Consensus on contentious issues relevant for breast cancer management for the Indian scenario: Statements following a multicentre expert group meeting

Optimal breast cancer management requires appropriate diagnosis and staging using clinical, imaging and pathological methods. The management plan depends on the extent of tumour burden and biology of the disease. Breast cancer treatment centres globally have standard policies based on available evidence. However, there are various practical challenges in implementing what is considered as gold standard depending on what is perceived as most appropriate by the medical team depending on the clinical, social, economic, geographical and other associated factors which affect access to therapy12. Standardization and quality assurance (QA) of therapy are the other issues that need to be taken into account. Emerging data, therefore, need to be analysed on a regular basis, to determine applicability for the local population, and important decisions on the cost-benefit ratio need to be taken before a recommendation is made. In addition, the mechanisms for basic QA and checks need to be in place within the multidisciplinary teams to ensure safe management policies. An expert team was constituted to discuss and generate consensus on the controversial issues faced in the management of breast cancer. A group of experts from the UK which participated in the development of the UK Consensus Guidelines for Breast Cancer Care, was also available as resource persons.

Consensus statements on breast cancer management included those released internationally by the American Society of Clinical Oncology (ASCO)3, St. Gallen International Consensus4, and National Comprehensive Cancer Network (NCCN)5. However, regional variations require a national consensus guideline, a good example of which is the document released by the UK team6. Indian consensus guidelines have also been developed7 and recent efforts from the National Cancer Grid8 have focussed on further enhancement and refinement in the protocol. With evolving evidence, some specific controversial issues emerge and a regional consensus needs to be agreed upon to ensure protocol adherent management. The objective of the present exercise was to achieve a consensus on some of these controversial issues among Indian experts.

Invitations were sent to academic, non-academic, private and public centres in India, where a multidisciplinary team-based breast cancer management approach was followed for breast cancer patients, and pathologists, surgeons, medical oncologists, radiation and clinical oncologists were invited. Controversial topics were summarized and specific areas with uncertainty were highlighted by the organising team at Tata Medical Center, Kolkata. These documents with these details were mailed to all invited experts at least two weeks before the consensus meeting which was planned in August 2019.

Consensus was defined as overwhelming with 90-100 per cent concurrence, 70-89 per cent concurrence was recorded as consensus/moderate consensus, 50-70 per cent as low concurrence and <50 per cent agreement on voting was recorded as non-consensus. The current document summarizes the results of the consensus meeting.

There were 14 experts from the public sector and 25 from the private sector. Six experts from the UK consisting of one surgical oncologist, one pathologist, two medical oncologists and two clinical oncologists acted as external resource experts.

Pathology consensus

The team discussed the need for following appropriate internal and external QA processes to ensure accurate histopathological and immunohistochemistry (IHC) reporting and how appropriate QA among other issues has improved the biological classification of breast cancer. The breast cancer oestrogen receptor (ER) and progesterone receptor (PR) positivity rates reported from India are similar to that reported in Western countries9. However, some reports have suggested that triple-negative breast cancers may occur in about 15-20 per cent of the Indian women. These cancers are associated with a younger age at presentation, advanced stage and a higher risk of visceral metastases10. Further research is needed to improve the outcomes in this population. The following (Table I) specific areas were discussed and votes were taken to ascertain compliance on the issues.

While consensus was reached on the IHC processes to be followed for ER and PR positivity, a similar consensus was not reached for Ki-67 reporting. This stemmed from the need to implement automatic analysis of Ki-67 staining in IHC as manual methods are associated with significant inter-observer variation. Initial reports suggest that deep-learning techniques may be useful in this area, but these techniques need to be evaluated prospectively1112.

Surgical consensus

The surgical discussions focussed on reaching consensus on topics ranging from basic issues like surgical margin requirements to others related to the practical and safe implementation of advanced procedures such as breast oncoplasty, sentinel lymph node biopsy (SLNB) and techniques of marking the tumour bed, especially after oncoplastic breast procedures. The experts appreciated that in the absence of a screening programme, breast cancers in Indian women are more advanced at presentation; hence, the options of treatment for advanced disease like neo-adjuvant chemotherapy (NACT) and mastectomy were discussed. Table II highlights the consensus reached on surgical issues.

The experts acknowledged that the advanced stage at presentation for patients of breast cancer did not necessarily rule out aesthetic and functional considerations when planning surgery. However, caution is indicated in Indian patients before practising de-escalation of surgical treatment as reflected in the lack of consensus on the applicability of SLNB after NACT in patients with clinically node positive disease at presentation. The meta-analysis by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) suggesting poorer locoregional control following NACT was extensively discussed13. However, the experts felt outcomes of patients receiving NACT in centres which followed a protocol-based management approach was sufficiently good to mandate continuing the practice1415.

While not directly discussed in the meeting, practical concerns regarding adherence to treatment protocol are paramount when selecting patients with locally advanced breast cancer (LABC) for breast conservation16. All members agreed that such patients should be offered breast conservation only under a well-defined breast cancer multidisciplinary service (Table II). Furthermore, low axillary sampling may be an alternative to SLNB in resource-constrained settings17.

Radiation oncology consensus

Several radiation oncology-specific controversial topics were discussed focusing on tailoring radiotherapy as per the risk profile of the disease as well as ensuring safer, less morbid radiotherapy treatments. The main topics of discussion were related to tumour bed boost after breast conservation, management of internal mammary nodal (IMN) disease, partial breast irradiation and avoidance of radiotherapy for the selected patients after breast conservation. The results of the discussion are summarized in Table III.

The experts concurred with the available evidence on the necessity of tumour bed boost1819 but emphasized that after complex breast surgery, boost cavity delineation was a challenging issue. The use of advanced techniques such as SIB (simultaneous integrated boost) was endorsed by the group members20. In contrast, there was a relative lack of consensus on elective irradiation of IMN. The UK team pointed out the evidence from Danish Breast Cancer Cooperative Group (DBCG) studies which was being increasingly used to guide IMN radiation in the UK21. The Indian team pointed out the uncertain benefit from the single randomized trial which evaluated IMN radiotherapy22 as well as the complexity of obtaining quality radiation plans with IMN radiation23. Most of the panel members agreed that personalizing radiation therapy as per the risk factors can be done in appropriately selected patients2425. There was a significant emphasis on the need for benchmarking and QA before routine implementation of partial breast irradiation.

Anti-HER2-targeted therapy

The use of HER2-targeted therapy was discussed extensively as significant advances have been made in combining agents and research has been focussed on evaluating resistance mechanisms (Table IV).

Increasing numbers of trastuzumab biosimilars2627 and availability of charitable funding have improved access to anti-HER2 therapy28. Thus, the experts felt that in the Indian context, one year of adjuvant trastuzumab should remain the standard of care. At the same time, it was acknowledged that abbreviated schedules might be considered on a case by case basis given the emerging evidence29303132. For patients who receive abbreviated trastuzumab regimens, it was not felt appropriate to simultaneously de-escalate chemotherapy using non-anthracycline regimens29.

With the advent of combination neoadjuvant HER2 blockade with pertuzumab and trastuzumab, improved pathological response rates have been reported3334. However, the evidence that this translates into meaningful clinical outcomes is weaker. It was perceived that increased pathological response rates with combination HER2 blockade were a reasonable surrogate for improved long-term disease outcomes.

Given the economic considerations of combination HER2 therapy and limited clinical data on long-term results, patient selection is the key. Patients with LABC, poor clinical response to NACT are the examples of situations where dual HER2 blockade may be offered after discussion of costs and potential benefits with the patient. On the other hand, there is robust evidence35 of a significant clinical benefit for a switch to TDM-1 in the adjuvant setting for patients with less than pathological complete response after NACT and HER2 therapy: TDM-1 should be offered to all eligible patients in this setting.

Ovarian suppression

Updated results from the SOFT (Suppression of Ovarian Function Trial) and TEXT (Tamoxifen and Exemestane Trial) as well as the Korean study336 suggest a significant and clinically meaningful overall survival advantage with ovarian suppression with tamoxifen. The experts discussed issues like method of ovarian suppression, as well as finer practice points related to follow up of these patients (Table V). Literature suggests that the majority of such patients derive a significant benefit with the addition of limited duration ovarian suppression to tamoxifen regardless of receipt of chemotherapy37. However, in the Indian context, the experts felt that surgical oophorectomy was an option given the economic status and lack of robust follow up mechanisms in most centres28. Switch to aromatase inhibitors when chemical castration is employed should be done carefully with serial hormonal assays.

Dose dense chemotherapy

Dose intensity is an important modifiable factor impacting control of micrometastatic disease in the curative setting and is largely determined by the selection of chemotherapy regimen. In the interest of maintaining dose intensity, there was a consensus that all planned NACT should be delivered prior to surgery (Table VI). Close monitoring of all such patients during chemotherapy was discussed and agreed upon. While the experts diverged in the kind of evaluation that should be done during monitoring, regular clinical evaluation was stressed upon. Members were in agreement that a mammogram can be considered as a part of response evaluation especially when breast conservation is considered. Members also agreed for early surgery in patients who were non-responders. The panel arrived at a consensus on the choice of chemotherapy regimen in the form of sequential anthracyclines and taxanes which have been shown to be better tolerated38. The panel agreed that dose dense chemotherapy regimens with compressed chemotherapy intervals and growth factor supported improve outcomes regardless of biological tumour subtype39.

Limitations

This expert meeting was a consensus meeting and was not aimed at guidelines development. As a consensus development meeting resource stratification was not considered, though it was a part of the debates. The lack of consensus on several topics considered to be standard of care in the West is reflective of this. Due to time constraints in the meeting many contentious issues like use of positron emission tomography computed tomography (PET-CT) in staging of breast cancer as well management of oligometastatic cancers were not discussed in detail. As this meeting took place in 2019, several recent advances such as use of CDK-4 inhibitors in metastatic and adjuvant settings have not been discussed.

Conclusion

The one and half day meeting was well received by all experts who agreed on the importance of such consensus development meetings and the need for regional consensus. It is believed that this consensus document will serve as a stepping stone for improving quality of service and patient care across centres.