need to summarize the current scenario regarding managing breast cancer care during COVID-19 across all countries, including any guidelines developed. We systematically searched three scientific databases and found 76 eligible articles covering the medical strategies of high-income countries versus LMICs. Typically, diagnostic facilities in hospitals were affected at the beginning of the pandemic following the lockdown and other measures. This resulted in more advanced-stage cancers being detected at initial presentation across countries, negatively impacting patient outcomes. Other than increased telemedicine, instigating neo-adjuvant endocrine therapy more often, reducing non-essential visits, and increasing the application of neo-adjuvant chemotherapy to meet the challenges, encouragingly, there was no other significant difference among patients in high-income versus LMICs. Numerous guidelines regarding patient management evolved during the pandemic to address the challenges posed by lockdowns and other measures, which were subsequently adopted by various high-income countries and LMICs to improve patient care. The psychological impact of COVID-19 and associated lockdown measures, especially during the peak of COVID-19 waves, and the subsequent effect on the patient’s mental health must also be considered in this high-priority group. We will continue to monitor the situation to provide direction in future pandemics.

Keywords: COVID-19, breast cancer, healthcare system, healthcare management, treatment, surgery, guidelines, unintended consequences

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing Coronavirus Disease 2019 or COVID-19, was identified in Wuhan, China, in December 2019. It was responsible for pneumonia-like syndrome, acute respiratory distress syndrome, and death.1 Covid-19 has been responsible for over 581 million cases and over 6.4 million deaths globally by the middle of August 2022.2 Preventative measures, including early diagnosis, social distancing, isolation, and lockdown activities, were introduced across countries to control the virus’s spread in the absence of effective treatments and vaccines.3–6 There was though considerable variation in the timing of lockdown and other measures across countries and their enforcement, which impacted subsequent morbidity and mortality rates.7–9

In the early stages of the pandemic, COVID-19 patient management resulted in an appreciable burden on healthcare systems, including Healthcare workers, across countries. The lockdown measures introduced to try and slow the spread of the virus, including the cancellation of elective surgery and hospital clinics as well as disruption in transport services, affected patients already suffering from non-communicable diseases (NCDs) and health systems’ ability to provide NCD-related care.10,11 This appreciably impacted achieving agreed-on sustainable development goals, including reducing current morbidity and mortality from NCDs.12–14 There have also been concerns that lockdown and other measures increased delays in the diagnosis and management of patients with cancer, increasing future mortality alongside the psychological, social, and economic costs associated with these delays.15–18 Within cancers, the optimal management of breast cancer is essential, with more than 1.8 million new cases detected annually worldwide and prevalence rates for breast cancer continuing to rise.19,20 Breast cancer is also the most common cause of mortality among women with cancer, with early detection and active management helping to reduce subsequent morbidity and mortality.21,22

Consequently, breast cancer should be well managed, including enhancing early detection. However, limited hospital resources during the COVID-19 pandemic, travel restrictions among patients, and fear of catching COVID-19 when visiting hospitals for diagnosis and potentially early management hampered care provision across countries, including breast cancer patients.22–24 This is a concern as delays in treating patients with breast cancer increase their morbidity and mortality, with a two-month delay in surgery potentially increasing the risk of mortality by 26% in early-stage invasive breast cancer.18

Different studies have been conducted across countries reporting on changes in diagnosis strategies, including delays, treatment approaches, including those brought about by delays in surgery, as well as patients presenting in the late stages of breast cancer brought about by the measures to limit the spread of COVID-19, all adversely impacting on the morbidity and mortality of these patients.15,18,22 This also includes the psychological impact brought about by delays in the diagnosis and management of breast cancer due to lockdown and other measures.25,26 Several studies also provided essential guidelines for managing breast cancer patients as safely and efficiently as possible during the pandemic.27,28 However, we are unaware of any study that has been undertaken to summarize key findings, reports, and recommendations across countries to provide future guidance on ways to improve all aspects of care for patients with breast cancer during the current and future pandemics. Consequently, we sought to address this. This review summarises available literature regarding all aspects of care of patients with breast cancer during the current pandemic, with the aim of documenting key aspects regarding diagnosis and treatment strategies, including the psychological impact of lockdown and other measures, as a basis for improving the care of these patients during current and future pandemics.

Methodology

Three different online databases (ie, Google Scholar, PubMed, and ScienceDirect) were searched for this literature review using specific keywords, which included “COVID-19”, “SARS-CoV-2”, “breast cancer”, “surgery” and “surgical”, and following the PRISMA method.29 The search was restricted from January 2020 to April 25, 2022, and relevant articles were extracted. The inclusion criteria included full-length papers discussing all aspects of managing breast cancer during the COVID-19 pandemic, including diagnosis and management, incorporating systemic treatments and surgery. In addition, articles discuss the management of breast cancer patients with COVID-19 and the psychological impact of COVID-19. Finally, any guidelines on the suggested management of breast cancer patients during the pandemic. Exclusion criteria included articles which were not relevant to our study interest or did not cover the topic of our inclusion criteria, ie, were not full-length research articles such as correspondence, letters to the editor, short communications or reviews, or those found outside our fixed search dates or not written in the English language. Duplicates of the same article found in multiple databases were also excluded (Figure 1).

Figure 1 Illustrating literature search strategy.

Three co-authors (AHMSUP, DZI, and SSK) independently assessed each identified study. Any confusion or concern with identified papers was thoroughly discussed, and a consensus was reached among the three authors before proceeding.

A simplified PRISMA diagram of methodology (Figure 1). Nine hundred eighty-six articles were identified through this search strategy. Eight hundred and eighty-four articles were excluded due to ineligibility. Of the remaining 102 articles, 11 were excluded as they did not match the study criteria of full-length research articles on managing breast cancer and the COVID-19 pandemic. After excluding the duplicate articles (n=15), 76 articles were included in this review.

The study findings were broken down into the key aspects of management, including diagnosis and treatment, as well as those from low- and middle-income countries (LMICs) versus high-income countries and worldwide. This is because there are considerable differences in the funding of cancer care between LMICs and high-income countries, with concerns about funding even older biological medicines, such as trastuzumab, in LMICs without significant discounts or donor support.30–32 Consequently, there may be differences between LMICs and high-income countries in managing breast cancer patients during any pandemic, with LMICs struggling with the financial impact of COVID-19 without donor support.7,8

In addition, each aspect of care was further broken down into the studied country, type of study, study period, number of participants and their age (if available), key measurements, study results, and comments/ suggestions contained in the published papers. Key areas included the impact of COVID-19 on diagnosis, including delayed diagnosis and presentation of patients with breast cancer, systemic therapy prescribed and the overall management of breast cancer patients during the pandemic, surgery strategies, management of breast cancer patients with COVID-19, and the mental health of patients with breast cancer during the pandemic. Finally, the Publication of specific guidelines for diagnosing and managing patients with breast cancer can provide future direction.

Results

The influence of COVID-19 on the stage of presentation and diagnosis, including any delays in diagnosis due to the pandemic in patients with breast cancer, will be discussed first, along with the implications for future management during further pandemics. Subsequently, the typical presentation of patients for treatment and the implications for different surgical approaches will be discussed. Finally, the impact of COVID-19 on managing patients with both COVID-19 and breast cancer, as well as the pandemic’s implications on patients’ mental health, will also be discussed.

Diagnosis, Presentation, and the Implications

Twenty-five studies were identified for the comprehensive literature review involving 7 LMICs (Brazil, China, Lithuania, Lebanon, Pakistan, Romania, and Turkey) and ten high-income countries (Canada, France, Italy, Japan, Netherlands, Singapore, South Korea, Taiwan, UK, and the USA) (Table 1) alongside additional studies that did not fulfil the inclusion criteria; however, they also reported on the impact of lockdown and other measures on diagnosis patterns for patients with breast cancer. There was a considerable reduction in the identification of new breast cancer patients, especially among LMICs, due to lockdown and other measures (Table 1). Among the LMICs, Li et al in China demonstrated a significant reduction in the number of new cases detected immediately post-quarantine in Hubei Province compared to pre-pandemic levels. However, variations were seen among the different provinces in China. In addition, lockdown and other measures adversely impacted subsequent patient management, including surgery and chemotherapy initiation delays.33 In Lebanon, quarantine measures also appreciably affected the presentation of patients with breast cancer. For instance, diagnostic activity was appreciably reduced in Lebanon during the first three months of lockdown measures (73%), with all but one out of 20 new cases in one hospital found to be invasive carcinoma.34 There was also an appreciable reduction in breast cancer screening activities in Brazil and Lithuania during the initial stages of the pandemic.35,36 However, there were variable findings in Turkey. Kiziltan et al demonstrated an appreciable reduction in the number of new breast cancer patients being identified in the early stages of the pandemic as well as those attending out-patients, with Koca et al showing similar findings, especially regarding out-patient visits.37,38 This contrasted with the findings of Güler et al, who found little impact of lockdown measures on delays in diagnosis and management of patients with breast cancer.39 Crisan et al in Romania also found an appreciable reduction in out-patient visits and mammograms during the early months of the pandemic.40 Advanced-stage breast cancer cases, along with breast cancer patients presenting later in the disease process, were also reported during the early stages of the pandemic in other LMICs, including Pakistan (Table 1).33,41

Table 1 Impact of COVID-19 on Diagnosis and Presentation of Breast Cancer Patients Across Countries

There were also similar findings in several high-income countries (Table 1). There was an appreciable reduction in the number of mammograms undertaken in Canada during the early stages of the pandemic; however, this was reversed by December 2020.42 In France, due to lockdown measures, patients presented with more aggressive tumours at diagnosis, which arose from the suspension of screening programs and postponement of biopsies and consultations, with an appreciable reduction in the number of surgeries performed.43 There were similar concerns and issues in Japan, the Netherlands, Singapore, and Taiwan.44–47 The pandemic seemingly had a more limited impact in South Korea, with only a 9.9% reduction in the number of newly diagnosed cases in the initial period of the pandemic; however, there was a reduction in breast cancer screening activities similar to other high-income countries.48

In Italy, there was also an appreciable upsurge in the number of patients presenting with node-positive and late-stage tumours following a reduction in screening activities due to lockdown measures, which resulted in recommendations to restore screening programs despite these measures immediately.49–51 There were though variable findings in the UK. MacInnes et al documented a partial lockdown effect on the number of new cases diagnosed, although referral rates were down.52 This contrasted with the findings of Romics et al, who found that the tumour size of patients with breast cancer undergoing surgery during the pandemic was significantly larger than before, with a higher number of estrogen receptor (ER) negative cases impacted by lockdown measures and a reduction in screening activities.53 Gheorghe et al calculated an additional 344 deaths due to diagnostic and management delays following lockdown measures, resulting in a loss of 4100 quality-adjusted life years and an estimated productivity loss of GB£ 23.2 million.54 There were also variable findings in the USA. Sprague et al and Yin et al reported appreciable reductions in diagnostic services following the pandemic.55,56 However, Boyd et al reported a lower reduction in mammogram activities (11%) initially coupled with a quick return to normal and even an increase (15%) in patients presenting between October to December 2020 versus pre-pandemic levels.57 Cairns et al also documented a significant decrease in the number of screening mammograms (44% reduction) and diagnostic mammograms (21% reduction) following lockdown measures in 2020 versus a similar period in 2019. However, they found no significant difference in the number of operations for new breast cancer patients in 2020 versus 2019.58

Self-screening breast cancer can be a possible alternative strategy given the limited diagnostic facilities available due to COVID-19 and the potential impact of late diagnosis. Jiwa et al, in their study in the UK, ascertained that undertaking NAF (nipple aspirate fluid -NAF) at home for early-stage detection of breast cancer during any pandemic was possible.59–61 As hospital visits are minimized during the COVID-19 pandemic, the usage of NAF can be a potential screening tool for early-stage breast cancer detection and reducing breast cancer risk. However, they found that 83.4% of women did not know about NAF, and 89.4% did not know that NAF can be expressed in 90% of women. Promisingly, 89.8% of women in their study were eager to learn about their future breast cancer risk, and 92% were keen to experience home testing, especially during pandemics. The authors suggested that public awareness should be increased regarding breast screening protocols like NAF testing to reduce the risk of breast cancer.61 There were similar findings across high-income countries and LMICs (Table 1).

Overall, a number of protocols and guidelines regarding screening the patient population for COVID-19 infection were proposed and followed in different high-income countries to maintain a balance between COVID-19 safety protocols and breast cancer diagnosis. In Italy, Maio et al proposed a protocol of screening patients for COVID-19 infections through a telephone-based questionnaire and classifying patients into one of four groups: Non-COVID-19 patients, confirmed COVID-19 in an asymptomatic screening patient, suspected COVID-19 in symptomatic or confirmed breast cancer and confirmed COVID-19 in symptomatic or confirmed breast cancer.62 Tari et al also proposed a tele-questionnaire-based screening protocol to separate the patients into distinct clinical scenarios: non-COVID-19 patients, suspected COVID-19 patients and confirmed COVID-19 patients before each diagnosis or a nasopharyngeal swab test before recovery. If not urgent, the COVID-19-confirmed or suspected patients were rescheduled.63 Seely et al in Canada proposed guidelines for pre-screening patients for any symptoms of COVID-19 at the time of scheduling and immediately before their imaging visit. The author added that any patient with recent travel history, close contact with a COVID-19 patient, or even mild symptoms should be rescheduled to 2 weeks after symptoms have resolved.64

Systemic Therapy and Patient Management

Twenty-five eligible studies were identified that fulfilled the inclusion criteria. These included 6 LMICs (Brazil, China, Egypt, Lithuania, Pakistan, and Turkey), 11 high-income countries (Canada, France, Netherlands, New Zealand, Portugal, Saudi Arabia, Singapore, Spain, UAE, UK, and the USA), as well as world-wide studies (Table 2). Typically, strategies and approaches of systematic therapies were compared, including prescribing neo-adjuvant chemotherapy (NEC) or neo-adjuvant endocrine therapy (NET) for breast cancer patients during the COVID-19 pandemic with pre-pandemic era following delays with surgery as a result of lockdown and other measures.

Table 2 Summary of Systematic Therapy and Management of Patients with COVID-19 During the Pandemic

Concerning LMICs, the menopausal and genomic status of patients played an appreciable role in choosing NET. In Brazil, NET was recommended for post-menopausal patients with HR+ tumours, with nuclear protein Ki-67<20% and Ki-67>30%, and for ≥1.0 cm tumours whilst waiting for surgery. 42.9% and 39.6% of the specialists, respectively, in Brazil recommended NET for TN and HER2+ tumours.67 In a study in China, 90.3% of patients were shifted from intravenous to oral therapy where appropriate in view of lockdown measures, including the closure of clinics and the need for immunocompromised patients to avoid being in contact with potentially affected personnel.68 77.4% of surveyed patients in China also took complementary and alternative medicines to help improve their physical and general wellbeing as they were concerned with the potentially reduced effectiveness of oral therapies versus intravenous therapies. During the pandemic, concerns with the switch to oral therapy also enhanced anxiety and depression levels among patients with more advanced tumours in China.69 This needs to be avoided going forward through effective educational activities among patients. There was also an increase in adjuvant therapy, typically endocrine therapy with low infection potential, among patients with breast cancer in Hubei Province in China, but a decrease in neoadjuvant therapy during the recent pandemic.33 In Lithuania, whilst there was an appreciable reduction in diagnostic services at the start of the pandemic, including mammograms for patients with possible breast cancer (−62%), there was also a reduction (−8% versus a similar period in 2019) in systemic anti-cancer treatment (−8% versus a similar period in 2019). However, systemic anti-cancer treatment services recovered and even increased in Lithuania in the last four months of 2020 versus pre-pandemic levels (Table 2).36

In Pakistan, guidelines were rapidly produced to sort patients based on the urgency of their care during the pandemic, with patients divided into three groups based on their perceived priority for treatment. The highest priority was for breast cancer patients whose condition was viewed as immediately life-threatening or urgently requiring treatment, with the next priority for breast cancer patients whose condition did not require immediate treatment, ie, could be altered or delayed by four to eight weeks before the pandemic was seen as under control, but still required treatment.69 Centres in Pakistan also saw patients presenting with more advanced tumours as an aftereffect of lockdown and other measures (Table 2).41

In Turkey, Ilgun et al found there was an increase in patients presenting with larger tumour size and more metastatic lymph nodes, along with de-novo stage IV breast cancer cases, during the pandemic.70 Alongside this, the admission of breast cancer patients was reduced by almost 15% during the pandemic, with delays in patients seeking care enhanced by the fear of catching COVID-19 whilst attending hospital. This was similar to other studies in Turkey, with patient-related time delays in seeking care increasing the number of de novo patients presenting with Stage IV breast cancer in Turkey.37,70 Of concern is that Kiziltan et al reported a decrease in neoadjuvant therapy during the early stages of the pandemic despite systematic neoadjuvant therapy being suggested in the Turkish guidelines to manage patients’ breast cancer during COVID-19, especially for human epidermal growth factor receptor-positive patients (HER+), small size triple-negative (TN), node-negative and luminal breast cancer patients (Table 2).37,71

A similar situation has been seen among high-income countries (Table 2). In Canada, Di Lena et al documented an increase in NET among patients with early-stage ER+ breast cancer cases where surgery was delayed due to the pandemic. Encouragingly, breast cancer patients with early-stage ER+ who were taking NET did not experience pathological upstaging of their cancer despite having a longer delay for their surgery.72 Similarly, 74% of oncologists surveyed in Egypt, Saudi Arabia, and the UAE preferred NET for hormone receptor-positive (HR+) and HER2 negative patients during COVID-19 with delays to surgery and concerns regarding the immune system following traditional chemotherapy. However, 58% of those surveyed still preferred 6 to 8 cycles of neoadjuvant chemotherapy to treat breast cancer patients where delays in surgery. 67% also preferred adjuvant trastuzumab if patients were HER2 positive before delayed surgery.73 In France, there was a rise in the number of patients presenting with large tumours during the early stages of the pandemic, those with SBR Grade 3 ER-ve tumours, and those with ER-ve tumours, resulting in increased use of NAC with reduced surgery.43 In the Netherlands, patients diagnosed in the first two months of 2020 also faced treatment delays, with treatments changed from surgical approaches to primarily hormonal therapy where possible to minimize the impact of delayed surgery.45

There was also a 40% decline in cancer reporting in New Zealand at the start of the pandemic and a sharp decrease in endoscopies following lockdown measures. Radiation therapy was also affected due to COVID-19 in New Zealand, with a move to deliver the same dose in a shorter time frame. However, activities had bounced back by August 2020.74 In Portugal, medical choice-making procedures remained unchanged in the most aggressive breast cancer cases. However, similar to other countries, the prescribing of neoadjuvant therapy increased when there were difficulties with undertaking surgery due to lockdown measures. Where possible, prescribing oral formulations was also proposed to limit attendance at hospitals with associated concerns with catching COVID-19 alongside increasing home delivery of medicines where possible.75 The prescribing of metronomic chemotherapy, ie, frequent low doses of chemotherapy versus maximum dosing, may also be beneficial during a pandemic to limit the impact of chemotherapy on the immune system and patient recovery times (Table 2).75,76

There were similar changes in Singapore to managing patients with breast cancer at the start of the pandemic with the postponement of care where possible. However, out-patient visits should not be postponed for newly diagnosed breast cancer, those with recent onset of symptoms, and those who recently initiated treatment and needed follow-up.46 In Spain, patients also received adjuvant treatment whilst waiting for surgery assisted by telemedicine support during COVID-19 to reduce hospital visits and the risk of COVID-19 transmission.77 Patients also presented for surgery with larger tumours during the lockdown in the UK, with NAC interrupted in one study.53 In another study in the UK, a number of patients still underwent surgery either because they had completed their NAC or because there were concerns with immunocompromising patients if NAC was continued. Alongside this, a number of suitable patients were prescribed endocrine therapy with surgery planned once the pandemic subsided.52 Increased prescribing of NET was also seen in the British B-MaP-C study, with theatre capacity reduced following the pandemic.78 In the USA, NET was again appreciable prescribing to reduce the impact of surgical delays during COVID-19, building on the findings of Goldbach et al65,79 Wilke et al also reported the increased use of NET for ER+/HER+ patients, patients with invasive disease, and those with ductal carcinoma in situ (DCIS) due to COVID-19.66 Similarly, Murphy et al reported successful selective de-escalation of axillary surgery in breast cancer patients treated with NET.80

Across Europe, there was a significant reduction in the workload at breast cancer centres among surveyed institutions at the start of the pandemic, with responders reporting a reduction in their overall workload of 50% or more at the beginning of the pandemic (Table 2). There was also increased time between diagnosis and treatment, increased use of NET with delays in surgery, modification of primary systemic therapy and chemotherapy protocols due to the fear of COVID-19 complications, which included switching to oral therapies where possible or prolonging the interval between cycles.81 Coles et al suggested an international guideline regarding radiation therapy to modify and limit its use where possible, for example, in patients prescribed NET; however, in the Pan-European survey of Gasparri et al, over 50% of surveyed responders had not altered their radiation therapy schedules during the pandemic.81,82 Ramdas et al suggested that in LMICs, TARGIT– intraoperative radiation therapy (IORT) could gain more acceptance to improve radiation efficiency and reduce hospital workloads with low complication rates.83 Dowsett et al also developed international guidelines for breast cancer patients with primary ER+ HER2− tumours. The authors also recommended that breast cancer patients with insufficient endocrine tumours should be managed with NEC or early surgery.84 Curigliano et al also developed international guidelines to manage patients with breast cancer during COVID-19. Their guidelines included suggested measures regarding triaging and prioritizing patients as well as treating patients on an out-patient basis as much as possible, minimizing hospital visits, and increasing the use of telemedicine. In addition, the place of NEC as well as the place of trastuzumab in HER2+ patients.85 In their multi-country review and a web-based poll, Rocco et al described the impact of COVID-19 on breast cancer surgical management. They reported that primary systemic treatment was widely accepted by surgeons as an alternative when surgery was postponed. For patients with T2N1 HR+/HER2- tumours, suspicious malignant biopsies, and malignant recurrence excision, more than 50% of surgeons surveyed prioritized NAC over surgery.86

Brown et al reported that in several countries, the use of adjuvant bisphosphonates to prevent bone metastasis during COVID-19 had been substantially compromised with delays in CT and bone scans and delays in palliative care radiotherapy for bone pain. These issues, including adequate pain relief for patients with breast cancer, need to be considered in future pandemics to minimize their impact on the morbidity and mortality of patients with breast cancer (Table 2).87

Surgical Approaches to Manage Breast Cancer Patients During the Pandemic

As seen in 3.2 (Table 2), the COVID-19 pandemic and associated lockdown measures significantly decreased breast cancer surgical volumes across countries, although the reduction was less in some countries. Among the LMICs, Li et al in China reported an appreciable reduction in the proportion of patients with breast cancer undergoing surgery (16.4% to 2.6%) during the initial pandemic period.33 In Iran, Sadri et al reported on the successful application of low specific activity of Tc-99m elutes to help with diagnosis and treatment approaches, including surgery with generator shortages.88 There was also a 35.5% reduction in breast cancer surgeries in Pakistan during the early stages of the pandemic.89 Breast cancer patients were typically divided in Pakistan into those that require urgent surgery, those where surgery can be altered or delayed for 4–8 weeks, and those where surgery can be postponed until the end of the pandemic combined with other management approaches.69,90 Sattar et al also documented that surgical patients in Pakistan were prioritized into 3 groups, with surgical procedures divided into elective, semi-elective, orange emergency, and red emergency groups depending on their priority and whether surgery can wait replaced by other treatment approaches.69 In Turkey, several studies also documented a decline in the number of breast cancer surgeries during the early stages of the COVID-19 pandemic; however, the number of surgeries increased soon after the initial reduction, with Kara et al documenting an increase during the inter-pandemic period (Jun 2020- Sep 2020) to pre-pandemic levels.37–39,91

In high-income countries, Illmann et al in Canada reported a 78% reduction in breast reconstruction cases with a complete cessation in breast reconstructive services among 27.4% of responders during the first wave of COVID-19, with less impact in successive waves, with patients prioritized based on their identified need.92 In France, there was a variable impact, with Dorri et al reporting an 18.05% decrease in surgeries during the first wave, whilst Murris et al reported a variable impact with 50% of participating centres actually increasing their surgical activities, with 33% reducing the number of surgeries during the pandemic, with 17% showing no change, with all centres looking to reduce post-operative stay to reduce the chances of patients catching COVID-19 during hospitalization.43,93 In Italy, there was a limited reduction in the number of breast cancer surgeries performed during the first wave (8.5%); however, a significant reduction in breast reconstructive surgery was seen during the first wave of the pandemic.49,94 A significant reduction in breast cancer surgeries was also seen in Japan in the early stages of the pandemic, with similar findings, especially in T1-T2 and N0 tumours, in the Netherlands.44,95 In South Korea, Kang et al also reported a decline in every type of breast cancer surgery during the pandemic, ie, lumpectomy, mastectomy, lymph node surgeries, sentinel biopsies, axillary lymph node dissections, and breast reconstruction, with appreciable reductions in surgical procedures also seen in the UK in the first wave.48,52,53 In their survey of surgeons in the USA, Wilke et al reported a partial cessation and modification in elective surgery schedules during the first months of the pandemic and even cessation of all surgeries initially in some hospitals.66 Yin et al in the USA also documented a weekly decline of 20.5% in surgical procedures versus pre-pandemic levels, with Boyd et al documenting breast cancer surgeries declining by 6.8% in the first wave with the level of breast reconstruction surgery also declining.57,66 However, Cairns et al in the USA reported no statistically significant difference in the number of breast cancer operations for new patients during the first wave of the pandemic versus pre-pandemic levels.58

Alongside these changes, there were also typical changes in surgical approaches due to the pandemic (Table 3). For instance, Vanni et al in Italy reported an increase in axillary lymph node dissection in the first wave, with awake breast conservative surgery being the most frequent surgical procedure during the pandemic.51,96 Pellini et al in Italy believed re-engineering approaches could optimize pre-operative and post-operative times during pandemics benefitting all.97 The use of dilutional local anaesthetic (DLA) was seen as a safe and effective alternative approach in the UK to general anaesthesia when performing breast cancer surgeries to help minimize the patient time in the hospital, with Sud et al documenting that even modest delays in surgery in the UK without suitable alternatives would have a significant impact on survival.98,99 Joseph et al in the USA reported that 39% of surgeons in their study still followed the original plan for breast reconstruction/mastectomy during the pandemic, with chemotherapy or hormonal therapy also used when there were delays in surgery, with Kennard et al reporting that 44% of patients with breast cancer faced treatment changes during the pandemic mainly due to surgical prioritization, with diagnosis to surgery times significantly higher during the pandemic.65,100

Table 3 Surgery Strategies Across Countries

Curigliano et al (2020), in their multi-country guidelines, suggested that patients should be grouped into urgent, high, intermediate, and low-priority categories based on surgical urgency during the pandemic, with all non-urgent surgeries deferred with systemic therapies and out-patient surgeries adopted were possible.95 Isaac et al developed guidelines for breast reconstruction services during the pandemic in Canada. They suggested that multidisciplinary teams could be strategically used for patient selection and triage, with centralized and collaborative approaches adopted, including surgical approaches.101 In Italy, Fregatti et al developed a telephone-triaged system to help avoid hospitalization of COVID-19 symptomatic patients. They prioritized agreed surgical procedures, with telemonitoring facilities initiated following discharge. Lisa et al also developed guidelines ensuring patient and clinician protection and discharging patients quickly, which was helped by appropriate pain management telemedicine facilities.102–104 In Singapore, Mok et al included deferring non-urgent surgeries in their guidelines, performing surgery with the shortest anaesthesia and post-operative period.46 In Spain, Brenes Sánchez et al introduced similar guidelines with surgery deferred where possible, aided by systemic therapy, and, when performed, designed to minimize complications and post-operative stay.77

Abdalla et al in the UK also reported on patient prioritization and screening for COVID-19 before surgery given reduced facilities.104 Specht et al in the USA reported that same-day mastectomy and breast reconstruction could be successfully performed following an agreed protocol, with surgical oncology and plastic surgery teams operating together and discharging patients after a few hours of surgery to reduce infection risk and optimize hospital resources.105 Mo et al in the USA evaluated the efficacy of follow-up after resectioning stage I/II breast cancer during COVID-19 situations. They suggested that breast cancer survival rates decline if follow-up care is not fully re-established.106

There was an appreciable increase in telemedicine and telecommunication facilities for treatment and training during the pandemic following lockdown and other measures, especially in high-income countries. In Canada, Cadili et al evaluated the patients’ perception of telemedicine and reported that among operated patients, 85% enjoyed telemedicine consultations, 93% found there was enough time to talk, and 66% wanted to resume the service, with appreciable satisfaction with telemedicine appointments also seen in the USA.107,108 Marcasciano et al in Italy reported on the role of online videos in the training of breast surgeons given the closure of medical schools across countries at the start of the pandemic; however, there were concerns about their reliability which need to be addressed going forward.109–111

Management of Breast Cancer Patients with COVID-19

There was a variable impact on breast cancer patients infected with COVID-19 (Table 4). In Pakistan, in the study of Vohra et al, 4.9% of asymptomatic patients were subsequently identified pre-operatively to have COVID-19. These patients were later operated on when tests were negative, with no complications post-operatively. 4.6% were identified as having COVID-19 when receiving neoadjuvant or systemic therapy. All patients recovered well, with chemotherapy re-commenced once virus-free.89 Mooghal et al found that most COVID-19-positive breast cancer patients in their study had disease upstaging due to a lack of awareness of their disease and lockdown measures.41

Table 4 Management of Breast Cancer Patients with COVID-19

Wei et al in China measured the clinical characteristics of breast cancer patients affected with COVID-19 and the risks related to anti-cancer treatment. They found that 73.3% of breast cancer patients developed non-severe COVID-19, while 26.7% of patients developed severe conditions, and 6.7% died. Those patients aged >75 and lower Eastern Cooperative Oncology Group (ECOG) scores were significantly related to COVID-19 severity. Those who initiated chemotherapy within 7 days before the onset of COVID-19 symptoms also had a significant association with COVID-19 severity, with more pronounced neutropenia compared with other breast cancer patients. As a result, patients receiving IV chemotherapy need to be carefully monitored until at least 7 days after stopping chemotherapy.113

Among the high-income countries, Kuderer et al found breast cancer to be most prevalent (21%, 191 out of 928) among cancer patients infected with COVID-19 in the USA, Canada, and Spain, which needs to be carefully handled in view of the immune system being compromised by chemotherapy (Table 4).114 Fregatti et al in Italy reported that COVID-19 posed an increased risk of mortality in breast cancer patients, with all 3 breast cancer patients (out of 207 studied) hospitalized in their study due to COVID-19 infections subsequently dying.102 However, Kathuria-Prakash et al in the USA in their study reported that patients who received endocrine therapy were less likely to suffer from adverse conditions with COVID-19 infections. Overall, 30.3% of breast cancer patients with COVID-19 infection had to be hospitalized in their study, 8.3% needed intensive care, and 6.1% died. Older age, the presence of comorbidities, lobular subtype, and Hispanic/Latinx ethnicity were significantly associated with hospitalization due to COVID-19.115

Perspectives and Mental Conditions of Breast Cancer Patients During Covid-19

Eight studies were identified, with the vast majority from high-income countries. Among LMICs, Juanjuan et al reported that poor general condition, aggressive breast cancer, and close contact with patients with COVID-19 enhanced anxiety, depression, and insomnia (Table 5).116

Table 5 Mental Health State of Patients with Breast Cancer During the Pandemic

Fear and anxiety among breast cancer patients due to COVID-19, and its associated impact on treatment schedules, were also seen in high-income countries. Interestingly, Fregatti et al in Italy found that 7.4% of breast cancer patients were more afraid of COVID-19 than their cancer.102 Low to moderate fear and psychological distress were also seen among breast cancer patients in the USA.108,117 Ludwigson et al observed fear among 50% of the patients presenting for surgical consultation about their cancer care and recovery during the pandemic, with 66% being anxious about contracting COVID-19.108 However, Sokas et al found that most patients were not surprised and accepted their treatment delays; however, there was poor communication with patients, and these patients were more distressed about their treatment during the pandemic.117 Soriano et al also had concerns with communication between patients and physicians during the pandemic in the USA, exacerbating fear and psychological distress.118

Fear of COVID-19 also resulted in more refusals for procedures, including surgery, among breast cancer patients during the pandemic. Providing mental support and warning patients about the adverse effects of treatment delays could minimize the number of refusals and alternative treatment strategies.119 Interestingly, Kennard et al in the USA found no difference in anxiety levels between patients who had undergone treatment change as a result of the pandemic and those patients who had no change in their cancer treatment regimen, with approximately 30% of the patients in both groups showing anxiety.65

Particular attention should be given to the psychological condition of breast cancer patients as part of management strategies, as most breast cancer patients undergo anxiety, depression, and distress exacerbated by lockdowns and other measures (Figure 2).

Figure 2 Strategies of Breast Cancer Management During The COVID-19 Pandemic.

Guidelines for the Management of Breast Cancer Patients

The various published guidelines (17 identified – 3 from LMICs, 11 from high-income countries, and worldwide) typically prioritized the patients into high, medium, and low-priority groups for management during the pandemic. Their content is summarised in Table 6.

Table 6 Specific Guidelines Used for Different Selective Patients

Discussion and Recommendations

As mentioned, at the start of the pandemic, there were no known effective treatments or vaccines for COVID-19 and primarily relied on early diagnosis.120,121 This impacted the diagnosis and management of breast cancer patients during the pandemic. This included concerns with late diagnosis due to lockdown and other measures, and the subsequent impact on potential neoadjuvant treatment regimes, including NET, as a result of delays in surgery. Potential approaches to surgery were suggested and undertaken, including prioritizing patients based on their needs given restrictions in available facilities, besides limiting post-operative stay where possible. Radiation changes were also implemented, along with changing IV chemotherapy regimens to oral therapies where possible to limit time spent with out-patients. Alongside, there was also an increase in telemedicine approaches before and after surgery to cut down on hospital visits across countries.

The various findings across countries (summarised in Tables 1–3) resulted in developed guidelines across countries (Table 6). There was little difference in the recommendations between LMICs versus high-income countries, with a key area being the agreed prioritization of patients. Significant reductions in breast cancer screening and diagnosis, reduction in out-patient visits, and extended diagnosis to treatment period were noticed among both LMICs and high-income countries. However, the situations were typically worse among LMICs. However, high-income countries, eg, Italy and Canada, followed different protocols and guidelines to screen and categorize patients based on their COVID-19 status and clinical scenarios to avoid spreading COVID-19. More adjuvant therapy and less neoadjuvant treatment, increased shift from intravenous to oral treatment, more complementary and alternative medicine, increased upstaging of advanced-stage breast cancer, reduced admission, and patient-related delay were more noticeable among the LMICs. In contrast, the high-income countries applied various strategies such as increased telemedicine, referring to NET more, reducing non-essential visits, and expanding the application of NAC to meet the challenges. The proportion of breast cancer surgeries dropped notably among various LMICs and high-income countries during COVID-19, primarily due to lockdowns and restrictions. However, different high-income countries adopted various strategies to address the challenges of lockdown and virus transmission, eg, telemedicine consultation, coordinated alternative treatment methods, proper screening, and dividing the patients into groups based on priority. Numerous guidelines regarding patient management, diagnosis, and surgery, such as prioritizing and classifying patients based on disease conditions, priority and other criteria, and pre-operative, operative, and post-operative strategies, were adopted and followed by various LMICs and high-income countries during COVID-19 to alleviate breast cancer treatment. However, the availability of more resources and preventive measures in high-income countries could lead to better care and management of breast cancer patients during the pandemic. This needs to be explored further going forward. In any event, the published guidelines provide a basis for discussions among all key stakeholder groups managing patients with breast cancer in new waves of COVID-19 and future pandemics. The published studies suggest that breast cancer surgeries can be safely and effectively performed during pandemic situations by strictly following safety protocols and surgical management guidelines. All non-urgent surgeries should be deferred and supported by adjuvant therapies, including NET, where applicable. All surgical patients must be tested for COVID-19 negative before surgery, with surgery delayed if needed until patients test negative.

It is also important that healthcare professionals involved in managing patients with breast cancer, including physicians, regularly speak with patients during the pandemic to discuss their situation and potential approaches, including planned changes in treatment. This is vital to help reduce rising levels of anxiety and depression among patients (Table 5). Studies have shown increased anxiety and depression among breast cancer patients if there is limited communication between physicians and patients, which needs to be avoided in the future. In addition, physicians talking with patients can help address their concerns about coming to the hospital for vital procedures rather than delaying surgery and subsequent management where this can be undertaken.117,118 This is vital to reduce future morbidity and mortality, which can be avoided by the prompt treatment that can be undertaken.

There was a variable impact on breast cancer patients who developed COVID-19. However, the administration of chemotherapy should be carefully monitored among these patients, given concerns about the impact on the immune system of patients and the potential for increased morbidity and mortality if they subsequently develop COVID-19 (Table 4). These concerns have resulted in moves to switch to oral therapies where possible and a re-look at chemotherapy administration regimes, including metronomic chemotherapy.76

Conclusion

It was a challenge for healthcare professionals to recommend and adopt ideal strategies to manage patients with breast cancer care during the current pandemic as countries had typically not experienced such events before, including extended lockdown activities. As diagnostic facilities became more limited at the start of the pandemic, advanced-stage cancers began to be detected. This resulted in multiple research activities across countries to ascertain the current situation and its impact to guide potential ways forward to address current challenges. Guidance and activities included developing potentially new diagnostic approaches, including self-screening, given concerns with undertaking clinics. Alongside this, instigating potentially new treatment approaches to alleviate the problems caused by the reduced number of surgical procedures. New strategies included greater use of neo-adjuvant endocrine or chemotherapy alongside changes in surgical strategies. In addition, increasing where possible, the use of telemedicine and oral chemotherapy to limit hospital attendance. These proposals, combined with suggestions for prioritizing breast cancer patients for treatment, including surgery, were contained in numerous guidelines developed across both LMICs and high-income countries to optimize the management of breast cancer patients during pandemics. We will continue to monitor the situation to limit the impact of successive waves of the pandemic on the morbidity and mortality of patients with breast cancer, including their mental health.

Abbreviations

AC, Adjuvant Chemotherapy; BCS, Breast Conservation Surgery; BR, Breast Reconstruction; DCIS, Ductal Carcinoma In-Situ; DLA, Dilutional Local Anesthetic; ER, Estrogen Receptor; ET, Endocrine Therapy; HER, Human Epidermal Growth Factor Receptor; HR, Hormone Receptor; IBR, Immediate Breast Reconstruction; IORT, Intraoperative Radiation Therapy; NAC, Neo-Adjuvant Chemotherapy; NAF, Nipple Aspirate Fluid; NET, Neo-Adjuvant Endocrine Therapy; PPE, Personal Protective Equipment; PR, Progesterone Receptor; SLNB, Sentinel Lymph Node Biopsy; ST, Systematic Therapy; TN, Triple-Negative; WLE, Wide-Local Excision.

Author Contributions

All authors made a significant contribution to the work, whether that is in the conception, study design, acquisition of data, analysis, and interpretation, or in all these areas; took part in writing, revising, or reviewing the article; gave final approval of the final version; have agreed on the journal choice; and agreed to be accountable for all aspects of the work. Consent for Publication: all authors reviewed and approved the final version and have agreed to be accountable for all aspects of the work, including any issues related to accuracy or integrity.

Funding

This paper was not funded.

Disclosure

The authors report no conflicts of interest for this work and declare that they do not have any financial involvement or affiliations with any organization, association, or entity directly or indirectly with the subject matter or materials presented in this article. This also includes honoraria, expert testimony, employment, ownership of stocks or options, patents or grants received or pending, or royalties.

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