The use of systemic and or radiation therapy prior to surgery (neoadjuvant therapy or NAT) has been studied since the early 1970s. There are several potential advantages to the use of NAT¹:

The key landmark study by Wolmark et al in 2001 (NSABP B-18) demonstrated that NAT (with chemotherapy) was safe, with no difference in outcomes of disease free survival (DFS) or overall survival (OS) in patients who received either pre-operative chemotherapy or post-operative chemotherapy². It was demonstrated, however, that patients who had a complete pathological response (pCR) to NAT had an improved OS compared to those who did not achieve a pCR with NAT.

NAT has been since studied in multiple settings, tumour subtypes, and with many different types of agents. NAT may be considered in certain patients with early stage breast cancer, and is the standard of care for patients with locally advanced breast cancer or inflammatory breast cancer. 

The neoadjuvant treatment of breast cancer requires a coordinated effort amongst surgical oncology, medical oncology, radiation oncology, nursing, pathology, radiology and clerical booking staff.³ 

In general, any patient who is a candidate for adjuvant systemic therapy can be considered for neoadjuvant chemotherapy. Patients with tumours < 2cm, low grade, ER positive/Her2 negative, may not require systemic chemotherapy and should undergo surgery first.⁸

Before starting NAT the following tests and procedures should be completed:^4,6,7

Following NAT, patients should undergo definitive locoregional therapy, which usually involves surgery and radiation. 

Surgery should be planned for 3-4 weeks following completion of neoadjuvant chemotherapy to allow adequate immune and general recovery first. This is consistent with timelines reported in randomized controlled trials of NAT in breast cancer patients.

Patients with technically inoperable tumours after NAT should have radiotherapy after chemotherapy with a view to further local downstaging. If their disease becomes operable, appropriate surgery should follow.

If the tumour enlarges while on NAT, treatment should be changed. Non-cross resistant chemotherapeutic agents, salvage radiotherapy, or surgery are all appropriate options to consider in this setting. Discussion of these cases at a multi-disciplinary tumour board should be considered. Cancers showing equivocal response may benefit the most from tumour board multidisciplinary review, to explore ways to improve clinical response.

Pathology findings following NAT are designated with a 'y' in front of the 'p" (example ypT2N1) to reflect that the cancer has been exposed to treatment. In general, the less disease present, the better the prognosis, with a large jump (improvement) in prognosis occurring with a pathological complete response (pCR).¹⁰ The improved disease free and overall survival associated with a pCR has been shown in cancers of all biomarker profiles (triple negative, ER positive, and her2 positive).¹¹

The definition of pathological complete response varies in clinical trials. The strictest definition allows no residual invasive disease or in situ disease in the axilla or breast. The least strict definition considers only the absence of invasive disease in the breast, allowing for residual nodal metastases. The Canadian expert consensus for the definition of pathological complete response is no evidence of invasive disease in the breast or axilla3. This definition allows for residual DCIS and is consistent with the definition most often reported in clinical trials of NAT.

There is not data to support that additional chemotherapy is of benefit in patients who have residual disease at surgery following NAT. Clinical trial options can be considered if available. Hormone therapy and trastuzumab should be given according to standard of care.

Preoperative chemotherapy (NAT) has several functions:

In general, there is a preference for chemotherapy regimens that include an anthracycline and a taxane, either concurrently or sequentially Chemotherapy Breast Protocols, based on demonstration of improved outcome compared with anthracycline only regimens.¹⁴ Recommended regimens include BRLAACD and UBRAJACTW, but avoidance of anthracyclines or taxanes, or abbreviated courses, may be necessary for some patients with co-morbidities. Trastuzumab (BRLAACDT) should be added if the cancer is her2+. NAT is typically given for about six months (8 cycles) prior to definitive local therapy, provided there is no adverse progression of the disease on therapy.

The likelihood of achieving a pCR with endocrine therapy is significantly lower than with chemotherapy.

Neoadjuvant endocrine therapy may be an appropriate option in patients found to have hormone receptor positive disease and who are unfit for chemotherapy. Canadian experts from the Canadian Consensus for the Treatment of Locally Advanced Breast Cancer recommend endocrine therapy for patients with ER+PR+Her2- disease and multiple co-morbidities, or who are older than 80 years. The duration of neoadjuvant hormone therapy is not well defined, but studies have been conducted using an interval of 4-8 months.¹² The overall goals of care should be discussed with the patient and the duration of therapy should reflect this (ie if the goal is curative then a pre-defined duration of NAT with endocrine therapy followed by surgery; if the goal of care is control then there may be no pre-defined duration of NAT).

Aromatase inhibitors and Tamoxifen have been studied in the neoadjuvant setting.¹³ In serial biopsy studies, aromatase inhibitors have demonstrated a greater drop in proliferation markers (Ki67) than tamoxifen. Anastrozole, Exemestane, and Letrozole have all demonstrated similar effect on proliferation indices. One study showed better clinical response rates with letrozole than tamoxifen.¹⁴ For these reasons, aromatase inhibitors are preferred in menopausal women, although tamoxifen can be used in patients with contraindications or intolerance to AIs.

The above guideline can be summarized in the following pathway of care: