Adaptation of international coronavirus disease 2019 and breast cancer guidelines to local context

Table 1 General recommendations for the management of breast cancer

High priority

Comments

(1) Choose regimens and therapeutic sequences consistent with the current situation to reduce the risk of COVID-19 in patients and health workers (Yes: 100%, No: 0%); (2) Differentiated triage for COVID-19 in all cancer centers before entrance (Yes: 100%, No: 0%); (3) Leave a medical register (informed consent) about the discussion of risk/benefits of treatments as well as therapeutic decisions and alternatives available (Yes: 78%, No: 22%); and (4) Individualize the need for blood transfusions when strictly necessary (Yes: 89%, No: 11%)

(1) These recommendations will be adapted according to the reality of each oncological center; (2) Treatment decisions are based on protocols (international/local) about the management of COVID-19; and (3) Multidisciplinary web meetings are recommended to decide the best choices of treatments and outcomes

COVID-19: Coronavirus disease 2019.

Table 2 Priorities of outpatient visits for breast cancer during the coronavirus disease 2019 pandemic

High priority	Medium priority	Comments
(1) Unstable postsurgical patients (hematoma, infection, bleeding) (Yes: 100%, No: 0%); (2) Oncological emergencies (febrile neutropenia, uncontrolled pain, symptomatic brain metastases) (Yes: 100%, No: 0%); (3) BC diagnosis during pregnancy (Yes: 100%, No: 0%); and (4) De novo locally advanced BC with aggressive phenotypes (HER2, TNBC) (Yes: 78%, No: 22%)	(1) De novo invasive BC (during the multidisciplinary evaluation, priority is guided by tumor biology and clinical stage) (Yes: 89%, No: 11%); (2) Intercurrences on-treatment patients (new signs/symptoms, abnormal findings during physical examination, adverse events (Yes: 100%, No: 0%); (3) Patients on active intravenous chemotherapy (Yes: 78%, No: 22%); and (4) Stable routine postsurgical patients (Yes: 100%, No: 0%)	In patients requiring urgent clinical evaluation, consider converting to telemedicine for follow-up, according to medical evolution

BC: Breast cancer; HER2: Human epidermal growth factor receptor 2; TNBC: Triple-negative BC.

Table 3 Priorities for telemedicine

Medium priority	Low priority	Comments
(1) During the pandemic, most patients could be evaluated using telemedicine (if feasible) (Yes: 100%, No: 0%); and (2) BC patients who can be evaluated with telemedicine: (a) Patients completing neoadjuvant chemotherapy and waiting for surgery (Yes: 89%, No: 11%); (b) Patients eligible for radiotherapy (Yes: 89%, Abst: 11%); and (c) Patients receiving oral chemotherapy or endocrine therapy + targeted therapy (Yes: 78%, No: 22%)	Patients can be evaluated with telemedicine (including after pandemic is over): (a) Routine evaluations in patients who are in periodic controls (observation) or endocrine therapy (Yes: 78%, No: 22%); (b) Survivorship follow-up (Yes: 100%, No: 0%); (c) Psychological visits (Yes: 100%, No: 0%); and (d) New diagnosis of non-invasive BC (Yes: 100%, No: 0%)	(1) During follow-up of patients with high-risk of recurrence, an in-person visit can be assessed according to evolution (if necessary); and (2) In some oncological centers, it is possible to evaluate in-person oral treatments of continuing patients (including whom with adjuvant therapy)

BC: Breast cancer.

Table 4 Priorities for diagnostic and imaging of breast cancer

High priority	Medium priority	Low priority	Comments
(1) Clinical diagnosis: (a) Diagnosis of a mass or lump (auto examination) or other signs with high suspicion of malignancy (Yes: 100%, No: 0%); and (b) Clinical evidence of relapsed locoregional disease (Yes: 100%, No: 0%); (2) Imaging: (a) Urgent situations that require imaging (oncological emergencies, serious postsurgical complications, etc.) (Yes: 100%, No: 0%); (b) Perform additional images upon abnormal mammogram results or suspected metastasis (depending on clinical stage and tumor biology) (Yes: 89%, Abst: 11%); and (c) Images for relapsed BC (Yes: 100%, No: 0%); and (3) Pathological diagnosis: Pathologic evaluation (cytopathology or histopathology) for abnormal mammograms or symptoms in the breast or symptomatic metastatic relapse (Yes: 100%, No: 0%)	(1) Imaging: (a) Perform additional images upon abnormal mammogram results or suspected metastasis (depending on the clinical stage and tumor biology) (Yes: 100%, No: 0%); and (b) Echocardiograms (every 6 mo, if feasible) in patients who require treatment based in anthracyclines or anti-HER2 agents (Yes: 78%, No: 22%); (2) Pathological: (a) Biopsy for BIRADS 4 or 5 lesions (Yes: 100%, No: 0%); and (b) Image-guided (or clinically) biopsy to determine a metastatic relapse (note: metastatic relapses should not be 100% biopsies) (Yes: 100%, No: 0%)	(1) Screening: All screening exams (mammograms or images) for symptomatic patients (e.g., ultrasound or MRI) may be performed after pandemic (Yes: 100%, No: 0%)—BRCA mutated carriers < 40 yr may be considered for screening if delays or more than 6 mo are expected[6,7]; and (2) Follow-up: (a) EBC patients that require images, reevaluation of disease, echocardiograms, and bone scans, should be deferred if patients are clinically asymptomatic (Yes: 100%, No: 0%); and (b) In MBC patients, follow-up oriented to symptoms is recommended. Images, disease reevaluation, echocardiograms may be deferred in large intervals (Yes: 100%, No: 0%)	All patients with a new mass lump with a high suspicion of malignancy or who have already undergone imaging with a high suspicion for malignancy (e.g., BIRDAS 5 in mammogram) should be immediately referred for histological diagnosis and imaging, as a high priority

BC: Breast cancer; BIRADS: Breast Imaging Reporting and Database System score; EBC: Early BC; MBC: Metastatic BC; MRI: Magnetic resonance imaging.

Table 5 Prioritization for early breast cancer

High priority	Medium priority	Comments
(1) General considerations: (a) All subtypes should complete their regimens that have already started[8]. Consider shorter regimens or dose-modifications (Yes: 100%, No: 0%); and (b) Patients with CS I-II (including N1) and those with intermediate/low grade, "low risk" genetic profile, or classified as luminal A subtype do not benefit from neo/adjuvant chemotherapy. They can receive endocrine therapy alone[9,10] (Yes: 100%, No: 0%); (2) TNBC EBC: (a) Chemotherapy neo/adjuvant is recommended. Sequential treatment with one agent reduces complications[11] (Yes: 100%, No: 0%); and (b) Adjuvant capecitabine is recommended in post-neoadjuvant residual disease (Yes: 100%, No: 0%); (3) HER2 (+) EBC: (a) Neo/adjuvant systemic therapy + targeted therapy anti-HER2 is recommended (Yes: 100%, No: 0%); (b) Complete neo/adjuvant chemotherapy (+/- anti-HER2 therapy) for HER2 (+) EBC (Yes: 100%, No: 0%); (c) Trastuzumab-based adjuvant therapy could be reduced from 12 mo to 6 mo without affecting outcomes[12,13] (Yes: 100%, No: 0%); (d) Consider the use of T-DM1 (+/- pertuzumab) in the neo/adjuvant scenario (reduces risk of neutropenia, hospital admissions, use of corticosteroids)[14-16] (Yes: 67%, No: 22%, Abst: 11%); and (e) Continue with T-DM1 in HER2 (+) patients as an adjuvant therapy for post-neoadjuvant residual disease[17,18] (Yes: 100%, No: 0%); and (4) Luminal EBC: (a) Neo/adjuvant endocrine therapy +/- chemotherapy for HR (+)/HER2 (-) BC is recommended (Yes: 100%, No: 0%); (b) Continue standard adjuvant endocrine therapy in pre and postmenopausal patients (use telemedicine to manage potential toxicities reported by patients) (Yes: 100%, No: 0%); and (c) Neoadjuvant endocrine therapy is an option for HR (+)/HER2 (-) BC patients allowing to defer surgery between 6-12 mo in BC with CS I or II (Yes: 100%, No: 0%)	(1) HER2 (+) EBC: Anti-HER2 therapy can be restarted after remitting SARS-CoV-2 infection, following a discussion, and approval by a multidisciplinary team (Yes: 78%, No: 22%); and (2) Luminal EBC: (a) In postmenopausal CS I patients with low/intermediate grade tumors or lobular BC, endocrine therapy may be started when surgery is deferred (Yes: 100%, No: 0%); and (b) For patients with low-risk genomic score/signature, endocrine therapy should be started alone (Yes: 89%, No: 11%)	(1) In patients with active infection due to COVID-19, stopping treatment is recommended; (2) Antihormonal therapy: Endocrine therapy (tamoxifen, AI, LHRH agonists) is safe (does not affect the immune system) and can be continued during the COVID-19 pandemic. LHRH analogs can be administered every 3 mo (although home administration of LHRH analogs is the preferred recommendation); however, fulvestrant requires intramuscular monthly application[19]; (3) Chemotherapy: schedules can be modified to reduce admissions (every 2 or 3 wks’ doses can be used instead of a weekly dose with selected agents). Consider the use of concomitant colony-stimulating factor (G-CSF), preferably pegfilgrastim for single-dose administration)[20]; and (4) Bone modifying agents (denosumab or bisphosphonates) can be deferred or administrated every 3 mo (without hypercalcemia), both for adjuvant therapy or in long-term treatments

AI: Aromatase inhibitor; BC: Breast cancer; COVID-19: Coronavirus disease 2019; CS: Clinical stage; EBC: Early BC; G-CSF: Granulocyte-colony stimulating factor; HER2: Human epidermal growth factor receptor 2; HR: Hormone receptor; LHRH: Luteinizing hormone-releasing hormone; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2.

Table 6 Prioritization for neoadjuvant medical treatment of breast cancer

High priority

Comments

(1) General recommendations: Patients with BC initiating therapy or ongoing neo/adjuvant chemotherapy and who present suspected symptoms of infection or contact history with an infected person is recommended to get tested (PCR) before starting or continuing it. In the case of positive results, defer treatment until confirmation of negative result with a new test (PCR) which could be performed between 2-3 wk later, and with previous evaluation from the Infectious Disease Department (Yes: 67%, No: 33%); (2) Neoadjuvant treatment according to subtypes: (a) A multidisciplinary team (using web platforms) should evaluate patients with invasive BC for the decision to initiate neoadjuvant therapy during the pandemic (Yes: 100%, No: 0%); (b) Neoadjuvant treatment in BC with “high risk” (TNBC, HER2 (+), luminal B with “high risk”) is recommended (Yes: 100%, No: 0%); and (c) In patients with HR (+) BC, neoadjuvant endocrine therapy allows deferring definitive surgery (Yes: 100%, No: 0%); (3) TNBC: (a) Standard neoadjuvant chemotherapy is recommended during the pandemic, although regimens that further reduce exposure and toxicity can be accepted (shorter duration, lower risk of immunosuppression and with an interval of every 3 wk) (Yes: 100%, No: 0%); (b) Consider the use of G-CSF (preferably pelfilgastrim for single-dose administration) in conjunction with chemotherapy (Yes: 89%, No: 11%); (c) The reduction of chemotherapy dose does not seem acceptable to reduce the risk of myelosuppression (Yes: 89%, No: 11%); (d) In older patients > 70 yr, the risk/benefit of neoadjuvant chemotherapy should be discussed. Initial surgery (as long as it is available) is an option, hoping that in 4-5 wk the situation improves to start chemotherapy (it should not be postponed more that period) (Yes: 89%, Abst: 11%); and (e) In patients < 70 yr who reject neoadjuvant chemotherapy for fear of COVID-19, initial surgery may be an option (if available) (Yes: 89%, Abst: 11%); (4) HER2 (+): (a) Neoadjuvant chemotherapy associated with anti-HER2 monoclonal antibodies is strongly recommended (Yes: 100%, No: 0%); and (b) A neoadjuvant regimen with dual anti-HER2 blocking for six courses without anthracyclines can be considered[26] (Yes: 67%, No: 11%, Abst: 22%); and (5) Luminal: (a) In those patients who do not accept surgery (initial therapy), the use of neoadjuvant endocrine therapy is considered to delay surgery until the pandemic is over, especially in patients > 70 yr, tumors with high expression of HR and low ki67 (Yes: 100%, No: 0%); (b) In luminal tumors, the benefit of adding neo/adjuvant chemotherapy to endocrine therapy can be estimated by clinic pathological factors: Tumors with histological grade 3, elevated ki67, or axillary involvement benefit more from chemotherapy (Yes: 100%, No: 0%); (c) Genomic platforms (oncotype, mammaprint, prosigna, endopredict) and online tools like ePrognosis provide additional value in establishing the need for chemotherapy (Yes: 100%, No: 0%); (d) In high-risk luminal tumors, neoadjuvant chemotherapy may provide benefits (e.g., an increased rate of conservative surgery) but not increased survival. This should be analyzed with the risk of SARS-CoV-2 infection and the availability of surgery (Yes: 100%, No: 0%); and (e) Recommendations of the use of neoadjuvant chemotherapy are the same as those described for TNBC subtype (Yes: 100%, No: 0%)

In patients with HER2 (+) EBC, trastuzumab can be restarted for up to 6 mo after stopping treatment

BC: Breast cancer; EBC: Early BC; HR: Hormone receptor; PCR: Polymerase chain reaction; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; TNBC: Triple-negative BC.

Table 7 Prioritization for adjuvant medical treatment of breast cancer

High priority

Comments

(1) General recommendations: (a) Recommendations in the neoadjuvant setting are similar to adjuvant therapy (Yes: 100%, No: 0%); (b) In patients > 70 yr, the evaluation of performance status for estimating the risk/benefit of chemotherapy is mandatory. Online tools (such ePrognosis) and genomic profiles can be useful (Yes: 100%, No: 0%); and (c) It is valid to defer the start of adjuvant chemotherapy until the pandemic is over, although decisions should be individualized according to the patient risk and tumoral subtypes (Yes: 100%, No: 0%); (2) TNBC: (a) Adjuvant chemotherapy must be administered in the most effective way (Yes: 100%, No: 0%); (b) It is recommended to initiate adjuvant chemotherapy up to 2 mo after surgery (Yes: 100%, No: 0%); (c) In patients with age > 70 yr, discuss risk/benefits of using adjuvant chemotherapy; consider a regimen less immunosuppressive to avoid hospital admissions (Yes: 100%, No: 0%); (d) Consider the use of concomitant G-CSF to reduce the risk of infections (Yes: 89%, No: 11%); and (e) The use of adjuvant capecitabine, during 6-8 mo, in patients with no PCR after neoadjuvant chemotherapy is recommended (Yes: 100%, No: 0%); (3) HER2 (+): (a) Adjuvant chemotherapy associated with anti-HER2 therapy is recommended (Yes: 100%, No: 0%); (b) Subcutaneous trastuzumab is an alternative to reduce time to hospital admission. (Yes: 100%, No: 0%); (c) In selected patients (low risk, CS I-II, with PCR after neoadjuvant chemotherapy and surgery), it is valid to consider a shorter time of treatment with adjuvant trastuzumab (6 mo) to reduce hospital admission (Yes: 100%, No: 0%); (d) In the case of completing neoadjuvant chemotherapy associated with anti-HER2 therapy, it is reasonable to continue anti-HER2 therapy until surgery (Yes: 89%, No: 11%); and (e) The use of T-DM1 in those patients who cannot reach pCR after neoadjuvant chemotherapy is recommended. Moreover, the use of T-DM1 can be delayed after surgery (Yes: 100%, No: 0%); and (4) Luminal: (a) In “high risk” luminal patients, it is recommended to assess a clinical risk and/or use of genomic platforms (including tumors with lymph node involvement) to limit the use of adjuvant chemotherapy, according to institutional clinical practice guidelines (Yes: 100%, No: 0%); (b) The assessment of clinical risk with online tools (such as Predict) to estimate the risk of recurrence and the benefit of adjuvant chemotherapy is recommended (Yes: 100%, No: 0%); and (c) If adjuvant chemotherapy is necessary (risk/benefit previous evaluation), its initiation can be delayed up to a maximum of 3 mo after surgery (without reducing efficacy) (Yes: 89%, No: 11%)

(1) Delaying adjuvant chemotherapy in TNBC is associated with an increased risk of relapse and death; and (2) To limit the use of adjuvant chemotherapy, luminal BC should be assessed by clinical and/or genomic risks

BC: Breast cancer; CS: Clinical stage; G-CSF: Granulocyte-colony stimulating factor; PCR: Polymerase chain reaction; TNBC: Triple-negative BC.

Table 8 Priorities for medical treatment of metastatic breast cancer

High priority	Medium priority	Low priority	Comments
HER2 (+) MBC: Dual anti-HER2 therapy (pertuzumab/trastuzumab) + chemotherapy is recommended in first-line HER2 (+) MBC (Yes: 100%, No: 0%)	(1) General considerations: (a) Goals for treatment in MBC: improvement of QoL, prolong survival (Yes: 100%, No: 0%); and (b) In absence of clinical infection for SARS-CoV-2, there is no specific recommendation to test a patient who initiates therapy (Yes: 89%, No: 11%); (2) Chemotherapy: (a) Consider the use of less toxic regimens (capecitabine, CM – cyclophosphamide/methotrexate) (Yes: 100%, No: 0%); and (b) If an anthracycline, a taxane, or eribulin is used, consider the concomitant use of G-CSF (Yes: 89%, No: 11%); (3) iCDK 4/6: (a) Offer clinical benefit in the first or second line in luminal MBC. They should be considered according to resources available and institutional practices[27] (Yes: 100%, No: 0%); (b) iCDK 4/6 can be deferred in selected patients if there is a high chance of controlling the disease with endocrine therapy alone (e.g., de novo luminal MBC with a low burden of disease without visceral metastases) (Yes: 100%, No: 0%); and (c) Palbociclib dose reduction does not reduce efficacy (Yes: 100%, No: 0%)[28,29]; (4) Visceral crisis: (a) In the case of a suspected visceral crisis, clinical practice guidelines recommend the use of chemotherapy immediately (Yes: 100%, No: 0%); and (b) In an established visceral crisis, chemotherapy is the treatment of choice, but this concept is actually in revision due to the use of iCDK 4/6 in clinical practice (Yes: 100%, No: 0%); (5) Luminal MBC: (a) There should be an analysis of the benefits of using iCDK 4/6 vs the risk of adverse events. Dose reduction can reduce treatment related toxicities (Yes: 100%, No: 0%); (b) In the case of premenopausal women, it is recommended to induce ovarian suppression with LHRH analogs monthly or quarterly in selected cases, to reduce hospital admissions (Yes: 100%, No: 0%); (c) First line of treatment: currently, there is insufficient evidence to discontinue treatment with iCDK 4/6 in patients with luminal MBC (Yes: 100%, No: 0%); (d) The second line of treatment: after progression to iCDK 4/6, moving to another endocrine therapy is recommended (e.g., AI or fulvestrant) (Yes: 100%, No: 0%); and (e) Other targeted therapies in luminal MBC: in second-line, consider avoiding or deferring the addition of mTOR inhibitors (everolimus induces immunosuppression and mucositis) or PIK3CA inhibitors (alpelisib induces hyperglycemia and risk of diabetes) to endocrine therapy, especially in elderly and/or comorbid patients (Yes: 100%, No: 0%); (6) HER2 (+) MBC: (a) In patients with more than 2 yr of disease control and minimal tumor burden with trastuzumab-based regimens, discontinuation of maintenance therapy may be considered[30] (Yes: 100%, No: 0%); (b) HR (+)/HER2 (+) MBC: (b1) Patients who initiate first-line treatment: Two options according to age—(i) patients < 70 yr: Consider less toxic regimens (paclitaxel every 3 wk + dual anti-HER2 blockade as a treatment option). If using docetaxel, consider the use of G-CSF from first cycle (Yes: 89%, No: 11%); and (ii) patients > 70 yr: Consider less toxic regimens (capecitabine) + dual anti-HER2 blockade. The option of using endocrine therapy associated to anti-HER2 therapy is valid if there is a low tumoral burden (Yes: 89%, No: 11%); and (b2) patients with controlled disease: Discontinuation of chemotherapy and use of oral therapy with AI +/- LHRH analogs (in premenopausal patients) may be considered as maintenance of anti-HER2 blockade (Yes: 100%, No: 0%); and (c) HR (-)/HER2 (+) MBC: (c1) In first-line setting (where an overall survival > 5 yr is expected) with a patient < 70 yr and symptomatic: Initiate taxanes every 3 wk and/or vinorelbine or capecitabine associated with anti-HER2 blockade (pertuzumab +/- trastuzumab). If using myelosuppressive regimens, consider G-CSF to reduce the risk of neutropenia (Yes: 89%, No: 11%); and (c2) Cases where the disease is in response with one line of chemotherapy + anti-HER2 therapy, in patients classified as “high groups for COVID-19” (e.g., > 65-70 yr and/or comorbidity (diabetes, hypertension, etc.): Consider maintaining anti-HER2 therapy as maintenance (Yes: 89%, No: 11%); (7) mTNBC: (a) Recommendations with use of chemotherapy: (a1) Use regimens less frequently and with less toxicity (e.g., use paclitaxel every 2 wk -Q2W- instead of docetaxel Q3W (Yes: 78%, No: 22%); (a2) Consider G-CSF to minimize the risk of neutropenia and reduce the use of corticosteroids (Yes: 89%, No: 11%); (a3) Prefer oral chemotherapy regimens (such as capecitabine) as an alternative to the EV route (if possible) (Yes: 100%, No: 0%); (a4) Consider less immunosuppressive regimens, with a preference for monotherapy regimens rather than combinations (Yes: 100%, No: 0%); and (b) For treatment with targeted therapies, it is recommended: (b1) Immunotherapy: Consider atezolizumab + chemotherapy in patients with PD-L1 (+) mTNBC (Yes: 100%, No: 0%); and (b2) PARP inhibitors (olaparib, talazoparib): Evaluate risk/benefit (myelotoxicity) and drug interactions (Yes: 100%, No: 0%); and (8) Second-line and subsequent lines: (a) Offer second-line, third-line, or subsequent lines of treatment when therapy can deliver clinical benefit and impact on outcomes (Yes: 100%, No: 0%); (b) In HER2 (+) MBC, after progression with trastuzumab, evaluate treatment with T-DM1 and/or other available therapies, always maintaining anti-HER2 blockade (Yes: 100%, No: 0%); (c) Some doses may be deferred to minimize risk of infection during the COVID-19 pandemic (Yes: 100%, No: 0%); and (d) In MBC, after a multidisciplinary discussion and according to the patient’s preferences, terms such as “therapeutic rest”, palliative therapy or maintenance regimens with dose reduction can be offered, depending on the case (Yes: 89%, No: 11%)	Bone agent therapy: Denosumab and zoledronic acid are no urgently needed (except in cases of hypercalcemia). It can be administered every 3 mo. Bone agents for patients with bone metastases should be deferred (Yes: 100%, No: 0%)	The rapidly evolving nature of the COVID-19 pandemic may change some recommendations. These will evolve over time with continuous updates

AI: Aromatase inhibitor; COVID-19: Coronavirus disease 2019; G-CSF: Granulocyte-colony stimulating factor; HR: Hormone receptor; LHRH: Luteinizing hormone-releasing hormone; MBC: Metastatic BC.