Historically, the treatment of breast cancer involved aggressive surgical resection, an approach based on the rationale that the more complete the removal of tissue the less likely the disease would be to recur. However, it became apparent that even  after radical mastectomy breast cancer could still recur.[1] The evolution of systemic therapy for breast cancer began in the early 1970s with the first studies assessing the use of chemotherapy after resection being driven largely by the surgical community.[2] Significant improvements in breast cancer outcomes followed, and chemotherapy is now largely accepted as the standard of care in patients with node-positive or high-risk node-negative breast cancer.[3] Currently, guidelines suggest that breast cancer patients with disease that has spread to the regional lymph nodes, tumors larger than 5 cm, or high-risk features such as estrogen receptor insensitivity or HER2 positivity be considered candidates for chemotherapy.[4] In recent years, the use of systemic therapy in the preoperative setting, referred to as neoadjuvant therapy (NAT), has been increasing. Although historically reserved for patients presenting with inoperable disease, NAT is gaining in popularity for use in operable, earlier stage disease for several reasons.[4]

The only true head-to-head comparison of neoadjuvant therapy with adjuvant therapy was in the NSABP B-18 study in which patients with operable breast cancer were randomized to receive either four cycles of doxorubicin and cyclophosphamide followed by surgery or surgery followed by four cycles of doxorubicin and cyclophosphamide.[5] The study found that postponing surgery until after chemotherapy had been delivered did not result in an inferior overall survival (OS) or disease-free survival (DFS), and that patients who had a pathologic complete response (pCR), defined as no invasive cancer in the breast or axilla, experienced improved DFS and OS compared with those who did not achieve a pCR. Other studies have demonstrated that neoadjuvant chemotherapy can increase surgical options, allowing many patients who were not originally candidates for breast conserving surgery to become candidates for this procedure.[6,7]

Since the early 2000s there has been a flurry of studies on neoadjuvant approaches. While there has never been a documented improvement in DFS or OS in patients receiving NAT compared with those receiving adjuvant therapy in clinical trials, this strategy is now largely accepted as appropriate. According to international guidelines, any patient who would be considered eligible for adjuvant therapy could be considered for neoadjuvant therapy.[4]

Patient selection
Several guideline committees have grappled with patient selection for neoadjuvant therapy using different methodologies and with varying degrees of rigor. The Canadian national expert consensus on neoadjuvant therapy for breast cancer was developed to address the question of patient selection and management. A modified Delphi protocol was used to obtain the opinions of 85 expert clinicians from across the country, and these opinions were then compared with available evidence.[8] Agreement of opinion was found regarding the most appropriate candidates for NAT, the types of investigations to conduct before initiating therapy, the ways to monitor patients during therapy, and the type and timing of therapy. The experts agreed that any patients presenting with inoperable locally advanced breast cancer (LABC) should be referred for neoadjuvant therapy in an effort to improve curability of their disease, an approach already well understood. In addition, experts agreed that patients presenting with operable locally advanced breast cancer should be preferentially considered for neoadjuvant therapy. The definition of LABC agreed upon by experts surveyed was “a T3 or T4 tumour of any clinical N status, or an N2 or N3 tumour of any size, which might be operable or inoperable upon presentation and which includes inflammatory breast cancer.”[8]

Other international committees have also addressed the question of patient selection for NAT by seeking consensus during meetings and panel discussions. The recommendations from these groups tend to be slightly less specific than those of the Canadian experts, and state simply that patients assessed as appropriate candidates for chemotherapy in the adjuvant setting can be considered for chemotherapy in the neoadjuvant setting. This implies that all information required to determine candidacy for chemotherapy is available (i.e., receptor status, clinical staging), and that the breast tumor is palpable and easily followed clinically for signs of response or progression on neoadjuvant therapy.[9]

In terms of local experience, patients receiving NAT at the BC Cancer Vancouver Centre have been studied prospectively since 2013 using a clinical database of information on patient characteristics at time of presentation, clinical stage, receptor status, type of neoadjuvant therapy delivered, response, and surgical outcomes. Reviewing these data ensures that goals for guideline adherence and wait times are met.

To date, information on over 650 patients has been entered in the database and has helped to improve wait times and standardize care. Approximately 75% of patients referred for NAT were offered therapy. Of these patients, 75% received chemotherapy and 25% received endocrine therapy. In terms of staging, 53% of patients offered NAT presented with clinical stage II disease, and 42% presented with clinical stage III disease. A small minority of patients presenting with clinical stage I disease (4%) were offered NAT, usually because of very aggressive biology or other complicating factors. In terms of breast cancer subtypes, about 50% of patients were ER-positive and HER2-negative, 35% were HER2-positive, and 20% were triple-negative. While there has been a trend toward decreased use of NAT for patients with ER-positive breast cancer, use of NAT for patients with triple-negative disease has increased, as shown in the Figure [8], because of a sensitivity to chemotherapy noted in this group. Overall, patient selection for neoadjuvant therapy at the BC Cancer Vancouver Centre follows the recommendations of the Canadian national expert consensus and international guidelines.

Although guidelines are helpful, in practice the decision to offer neoadjuvant therapy to a patient is made primarily by the family doctor and surgeon. Thus it is important to ensure that all clinicians involved understand the indications and value of neoadjuvant therapy over adjuvant therapy, especially because patients will often return to their family doctor or surgeon for advice about this approach. The absolute and relative indications for neoadjuvant therapy for breast cancer are summarized in Table 1 [9].

Pathway of care
A review of the medical literature indicates that an estimated 10% to15% of breast cancer patients are treated with neoadjuvant therapy[10] and that the pathway of care can be confusing for patients and sometimes for clinicians as well. To establish an optimal pathway of care, the group responsible for developing the Canadian national expert consensus on neoadjuvant therapy for breast cancer considered clinician opinion and the management strategies employed in phase 3 randomized controlled trials.[8]

Initiating therapy
One of the benefits of initiating neoadjuvant therapy is expedited treatment of both in-breast disease and micrometastatic disease. Understandably, most patients and clinicians agree that timely initiation of therapy is crucial. While it has not yet been determined if more expeditious initiation of therapy leads to improved outcomes, expert opinion holds that chemotherapy should be started within 28 days of biopsy, and ideally earlier in the setting of HER2-positive and triple-negative disease.[8]

Data from the neoadjuvant therapy database of the BC Cancer Vancouver Centre indicate that 82% of patients started therapy within 31 days of biopsy, and that the mean wait time for patients with triple-negative disease was 23 days. While this is not far from ideal, there is still room for improvement. Continuous audit and feedback have helped key stakeholders reduce the time from biopsy to chemotherapy, with a median decrease in wait time of 3 days since this audit and feedback quality assurance initiative began.

Monitoring response
Once therapy is initiated, it is important to monitor clinical response. We know from previous studies that roughly 10% of patients have no response to neoadjuvant therapy.[11] In such cases, the systemic therapy should be changed or the patient should be scheduled for surgery as soon as possible. If disease progression or lack of response occurs and the patient does not have operable disease, salvage radiation therapy can be considered. Multidisciplinary review and discussion of any patient who is not responding to neoadjuvant therapy are needed to choose optimal second-line therapy—be it an alternate chemotherapy agent, surgery, or radiation.[8]

When undergoing NAT, patients should be monitored using physical examination as well as clinical measurement of the breast and, if present, axillary lymph nodes. While other guidelines are not specific about assessing tumor response during neoadjuvant treatment, the Canadian national expert consensus recommends methods to assess tumor response during treatment. According to the experts surveyed, clinical assessment of patients undergoing a course of neoadjuvant endocrine therapy should be performed monthly, and clinical assessment of patients undergoing chemotherapy should be performed at each cycle of treatment. In both cases a tape measure or calipers should be used to facilitate standardization and reduce the chance of observer bias.[8]

As during adjuvant therapy, assessment during neoadjuvant therapy should focus on side effects and the need for any adjustments to the therapeutic protocol or supportive therapies to ensure tolerability of treatment. The side effect profile for neoadjuvant therapy does not differ from that of adjuvant therapy, as shown in Table 2 [10].While each chemotherapeutic protocol has slightly different effects, alopecia, neutropenia, and nausea are common. Side effects common to endocrine therapy include hot flushes, night sweats, and arthralgias/myalgias.

After therapy
A review of all randomized controlled trials involving neoadjuvant therapy considered the timing of surgery upon completion of NAT. In these studies, patients underwent surgery 3 to 4 weeks after the last dose of chemotherapy.[12-14] Radiation was then offered to these patients based on initial clinical stage. This is consistent with the Canadian national expert consensus. The transition periods in the pathway of care (from systemic therapy to surgery, from surgery to radiation) can be confusing for patients and requires coordinated multidisciplinary communication. Data from the prospective neoadjuvant database of the BC Cancer Vancouver Centre show that the median time from completion of chemotherapy to surgery is 32 days. Again, this has improved since the audit and feedback quality assurance initiative began, but is still not ideal. Ongoing strategies to improve communication between disciplines is essential to ensure continued optimization of patient outcomes.

Outcomes
As Wolmark and colleagues[5] demonstrated in 2001, patients who experience a pathologic complete response to NAT have improved survival compared with those who do not achieve a pCR.[4] Whether pCR can be used as a reliable surrogate marker for disease-free survival or overall survival in randomized controlled trials has been a subject of debate. Nonetheless, in clinical practice, pCR is a very reassuring outcome and suggests that the patient has achieved maximal benefit from the neoadjuvant therapy provided.

Data from the BC Cancer prospective neoadjuvant database show that in a nontrial setting, the overall pCR rate achieved in patients with triple-negative breast cancer is 30% and the rate achieved in patients with HER2-positive disease is 40%, but patients with ER-positive disease achieve a pCR rate of only 7% on average. Other prognostic methods based on response in those with ER-positive disease have emerged, such as the RNA degradation index and CPS+EG staging system, but these are being used predominantly in research settings.[15,16] As further work is done to validate these outcomes we may move toward differential assessments of response based on subtype of disease. For the time being, however, pCR remains the main goal of neoadjuvant systemic therapy because of its association with improved DFS and OS. Tumor downstaging to allow breast conserving surgery is another valuable outcome in the treatment of these patients, but has not been shown to be as reliably associated with improved prognosis. Further studies will help to delineate the value of achieving this outcome.

Future directions
Currently, further chemotherapy is not recommended if complete pathologic response is not achieved after neoadjuvant therapy. Targeted therapy in the form of endocrine agents for ER-positive disease and anti-HER2 agents for HER2-positive disease should be continued for patients who undergo primary surgery upfront, but additional chemotherapy is not the standard of care.

The issue of what to do when pCR is not achieved has been the subject of many clinical trials. To date, only the CREATE-X study[17] has demonstrated an improvement in DFS and OS in HER2-negative patients who went on to receive capecitabine after surgery if residual disease was found. This benefit was primarily seen in the triple negative subgroup of patients who experienced an 8% absolute improvement in OS, with more modest gains seen in the hormone receptor positive subgroup of patients.Several ongoing international multicentre clinical trials are assessing the role of further targeted therapy in the adjuvant setting in patients who do not achieve pCR.

Focusing on residual ER-positive disease, PENELOPE is a phase 3 randomized controlled trial of endocrine therapy alone compared with endocrine therapy and a CDK4/6 inhibitor.[18] Focusing on residual triple-negative disease, OlympiA is a trial available to patients with BRCA1 and BRCA2 mutations, and will assess the role of an adjuvant PARP inhibitor to improve outcomes.[19] Focusing on residual HER2-positive disease, KATHERINE is a trial assessing the benefit of increased anti-HER2-directed therapy.[20] As these studies continue, our understanding of adjuvant therapy in patients with residual disease will likely shift. Patient enrolment in these studies should be encouraged.

Summary
As well as considering neoadjuvant therapy for patients with inoperable disease or inflammatory breast cancer, NAT should be considered for patients with operable locally advanced breast cancer: palpable T2 or T3 with any clinical N status or clinical N2 or N3 disease regardless of T stage. Ideally, patients should start systemic therapy within 28 days of diagnosis by core biopsy, and should be monitored with careful clinical examination at each cycle of chemotherapy or each month of endocrine therapy. Surgical excision 4 weeks after a last dose of chemotherapy is the standard used in randomized controlled trials. Adjuvant radiation should be offered based on the patient’s initial clinical stage, but adjuvant chemotherapy is not recommended if a full course of neoadjuvant therapy has already been received. Studies assessing the role of targeted therapies in the adjuvant setting for those with residual disease are ongoing and may further delineate the overall pathway of care for these patients. Several centres adopting this strategy, including the BC Cancer Vancouver Centre, have noted an improvement in wait times and outcomes when an audit and feedback quality assurance initiative is employed. Continuing to monitor real-world experience will help inform the best strategies to ensure that our patients benefit from improved outcomes in years to come. 

Competing interests
None declared.

This article has been peer reviewed.

Dr Simmons is a medical oncologist at the BC Cancer Vancouver Centre and a clinical associate professor in the Division of Medical Oncology at UBC.