Treatment
Neoadjuvant therapy to allow delay of surgery
The clinical management guidelines for breast cancer were recently updated in the COVID-19 era. Clinical cases eligible for neoadjuvant treatment are 9,24:
• Triple-Negative Breast Cancer (TNBC), HER2-positive and luminal B tumors >/= 2cm and/or with positive axilla (≥N1).
• Luminal A tumors stages T1-T2 and N0-N1 (neoadjuvant endocrine therapy [NET] may be recommended, especially in postmenopausal patients).
• Inflammatory and locally advanced breast cancer (NET or neoadjuvant chemotherapy [NCT]).
• Any type – to complete NCT that has already been initiated.
Specifically, for ER-positive and HER2-negative patients, both ESMO and ACS have stated that NET is an option to enable deferral of surgery by 6 to 12 months in clinical stage I or II breast cancers according to menopausal status 9,24.
Although constraints are often present in terms of resources, workforce, and hospital bed availability in the COVID-19 pandemic, causing a delay in procedures, both NET and NCT appear to be safe choices to postpone surgery in non-urgent indications of ER-positive early-stage breast cancer, also potentially contributing to a reduction in outpatient visits.
Managing axilla after neoadjuvant systemic therapy
According to the panel, if the sentinel lymph node (SN) is negative at the time of surgery, axillary dissection (AD) is not recommended, even in previously positive axilla. If the SN is positive, however, then course of action should be discussed on a case-by-case basis, especially after NET 48.
There has been increasing interest in omitting AD after NCT in past years, even in those with residual disease on sentinel lymph node biopsy (SNB). A recent American study 49 demonstrated that the use of isolated positive SN after NCT has an upward trend after the publication of the results of ACOSOG Z0011 50. In fact, the Z0011 study demonstrated excellent local and locoregional control with isolated SLNB but excluded patients who underwent neoadjuvant systemic treatment (NCT or NET) 50. In women undergoing NCT, residual axillary disease can be associated with resistance, and there is no data on cancer safety when omitting axillary dissection at this time. A retrospective review evaluated residual disease burden in positive SN after NCT and demonstrated an additional high disease burden, regardless of whether it was micrometastasis (59%) or macrometastases (63%), possibly an indication for AD 51. Another analysis showed that the likelihood of non-SLN-centered metastasis at axillary lymph node dissection (ALND) was high across all tumor subtypes 52. The core point is whether AD would play a role in residual lymph node disease cases or whether axillary radiation therapy could replace surgery in such cases. For instance, a retrospective study using data from the National Cancer Database (NCDB), with 1617 women with N1 disease after NACT, compared patients who received AD associated with nodal radiotherapy with those who received only SNB and radiotherapy, similar to the design of an ongoing randomized study of ALLIANCE group (A11202) 53 showing increased survival in women undergoing AD 54. However, in an exploratory analysis, the authors found that SN was comparable to AD in luminal tumors with single metastases. The panel recommends caution in omitting AD in such cases.
On the other hand, after NET, pathologic complete response (pCR) is generally not expected following systemic treatment 55. The question is whether these patients match the ACOSOG Z0011 study profile or otherwise. The data in this scenario is limited. A study using the NCDB and Dana-Farber/Brigham and Women's Cancer Center database evaluated tumor burden after NET and the type of axillary surgery performed (SNB or AD): more than 90% of patients who had cN0 axilla at initial presentation, in both cohorts, they had <3 positive lymph nodes in the final pathology, with no difference in overall survival regardless of the type of axillary surgery 48. In another study, using the NCDB, for stages 2 and 3, SNB use after NET was similar to that for upfront surgery and, among those with pN1 disease, the NET patients were less likely to undergo AD 56. In this scenario, the panel recommended a case-by-case assessment, with the possibility of omitting axillary dissection, especially in initially clinically negative axilla.
Breast conservative surgery and risk of infection by COVID-19
BCS is associated with lower rates of hospital stay and visits after surgery and hospitalization than mastectomy 57: a study with patients undergoing nipple-sparing mastectomy (NSM) had total complication rates of 47% and reoperations around 9% 58. Regarding the use of oncoplastic surgery, complication rates also tend to be higher than in BCS. In a study using the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database, complications within 30 days were greater in patients undergoing oncoplastic surgery compared to BCS (3,8% vs. 2.6%; p <0.001) 59. Another prospective cohort (TeaM Study) identified a reoperation rate of 2.8% 60. In a survey conducted during the pandemic among mastologists from the Brazilian Society of Mastology (SBM), 75% of surgeons would recommend partial reconstruction after BCS; however, 54% of those would contraindicate mammoplasty techniques during the pandemic period 61. The panel recommends caution in recommending major surgery during the pandemic.
Although there are still limited data on this subject, it is possible to infer that the risk of contamination for less invasive surgeries, such as BCS, is low because risks of procedure complications and surgery times are lower. In addition, all precautions mentioned previously should also be taken for this surgical procedure.
Elective surgeries that cannot be delayed
Elective surgeries, by definition, can be postponed for up to 8 weeks. There are a few elective situations that are considered essential and require planned or immediate medical assistance surgery-wise. Emergency or urgent surgeries are those that, if not performed might compromise patient survivorship. Examples of this type of surgery are revision of an ischemic mastectomy flap, surgical evacuation of breast hematoma, drainage of breast abscess and revascularization of an autologous tissue flap 9.
Bilateral mastectomy
Regarding patients with contralateral prophylactic mastectomy in unilateral breast cancer indication, although there is still limited data on this subject, historically these cases have a longer hospital stay compared to breast-conserving surgery or unilateral mastectomy, and also have more post-surgery visits and higher rates of hospitalization57. This potential increase in patient exposure could lead to a greater risk of infection by COVID-19 25. The expert panel suggested that a contralateral prophylactic mastectomy is not recommended during this period and conservative breast surgery, or even unilateral mastectomy should be carried out instead. The panel recommended that immediate breast reconstruction should be evaluated on a case-by-case basis, according to the local conditions or resource availability due to the pandemics.
COVID-19 vaccines and breast cancer
According to the panel, breast cancer patients should receive the COVID-19 vaccine as soon as it becomes available, since benefits are likely to outweigh the risks of adverse effects from SARS-CoV-2 vaccination62. The National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology recently reinforced this position 26,27. It is essential to point out that there is limited clinical data supporting COVID-19 vaccination in cancer patients 63. A multicenter, observational, prospective study has shown that SARS-CoV-2 specific IgG antibody response does not differ in cancer patients and HCP 64. It is uncertain, however, whether long-term immunization can be achieved in the oncologic population 63. In the same vein, data from influenza vaccinations indicates the development of immune protective response in cancer patients and, although, potentially, not the same level as compared to the general population, it is generally safe 28,65–67. Again, there are long-term uncertainties, and the protection may vary depending on antineoplastic therapies, administration timing, disease stage, and comorbidities 68.
It is important to note that patients who received monoclonal antibodies or convalescent plasma as part of COVID-19 treatment should defer vaccination for at least 90 days as stated by CDC recommendations 29. After the final dose is received, an individual is considered fully vaccinated after a minimum of two weeks 30. If the patient is asymptomatic and has not been in close contact with someone with SARS-CoV-2 infection in the prior 14 days, the panel deemed it safe to conduct a surgical procedure. The expert panel recommendation for vaccination against COVID-19 for eBC is presented in Figure 1. Table 3 summarizes the main vaccines approved worldwide as of April 14th, 2021.
Recently, an unexpectedly high incidence of axillary adenopathy findings after Moderna and Pfizer-BioNTech COVID-19 vaccines occurred69. For patients receiving the Moderna vaccine, a solicited adverse event was reported in 11.6% vs 5.0% for placebo following dose 1, and 16.0% vs 4.3% for placebo following dose 2 70. Adenopathy occurred in the arm and neck 2-4 days after vaccination with a median duration of 1-2 days 69. For those receiving the Pfizer-BioNTech vaccine, resultant lymphadenopathy lasted for a mean of 10 days. However, in the Pfizer-BioNTech study, adenopathy was only reported as an unsolicited adverse event 69. A single institution report found similar findings and the authors are considering “MRI-detected isolated unilateral lymphadenopathy ipsilateral to the vaccination arm to be most likely COVID-19 vaccine-related if within four weeks of either dose” 71.