Breast oncology and the COVID-19 pandemic: Recommendations from the Brazilian Society of Clinical Oncology (SBOC)

The current pandemic moment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has completely changed health services, with most services being directed to the treatment of aﬀected patients. Even during this critical period, cancer patients need to be treated, as delayed treatment can compromise the chances of a cure. The Brazilian Society of Clinical Oncology (SBOC) has developed recommendations to guide decisions in breast cancer treatment during the SARS-CoV-2 pandemic through their Breast Tumors Committee. Due to the scarcity of relevant data, discussions on systemic treatment and surgical decisions related to breast cancer biological sub- types, chemotherapy schemes, anti-HER2 therapy, adjuvant endocrine therapy, breast surgery, radiotherapy, follow-up and routine exams, long-term central venous catheters, bisphosphonate and denosumab, genetic counseling and metastatic disease were evaluated and recommendations were issued. For newly diagnosed breast cancer, if appropriate, start systemic treatment with neoadjuvant endocrine therapy or neoadjuvant chemotherapy (NACT) with anti-HER2 blockage if HER2 positive disease. Surgery should be promptly considered if disease progression during NACT, malignant phyllodes tumor or breast sarcoma. These recommendations should be adjusted according to the reality of each service (private or public) and according to the epidemiological issues COVID19 presents in each area and revised recommendations may arise at any time. ABSTRACT


INTRODUCTION
The coronavirus disease 2019 (COVID-19) pandemic has challenged the medical community, including those in the field of clinical oncology, which has always required priority in the diagnosis and treatment of patients.
The Breast Tumors Committee of the Brazilian Society of Clinical Oncology (SBOC) brought to light some relevant decisions to guide medical oncologists during this pandemic, pointing out that there is a scarcity of scientific data related to this scenario. The following recommendations for systemic treatment and surgery decisions are based on biological subtypes of breast cancer.

RECOMMENDATIONS ON BREAST CANCER TREATMENT ACCORDING TO BIOLOGICAL SUBTYPES 1-8 LUMINAL A INVASIVE BREAST CANCER
These recommendations include luminal A-type cancers (immunohistochemistry profile of high expression of estrogen receptor [ER] and progesterone receptor [PR], negative human epidermal growth factor receptor 2 [HER2], and low Ki-67) and luminal A breast cancers assessed by genomic tests.
• Perform surgery after 3-4 months or when appropriate if responding to ET (Stage I and II luminal tumors are usually indolent and respond very well to ET).
• Surgery may be postponed with apparently no impact on survival. [9][10][11] Clinical stage III disease In the case of pathological fractures, a multidisciplinary discussion of the risks and benefits of surgery in a pandemic environment should take place. The decision must take into account the potential for functional recovery with good quality of life.

CONSIDER DELAYING SURGERY WITH VERY MILD IMPACT ON PROGNOSIS IN THE FOLLOWING CASES:
• Prophylactic surgeries (patients with pathogenic genetic variants) • Resections of atypical findings and/or precursor lesions (atypical ductal hyperplasia; atypical lobular hyperplasia; lobular carcinoma in situ)

CASES OF IN-SITU DUCTAL CARCINOMA (DCIS) CASES WITH NO SUSPECTED ASSOCIATED INVASIVE DISEASE:
The cases of low risk DCIS are defined by the criteria of LORIS: -Age > 45 years; -Low grade DCIS with biopsy; -Microcalcifications in the image as the only finding; -Extension < 5 cm; -No palpable lesions; or -Paget papillary discharge.
• In cases that are hormone receptor (HR)-positive, consider initial pharmaco-prophylaxis.
• In cases that are HR-negative, pharmacoprophylaxis is not indicated (consider the statement below).
• Consider postponing surgery for 3-4 months or performing surgery once it is deemed safe.

CASES OF DCIS WITH SUSPECTED ASSOCIATED INVASIVE DISEASE:
High-risk DCIS is defined as extensive/ palpable lesions accompanied by the possibility of invasive disease, or which do not meet the above criteria for low-risk DCIS.
• In cases that are HR-positive, consider initial pharmaco-prophylaxis.
• In cases that are HR-negative, there is no indication for pharmaco-prophylaxis (consider the statement below) • Consider surgery promptly.

SURGERY AFTER NEOADJUVANT TREATMENT:
• Consider delaying surgery after neoadjuvant treatment as long as possible (technical limit of 4-8 weeks or until improvement of logistics and adequate safety conditions).
• If NACT is concluded and the disease is HRpositive, consider ET as a bridging measure with or without SOF until surgery may be safely performed (it is not recommended to increase the number of NACT cycles).
• In cases of HER2-positive disease, consider maintaining double-blockade if available (or at least trastuzumab) for a few additional doses after completion of NACT, based on the previous argument.
• In cases of TN disease, prompt surgery is recommended, considering the risk vs benefit, 4-6 weeks after NACT. In exceptional cases where surgery is not available within a reasonable period of time, consider neoadjuvant radiotherapy (RT).

SCENARIOS IN WHICH SURGERY SHOULD BE PROMPTLY CONSIDERED:
• Patients with disease progression during NACT

RECOMMENDATIONS OF FOLLOW-UP AND ROUTINE EXAMS 1-8
• To avoid unnecessary medical office visits, some follow-up exams should be postponed until the end of the pandemic period, without increasing patient risks or influencing prognosis; consider tele-medicine if available.
• Screening tests for patients with suspected metastatic disease and biopsies in new cases or in suspected cases of recurrence should be performed when feasible, still aiming to avoid multiple visits and unnecessary patient exposure to the risk of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
• Imaging tests to assess the response of metastatic disease in patients with clear clinical benefits and oligo/asymptomatic disease may be postponed at the clinician's discretion.
• Withdrawal of these catheters should be postponed until the pandemic period has passed.
• Catheter placement should be avoided if possible, after discussing the risks and benefits according to the treatment protocol.

RECOMMENDATIONS ON INJECTABLE BISPHOSPHONATES AND DENOSUMAB 1-8
• Consider postponing these treatments during the pandemic period if the indication is for adjuvant use or prevention and / or treatment of osteoporosis.
• In the case of metastatic disease, delay infusion of zoledronic acid to every 12 weeks; if zoledronic acid is used monthly, consider switching to every 12 weeks. • Space monthly denosumab as needed if the patient has oligo/asymptomatic, low-volume disease without high risk of skeletal events, and no hypercalcemia.

RECOMMENDATIONS ON GENETIC COUNSELING 1, 2, 4, 5, 18
• Consider postponing genetic counselling if there is no clear impact on medical practice for the next 3-6 months; consider tele-medicine if there is an urgent need for an appointment.
• Consider performing genetic testing for the evaluation of pathogenic variants of BRCA 1 and BRCA 2 for possible indication of platinum and/ or olaparib; the tests should be performed using a simple salivary home-based test kit, if available, to avoid unnecessary visits to the laboratory.

RECOMMENDATIONS FOR METASTATIC DISEASE 1-8
• Do not stop treatments that provide a clear clinical benefit such as chemotherapy, endocrine treatment, immunotherapy or biological anti-HER2 treatments.
If feasible, consider spacing medical visits and exams. Use tele-medicine whenever possible.
• Whenever possible, choose treatments with fewer toxicities to minimize visits to the emergency department and facilitate fewer clinical appointments and evaluations.
• Whenever possible, prescribe fewer cycles of chemotherapy, concluding CT after 4-6 cycles or upon improved response, utilizing anti-HER2 therapy, bevacizumab, atezolizumab or single ET (in HR-positive tumors) as maintenance therapy, thus reducing the duration of exposure to immunosuppressive chemotherapy and steroid treatments.
• Preferentially prescribe monotherapy in cases of palliative CT; in HR-positive disease, consider single endocrine treatment, avoiding initiation of treatments with increased risk of pulmonary toxicity such as everolimus. In cases where alpelisib is used, perform an endocrinologic assessment to better control blood glucose in order to reduce the risk of grade III hyperglycemia (and therefore the risk of hospitalization). Patients using everolimus or alpelisib with adequate responses and good tolerance must be carefully evaluated for continuation of these treatments.
• Cyclin inhibitors can be started and continued in combination with ET, due to the robust increase in overall survival associated with these combinations. Patients must be closely monitored for hematological, gastrointestinal and other side effects and exams can be performed and shared with the medical team electronically by tele-medicine.
• Patients with advanced disease and life expectancy less than 3 months should be referred to palliative care, avoiding futile treatments that overwhelm the health system with toxicities, unnecessary hospitalizations and possible mechanical ventilators aimed at use in terminally ill patients.
• Delays in cycles, dates of treatment, and routine visits in the context of the pandemic and in the context of a non-curative treatment are perfectly acceptable.
• Patients with good performance status, irrespective of age, should receive appropriate cancer treatment notwithstanding the pandemic. In most cases it will not be possible to delay the start of treatment for 3-4 months, therefore, a shared decision should be proposed, respecting the patient's opinion and considering limitations and difficulties in the access and availability of emergency services. • Advise patients to always contact their medical team. If there is no shortness of breath, they are advised to stay at home in social isolation for 14 days unless the medical team can provide a COVID-19 test, and to maintain contact with the doctor by tele-medicine throughout this period.

RECOMMENDATIONS FOR PATIENTS
• Cases with warning symptoms (shortness of breath, respiratory distress, O2 saturation <95%, worsening in the clinical conditions of pre-existing disease, severe abdominal pain) should seek emergency service.
• Patients with fever and respiratory symptoms should discontinue any systemic cancer treatments until symptoms are resolved.

FINAL CONSIDERATIONS:
These are general recommendations. All cases should be discussed on an individual basis with the multidisciplinary team and shared decisions between the medical team and the patient must be guided. It is strongly recommended to maintain multidisciplinary meetings through web conferences for the optimal management of all cases. It is also recommended that these recommendations be adjusted according to the reality of each service (private or public) and according to the epidemiological issues COVID19 presents in each area. Revised recommendations may arise at any time.