Challenges in the journey of breast cancer patients in Brazil

A good outcome in BC treatment is dependent on an early and accurate diagnosis. The main methods for an early diagnosis are self-examination, mammogram, and clinical examination by experienced physicians. Following clinical suspicion, the diagnosis needs to be confirmed by histopathological and immunohistochemical analysis of a tissue biopsy. Once the tumour characteristics are defined, a multidisciplinary team should discuss the ideal treatment which needs to be initiated quickly. All interventions must be offered in timely and appropriate intervals throughout the whole process14. Unfortunately, 60% of BCs in Brazil are diagnosed at later stages, which significantly reduces the chances of a good outcome15.

The path from clinical suspicion to BC diagnosis can be long. Experts indicated that (1) gynecologists, (2) breast cancer surgeons, (3) clinical oncologists, (4) radiologists, (5) pathologists, (6) clinical geneticists, (7) psychologists and (8) nurses are essential at this initial stage of the patient's journey.

In Brazil, the gynecologist is the professional who usually raises the initial suspicion of BC during a routine clinic appointment. While all specialties should share this responsibility, expanding BC screening programs and educating patients about the importance of early diagnosis should be a focus for gynecologists. After the initial clinical suspicion, the breast cancer surgeon and the interventional radiologist are the professionals who coordinate the initial procedures, perform breast and axillary biopsies, and double-check the diagnosis in partnership with the pathologist. Together, they perform and interpret imaging tests, histopathology and immunohistochemical slides. Additionally, the clinical geneticist will provide genetic pre-counselling and define if the patient should undergo genetic testing. Genetic counseling may also be provided by an oncologist or a surgeon with adequate training for cancer genetics16.

BC diagnosis does not depend exclusively on the commitment of the professionals reported above. Proper biopsy processing for histopathological analysis is essential in tumour investigation. Most errors occur in the pre-analytical phase of biopsy processing17. The adequate handling of surgically removed breast cancer specimens involves transport, fixation, and storage. In Brazil, many hospitals do not have their own pathology laboratories and need to outsource samples to larger laboratories. Proper postoperative handling of surgical specimens might reduce and avoid errors in the diagnosis (tumour typing and grading), and immunohistochemical or molecular breast cancer biomarker testing. Factors that influence pathological analysis include size of the specimen, time to fixation from tumour removal, type of fixative and duration of fixation. Additionally, the experts highlighted that samples obtained on the eves of days off (such as weekends) are more susceptible to diagnostic error. The breast specimens are likely to be stored without adequate grossing, cutting and fixation in formalin. The tumour sample will stay without adequate cutting and fixation for a longer time than recommended. Ideally, the breast biopsy should be immediately sliced and fixed in buffered formalin for at most 48 hours. Delays in fixation or over-fixation may interfere with morphology and the integrity of proteins and nucleic acids, and negatively affect testing for BC biomarkers18 19 20. If the pre-analytical phase is not adequate, all subsequent processes will be compromised, resulting in improper treatment.

While more than 30-day delays in the exam result can compromise patient survival even shorter delays of more that 10-20 days should be considered unnecessary and unacceptable for the adequate management of a newly diagnosed BC21 22. The quality of treatment depends on a correct diagnosis and the speed at which it is provided and passed on to the team responsible for the treatment.

To improve the pre-analytical phase of diagnosis, institutions need to develop workflows that must be strictly followed by the entire team involved in biopsy tissue removal and properly delegate the responsibility of the sample, from the operating room to its final destination, to one member of the team. The inclusion of automated steps was cited by the experts as an interesting solution that would reduce errors. In the state of São Paulo, a resolution obliges all hospitals that work with cancer to have a frozen section room with cryostat, microscope, and a pathologist available for analysis of suspicious breast samples close to operating suites. This resolution was made in partnership with the Regional Council of Medicine of the State of São Paulo (CREMESP), which inspects and penalizes centers that do not comply with the law. The experts agreed that this measure should be extended to all Brazilian states. Additionally, it was noted that there should be an official program that reviews the histology and immunohistochemistry slides and that centers specialized in performing these exams should be adequately certified with regard to the quality control of the services provided.

When a breast biopsy sample is appropriately handled, errors in the analysis or interpretation of the results by the pathologist should be minimal. Nevertheless, the group of experts recognized frequent communication problems among the professionals in the multidisciplinary team responsible for the BC patient care. Furthermore, in Brazil, most centers do not have all the specialties required for adequate screening, diagnosis, and BC treatment available in-house, and most professionals are not specifically dedicated or specialized in BC. This situation raises problems in the interaction among professionals. Details that would be critical for the diagnosis and management of a specific case may sometimes go unnoticed. Lack of integration among the multidisciplinary team involved in the BC diagnosis can result in misinterpretation of results and loss of important information.

Genetic counseling should be provided promptly to all early-onset BC patients, those that are triple negative before age 60 and those with a significant family history of cancer23. The presence of pathogenic variants in high- and moderate penetrance genes may provide important insights and help surgical management decisions and overall management approaches23.

However, there is a reduced number of trained professionals in Brazil to address current genetic counseling needs. Adequate training of health professionals in genetic counseling and oncogenetics is essential to provide a better care.

The ideal scenario for a rapid and accurate BC diagnosis in Brazil requires significant improvement in the education of the general population and the development of an effective screening program distributed throughout all regions of the country. Education includes the awareness that BC is a serious problem that must be diagnosed early and treated by specialized professionals in properly qualified centers. Although one of the experts raised the issue that the majority of mammography equipment in the country can be considered outdated or non-functional8 and suggested replacement with more modern and digital equipment, most experts agreed that before creating centers with the latest technology, it is necessary to improve access to currently available equipment and improving the number of women undergoing exams in a timely manner.

The experts also indicated that the multidisciplinary team involved in BC diagnosis should be properly trained to deal specifically with the disease. Guidelines need to be defined to standardize diagnostic procedures. Finally, the experts suggested that large centers specialized in BC should be created with specialized multidisciplinary teams to lead the treatment of BC patients in all Brazilian states. However, the multidisciplinary professionals should exchange information by phone or video call as alternatives, until these centers become a reality in Brazil. Multidisciplinary discussions should ensure that dubious exams are analyzed from different perspectives and specialties. Furthermore, part of this interaction should also include the creation of a simple and informative online platform that can disseminate information prospectively about the approaches to BC being undertaken across Brazil.Table 2 gives a brief summary of this session.

Early stage BC is a highly curable disease. Broadly, tumours can be subdivided into four subtypes: (1) luminal A-like subtype; (2) luminal B-like subtype; (3) triple-negative subtype; and (4) HER2-positive subtype24. Guideline recommendations clearly indicate that patients should be managed in specialized breast centers by a trained multidisciplinary team24.

The breast cancer surgeon and the oncologist are the main decision-makers in the early stage of BC; nevertheless, other specialists also have important roles in the treatment discussion. The participation of (1) breast cancer surgeons, (2) plastic surgeons, (3) radiation oncologists, (4) clinical oncologists, (5) radiologists, (6) nuclear medicine physicians, (7) clinical geneticists, (8) psychologists and (9) nurses is essential to ensure quality care for women with eBC.

The therapy of BC should be individualized and depends on the precise extension of the tumour11. According to the experts, in non-palpable lesions, the correct diagnostic and therapeutic definition initially relies on the interaction between the radiologist, the nuclear medicine physician and the breast cancer surgeon. Image-guided localization should be performed. At this point, sentinel lymph node biopsy (SNB) should be planned by the breast cancer surgeon and the nuclear medicine physician. The latter, however, is not available in most Brazilian medical centers. In fact, according to the Brazilian Society of Nuclear Medicine, there are fewer than 300 registered professionals in Brazil, and in some states, there are no specialists at all25. In this scenario, patent blue dye should be used for SNB. Meanwhile, triple-negative tumours or initial HER2-positive tumours are potential candidates for treatment with neoadjuvant chemotherapy (NACT). Importantly, a multidisciplinary meeting is essential to define the best treatment for each case. Tumours should be clipped before systemic therapy to facilitate localization at the time of surgery and after neoadjuvant treatment.

If the axilla is clinically negative after NACT, SNB should be planned as well. While many unresolved and controversial questions are still a matter of international discussion, a multidisciplinary decision process is essential to define the ideal management strategy.

Radiation therapy (RT) is an important component of eBC treatment because it reduces local/ regional recurrence and improves BC mortality for patients after breast conservation and for node positive patients after mastectomy, respectively26. Unfortunately, there are not enough radiation machines to address the demand in Brazil. According to the World Health Organization (WHO), there is a need for one linear accelerator for every 300,000 individuals. Even accounting for a young demographic distribution, there are parts of Brazil with one machine for every 1,000,000 people or more. Approximately only half of the machines needed are available, and sadly, half of those will be obsolete by 2021 (i.e., over 15 years old and no longer subject to maintenance programs by the manufacturer). Human resources are also scarce but still adequate for the underserved machine infrastructure. There are 738 registered radiation oncologists in the Federal Council of Medicine (CFM) and 426 certified by the National Nuclear Energy Commission (CNEN)27 28 29. Overall, there are approximately 550 to 600 physicians directly working in the 242 radiotherapy departments in the country30. Approximately 30 to 35% of patients treated by radiation oncologists have BC, emphasizing the need for constant interaction between the breast cancer surgeon, the clinical oncologist and the radiation oncologist.

Genetic counseling followed by molecular testing for genes that predispose to breast cancer, regardless of tumour histopathology, were considered by the experts as important steps in eBC diagnosis and treatment. However, as clinical geneticists in Brazil are scarce and cannot fulfill the current needs, alternative models of providing minimum information to patients required before testing should be sought.

Streamlined education provided by the medical oncologist and/or breast surgeon are important in informing and treating the patient. In this way, the process is somehow abbreviated allowing the patient and physician to make initial treatment decisions (i.e. extension of the initial surgery). Nevertheless, it is important that questions regarding cancer predisposition and its consequence on patient management be discussed at some point with a clinical geneticist, a breast cancer surgeon, and the clinical oncologist.

In this stage of the patient journey as well, the experts also noted that lack of communication between the members of the professional health team involved in eBC management can result in inappropriate therapy. In an ideal scenario, multidisciplinary meetings should be held at least once a week. Complicated cases or those difficult to diagnose or treat should always be highlighted and discussed. This interaction enhances knowledge, educates, and allows an exchange of experiences between all professionals involved. The experts believe that a multidisciplinary approach can improve the diagnosis, the treatment, and consequently, the prognosis of BC patients. However, these discussions and decisions need to be made in a timely manner. As face-to-face meetings with the entire multidisciplinary team are not always feasible, the experts suggested that communications be as practical as possible using the virtual tools currently available as an alternative. Additionally, it would be interesting if the discussions of the multidisciplinary meetings could address potentially available research protocols and address guidelines published via online platforms and be made available to other physicians. This practice is common abroad and should be stimulated in Brazil.Table 3 gives a brief summary of this session

On average about 10% of breast cancer patients have distant metastasis at the time of diagnosis31. Furthermore, between 20 and 30% of women with eBC develop metastatic disease that is considered incurable31. Currently, less than 5% of patients survive long term32. In some cases, the idea of mBC as a chronic disease that remains under clinical control by a long time with sequential therapies is a realistic expectation33.

The therapeutic objectives for mBC are palliation of symptoms and maintenance of the patient's quality of life. Based on that, the experts indicated that (1) palliative care physicians, (2) clinical oncologists, (3) radiation oncologists, (4) clinical geneticists, (5) pathologists, and (6) general surgeons should be mainly involved at this point of the patient's journey. Therapy principles are generally more individualized in mBC than in eBC, as patients differ regarding preferences, pre-treatments and residual side effects from previous therapies11 34.

During metastatic disease, delivering the most effective and at the same the less toxic treatment should be the rule. In the group of patients with expression of hormone receptors, different endocrine therapies should be recommended sequentially. After documentation of endocrine resistance, different chemotherapies initially as combinations in earlier lines and as single agents in later lines is the main treatment strategy. Radiotherapy can have a significant and very positive impact on the patient's quality of life mainly addressing treatment of painful or symptomatic lesions.

More recently, the identification of patients with oligometastatic disease has spurred treatment plans with a more aggressive combination of approaches that may be warranted as control of the disease and prognosis could be particularly improved in individual patients. An added difficulty in Brazil, is the access to specific drugs or treatments. As many of the new agents take some time to go through the regulatory approval process and are not included in the list of the National Supplementary Health Agency (ANS), many health insurances do not approve their routine use35.

Is essential that treatment for metastatic disease to be individualized based on the biology of the tumour, prior treatments and the patient's comorbidities. In this regard and in accordance with the previous discussion, mBC treatment should also be addressed with a multidisciplinary team to allow for the best possible prognosis. Additionally, the close relationship between the patient and the main treating physician needs to be considered. The decision-making process and any change in the patient's treatment should include the opinion and experience of the medical team and include patient expectations, family context and previous experiences during the journey.Table 4 gives a brief summary of this session.