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Dr Rika Pienaar makes the case for neoadjuvant therapy in breast cancer: by giving chemotherapy prior to surgery, the benefit of the treatment can be measured. The behaviour, not the size, of breast tumours can be assessed in the preoperative setting providing a new dimension and clarity to the traditional approach of breast cancer chemotherapy.
Neoadjuvant therapy, defined as chemotherapy before surgery, in patients with breast cancer, has until recently been reserved for locally advanced and inoperable tumours. This treatment was given in an attempt to shrink the tumour before surgery, so allowing for patients with previously inoperable tumours to be operated on. In addition, for women who wished to keep their breast, the chemotherapy can down-size the tumour before surgery so allowing for a less cosmetically and psychologically scarring surgical procedure such as a mastectomy.
The management of breast cancer has undergone pivotal changes over the last few decades. Radical mastectomy and extensive axillary clearances are no longer considered standard practice and this has meant better quality of life for breast cancer survivors. Adjuvant systemic therapy has long been associated with improved survival and investigations have been made into whether the earlier administration of systemic therapy, in a pre-surgical setting, could further improve survival by the early elimination of microscopic metastases.
“Traditionally, if the tumour was operable, the surgeon would jump in, remove the tumour and then refer the patient to the oncologist, who often would not even have seen the extent of the initial tumour,” says Dr Rika Pienaar, an oncologist specialising in the treatment of breast cancer at Panorama Oncology
Dr Pienaar, in her talk Expanding the Role of Neoadjuvant Treatment in Breast Cancer at the recent ICON Conference, explained the contemporary, biological rationale for neoadjuvant therapy in breast cancer.
In her presentation, Dr Pienaar cited a number of clinical trials where neoadjuvant chemotherapy was compared against adjuvant treatment using the same combination of chemotherapy. The largest of these trials was the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 trial, that included 1 523 patients with localised (T1-3N0-1M0) breast cancers. (1)
Of these patients, about half were randomised to receive the chemotherapy before and the other half after the surgery. In the group that received it before (neoadjuvant), there was an 80% clinical response rate (CRR) or shrinkage of the tumour of which 30% had a complete clinical response (CCR). The breast conservation therapy rate was higher among the neoadjuvant patients (67%) compared to the adjuvant group (60%).
Based on these trials, the neoadjuvant patients were also more likely to have negative axillary lymph nodes at the time of surgery when compared to the adjuvant group. The definitive results of the trials indicate the potential of neoadjuvant therapy to downstage the disease and facilitate breast conservation therapy, but also to decrease the morbidity or side effects associated with axillary surgery.
The benefits of neoadjuvant therapy
Dr Pienaar points out that the prognostic information obtained by pathological assessment of the tumour site and lymph nodes after surgery, is a substantial benefit of administering neoadjuvant chemotherapy. “Aside from the potential clinical benefits that are achieved by down-staging, neoadjuvant therapy allows direct and early observation of the response to treatment, which in theory could lead to modifications of the treatment plan in the event of poor response.
“But if the tumour is removed, and I just go in blindly doing a standard course of adjuvant chemotherapy, you won’t know if there was any benefit for the patient.”
Dr Pienaar highlighted five individual breast cancer ‘subtypes’ in her research: Luminal A, Luminal B, “Normal”, HER2 positive, and Basal-like or ‘triple negative’, and pointed out that each has its own implications both for tumour development and therapeutic outcomes.
“We observed that the different subtypes had distinct survival predictions when compared to general breast cancer data,” she says, explaining that, unlike the other subtypes, the Luminal A tumours are associated with a good prognosis.
“We know some of these intrinsic subtypes, like Luminal A types, invade locally, but don’t spread early to the vital organs. Whereas, if we look at the triple negative breast cancers and the HER2 amplified tumours, there’s an early and high risk of spread via the blood stream. It is these differences that determine the outcome of the patient.
“So by knowing you’ve got a basal-like triple-negative, three centimetre tumour and, although it’s operable, from the start it is programmed to spread and surgery upfront is not the best course of treatment”
The main aims of neoadjuvant therapy are three-fold: to treat occult metastases, decrease the bulk of the tumour in the breast and allow breast conserving surgery as well as less intensive surgery to the axilla.
Dr Pienaar says that what should preferably happen is that the diagnosing physician should perform a core biopsy to properly histologically type the breast cancer. Following this, a multidisciplinary team should then come together – the oncologist, the breast surgeon, the reconstructive surgeon, and sometimes even the geneticist – to discuss the optimal way forward for each patient. This should happen before any treatment is started or even discussed with the patient and family in order that there is a clear plan upfront. This can then be discussed with the patient so they understand what the options open to them are.
“Breast cancer is now considered to be a heterogeneous and systemic disease from the outset, with most patients with early breast cancer developing metastases in spite of extensive local therapy. The ‘one size fits all’ strategy in breast cancer management should be adapted to the new biological knowledge of the different disease subtypes with tailored treatment plans for every individual woman’s breast cancer,” she concludes, adding that physicians and patients should also be better educated as to these options to ensure optimal treatment outcomes.
Fisher B, Brown A, Mamounas E, Wieand S, Robidoux A, Margolese RG, Cruz AB Jr, Fisher ER, Wickerham DL, Wolmark N, DeCillis A, Hoehn JL, Lees AW, Dimitrov NV. Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol. 1997 Jul;15(7):2483-93.