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Neoadjuvant therapy for breast cancer, including surgical considerations
Introduction
Over the past half century, breast cancer management has evolved from primarily surgical therapy to a multidisciplinary approach including surgery, radiation therapy and systemic therapy. This shift is based on an increased understanding of invasive breast malignancy as a systemic disease and is based on improved outcomes with the addition of systemic therapy to local regional therapy.
Observations of micrometastatic disease in early stage breast cancer led to the initial rationale for prospective randomised clinical trials evaluating the survival outcome of neoadjuvant or preoperative chemotherapy as compared to adjuvant chemotherapy in this population. While these trials were unable to demonstrate a survival benefit to preoperative chemotherapy, several advantages were realised, including the prognostic impact of response to therapy and facilitation of breast-conserving therapy (BCT) for increased numbers of women.
Rapid advances in care and improved understanding of tumour biology have continued to guide treatment recommendations and allow for limited surgery in certain populations with downstaging of disease in the breast and axilla. Furthermore, the neoadjuvant platform and assessment of response has allowed for an improved understanding of tumour biology and drug development. In the setting of hormone receptor (HR)-positive disease, neoadjuvant endocrine therapy is gaining favour in postmenopausal women. Future studies may be able to further personalise therapy by avoiding surgery completely in exceptional responders to neoadjuvant therapy.
In contemporary practice, a neoadjuvant chemotherapy approach is utilised in patients with inflammatory breast carcinoma, locally inoperable breast cancer, locally advanced disease and selected patients with early stage operable breast cancer, particularly when the use of neoadjuvant therapy will allow for more cosmetically acceptable BCT and increasingly for those who will be recommended adjuvant chemotherapy as determined by tumour molecular subtype.
The evidence base for neoadjuvant systemic therapy in breast cancer is reviewed, as is the evolving landscape and implications for clinical practice.
Landmark clinical trials evaluating neoadjuvant chemotherapy in operable breast cancer
Several randomised clinical trials have been performed worldwide comparing neoadjuvant chemotherapy with adjuvant chemotherapy in women with operable breast cancer (see Table 15.1 ). In the USA, the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 was a landmark trial comparing adjuvant and neoadjuvant chemotherapy with four cycles of adriamycin cyclophosphamide (AC) in stage I–IIIA (T1–3 N0–1) operable breast cancer. This randomised trial of over 1500 women showed no difference in overall survival and disease-free survival if chemotherapy was delivered in the neoadjuvant or adjuvant setting, a finding that has persisted after 16 years of follow-up. Thirteen per cent of patients in the neoadjuvant chemotherapy group were found to have no residual disease on final pathology. Improved survival was associated with pathological complete response (pCR) and pathologically negative axillary nodes in the neoadjuvant chemotherapy group. Furthermore, rates of breast conservation were increased in the neoadjuvant chemotherapy group as compared to the adjuvant chemotherapy group (67.8% vs 59.8%).
Table 15.1
Landmark prospective randomised clinical trials of neoadjuvant chemotherapy compared to adjuvant chemotherapy in operable breast cancer
| Overall survival | Disease-free survival | BCS | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Trial | Neoadjuvant regimen | Neoadj. | Adj. | Neoadj. | Adj. | Neoadj. | Adj. | pCR | |||
| NSABP B-18 , | AC | 5 years | 80% | 81% | 67% | 67% | 68% | 60% | 13% | ||
| 8 years | 72% | 72% | 55% | 55% | |||||||
| 16 years | 55% | 55% | HR 0.99; 95% CI 0.85–1.16, P = 0.90 | 39% | 39% | HR 0.93; 95% CI 0.81–1.06, P = 0.27 | |||||
| NSABP B-27 ∗ 3 | AC AC + T |
5 years | 82% 83% |
82% | 68% 71% |
70% | 13% 26% |
||||
| 8 years | 74% 75% |
75% | P = 0.76 | 59% 62% |
62% | ||||||
| EORTC 10902 | FEC | 10 years | 64% | 66% | HR 1.09; 95% CI 0.83–1.42, P = 0.54 | 48% | 50% | HR 1.12; 95% CI 0.9–1.39, P = 0.30 | 35% | 22% | 4% |
AC , Adriamycin cyclophosphamide; adj ., adjuvant; BCS , breast-conserving surgery; 95% CI , 95% confidence interval; FEC , fluorouracil, epirubicin, cyclophosphamide; pCR , pathological complete response; T , taxane (docetaxel).
∗ NSABP B-27 had three treatment groups, all of which received neoadjuvant AC; group 1 did not have additional adjuvant therapy, group 2 also received docetaxel without adjuvant chemotherapy and group 3 received neoadjuvant AC with adjuvant docetaxel.
The survival equivalence of chemotherapy given in the preoperative or postoperative setting has been confirmed by subsequent prospective randomised trials including the NSABP B-27 trial comparing the addition of preoperative and postoperative docetaxel to the neoadjuvant anthracycline-based regimen and the European Organization for Research and Treatment of Cancer (EORTC) 10902 study comparing preoperative and postoperative fluorouracil, epirubicin, cyclophosphamide (FEC) for four cycles. Furthermore, a meta-analysis of 14 published randomised controlled trials evaluating the optimal timing of chemotherapy in relation to surgery supported this conclusion in the 10 trials describing survival outcome among 4620 women.
These trials determined that in operable breast cancer there is no survival advantage to neoadjuvant chemotherapy over adjuvant chemotherapy. However, several advantages to a neoadjuvant chemotherapy approach emerged from these early randomised trials, including improved survival in patients who achieve pCR and pathologically node-negative disease as well as increased rates of breast conservation in patients initially planned for mastectomy.
Response to neoadjuvant chemotherapy
Perhaps one of the most striking insights from the neoadjuvant trials is the ability to assess tumour response in vivo and the prognostic significance of this response to therapy with respect to outcome. Although varying definitions exist in the literature, pCR typically refers to no pathological evidence of residual invasive disease after neoadjuvant chemotherapy in the breast (ypT0 or ypT0/is) and axilla (ypN0). Achieving pCR has been associated with improved survival in virtually every individual trial and has been used as a surrogate endpoint for prognosis in several neoadjuvant clinical trials.
The pCR rate among the randomised trials evaluating neoadjuvant and adjuvant chemotherapy ranged from 4% to 29.2%. , Factors associated with increased likelihood of pCR include age less than 40, smaller tumour size (<2.0 cm), ductal histology, high grade, high Ki67, oestrogen receptor (ER)-negative, triple-negative and human epidermal growth factor receptor-2 (HER2)-positive disease. A recent pooled analysis of the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC) evaluating 12 international neoadjuvant clinical trials including 11 955 patients found patients with pCR in the breast and axilla to have improved survival outcomes as compared to those with pCR in the breast alone. This association was strongest in the more aggressive tumour subtypes, triple-negative and HER2-positive. On a trial level analysis, however, improvement in the pCR odds ratio did not correlate with survival outcome. Unfortunately, despite attaining pCR, a small percentage of patients do develop distant disease or local recurrence, particularly those who were clinical stage IIIB or higher at presentation, were premenopausal and had 10 or fewer lymph nodes examined.
Moving beyond pCR to predict outcome, calculation of the residual cancer burden (RCB) can further discriminate response to neoadjuvant therapy by evaluating the primary tumour size, cellularity of the invasive component, size of largest nodal metastasis and number of pathologically positive nodes. The RCB index has been shown to be associated with outcome such that an increased RCB is associated with increased risk of 5-year distant relapse from 2.4% for RCB-I to 53.6% in RCB-III, and RCB-0 or RCB-I is comparable to pCR with respect to prognosis.
Neoadjuvant chemotherapy allows for an in vivo evaluation of tumour chemosensitivity and assessment of response to therapy which has prognostic significance with respect to outcome. pCR and pathologically negative axillary nodes are associated with improved survival outcomes.
Influence of tumour molecular subtype on response to therapy
One of the most striking advances in understanding breast cancer tumour biology came with the classification of molecular subtypes described by Perou and colleagues in 2000. These subtypes of breast malignancy, described as luminal A, luminal B, basal-like and HER2-enriched, are associated with differing activity and biological behaviour. Clinically, the ER, progesterone receptor (PR) and HER2 receptor are used as surrogates to approximate these subtypes and guide clinical decision-making.
A differential response to neoadjuvant chemotherapy by subtype has been documented by several studies and clinical trials. A meta-analysis of 30 studies showed an overall pCR rate (breast) of 19.2% after neoadjuvant chemotherapy. By subtype, estimates of pCR were 8.3% in HR-positive HER2-negative disease, 18.7% in HR-positive HER2-positive disease, 31.1% in triple-negative disease and 38.9% in HR-negative HER2-positive disease. Moreover, recent analysis of the ACOSOG Z1071 trial evaluating sentinel lymph node (SLN) dissection following neoadjuvant chemotherapy in biopsy-proven clinically node-positive patients found pCR rates (breast and axilla) of 11.4% in HR-positive HER2-negative disease, 38.2% in triple-negative disease and 45.4% in HER2-positive disease.
Tumour subtype has a profound impact on response to neoadjuvant chemotherapy, with HER2-positive HR-negative tumours having the highest rates of pCR followed by triple-negative tumours.
Triple-negative breast cancer
Triple-negative breast cancer (TNBC) is characterised by lack of expression of the oestrogen, progesterone and HER2 receptor. These tumours are typically more aggressive with increased cellular proliferation, high grade and poor prognosis. TNBC, however, can be highly responsive to neoadjuvant chemotherapy with pCR in approximately one-third to one-half of patients and furthermore, in the setting of pCR, overall survival is comparable to that of the more favourable HR-positive subtype.
Currently, there is no targeted therapy for TNBC, limiting systemic therapy options to chemotherapy alone. There is an association between TNBC and BRCA mutations. Because of the value of platinum compounds in other malignancy due to such mutations, cisplatin and carboplatin have been investigated in combination with conventional chemotherapy as to their impact on pCR and outcome in TNBC. The CALGB 40603 (Alliance) trial compared carboplatin or bevacizumab concurrent with weekly paclitaxel and dose-dense AC. The investigators found an increase in pCR with the addition of both carboplatin (60% vs 44%, P = 0.0018) and bevacizumab (59% vs 48% P = 0.0089). However, increased toxicity was noted with the additional therapy. A meta-analysis of 28 trials, six of which were randomised trials, evaluating the role of platinum-based therapy (cisplatin, carboplatin) in the neoadjuvant setting found an overall pooled pCR of 45% (41.9% with cisplatin and 46.3% with carboplatin). Compared to non-platinum-based therapy, the pCR rate increased from 32% to 48% ( P < 0.0001). Furthermore, pCR was two-fold higher in TNBC than that of non-TNBC treated with platinum-based chemotherapy (48.4% vs 19.6%).
Additionally, TNBC does not appear to be one single molecular entity, which may account for heterogeneity in terms of response. Gene expression studies have classified seven molecular subtypes of TNBC – basal-like 1, basal-like 2, mesenchymal-like, mesenchymal stem-like, immunomodulatory, luminal androgen receptor (LAR) and unstable, with differing response to conventional chemotherapy. With respect to pCR, one study found the highest pCR rate in the basal-like 1 group (52%) with the lowest pCR rate in the basal like-2 (0%) and LAR (10%) groups. Further clinical trials are needed to determine the clinical significance of non-responders and to identify opportunities for targeted therapies that may increase the pCR rates.Keynote 522 was a practice changing randomized clinical trial evaluated the addition of pembrolizumab to standard neoadjuvant chemotherapy in early stage II or III TNBC (cT1 N1-2 or T2-4 N0-2). The investigators identified significantly increased pCR rates (64.8% vs 51.2%) and 3-year event free survival (84.5% vs 76.8%) with the addition of pembrolizumab. , Notably, increased treatment related adverse events were also noted among patients receiving pembrolizumab and chemotherapy compared to chemotherapy alone.
In contemporary clinical practice, patients with stage II or III TNBC are treated with anthracycline–taxane-based chemotherapy in the neoadjuvant setting (with the addition of pembrolizumab if not contraindicated), with significant rates of pCR in approximately one-half to two-thirds of patients and improved event-free survival.
HER2-positive breast cancer
HER2-positive or amplified breast cancers historically have been associated with an unfavourable outcome. However, the addition of anti-HER2-directed targeted therapies to standard chemotherapy regimens has revolutionised clinical care and outcomes within this subtype. In 2005, Buzdar et al. were the first to describe the response to trastuzumab in the neoadjuvant setting. This trial conducted at the University of Texas MD Anderson Cancer Center (MDACC) found an increased rate of pCR in stage II and IIIA patients treated with neoadjuvant chemotherapy and trastuzumab as compared to chemotherapy alone (65.2% vs 26.3%; P = 0.016). This trial was stopped early as there was no longer equipoise given the significant response with the addition of trastuzumab. Furthermore, disease-free survival was improved from 85.3% to 100% with the addition of trastuzumab ( P = 0.041). These findings were redemondstrated in the NOAH trial, with a pCR of 19% in the chemotherapy alone arm versus 38% with the addition of trastuzumab. Similarly, improved disease-free survival was demonstrated with the addition of trastuzumab at 3 years (56% vs 71%; P = 0.013) and relapse-free survival at 5 years (47% and 65%; P = 0.012). ,
Subsequent studies have demonstrated a similar finding with increased pCR with addition of trastuzumab to neoadjuvant chemotherapy in HER2-positive disease. With the development of subsequent HER2-targeted agents, lapatinib and pertuzumab, trials evaluating the response to dual anti-HER2-targeted therapy in the neoadjuvant setting have been extensively studied ( Table 15.2 ). Perhaps the most notable of these trials was the NeoSphere study. This trial evaluated trastuzumab and pertuzumab in the neoadjuvant setting with docetaxel in stage II and III invasive breast cancer. Anthracycline-based chemotherapy was administered in the adjuvant setting. The pCR rate (breast) was highest in the group treated with neoadjvuant trastuzumab, pertuzumab and docetaxel (45.8%) as compared to trastuzumab or pertuzumab with docetaxel alone (29% and 24%, respectively). Interestingly, in the group treated with dual-agent therapy alone without docetaxel, in the preoperative setting the pCR rate (breast) was 16.8%, suggesting a subset of patients benefit from dual anti-HER2 therapy without chemotherapy. Furthermore, within this group the pCR was notably higher in ER-negative disease as compared to ER-positive disease. Toxicities include decreased left ventricular systolic function, diarrhoea, hepatotoxicity, neutropenia and skin-related reactions.
Table 15.2
Neoadjuvant clinical trials evaluating dual anti-HER2-targeted therapy in HER2-positive invasive breast cancer
| Neoadjuvant regimen | pCR breast | pCR breast and axilla | |
|---|---|---|---|
| NeoALTTO | Lapatinib → lapatinib + paclitaxel Trastuzumab → trastuzumab + paclitaxel Lapatinib + trastuzumab → lapatinib + trastuzumab +paclitaxel |
24.7% 29.5%∗ 51.3%∗ ∗ P = 0.0001 |
20% 27.6%∗ 46.8%∗ ∗ P = 0.0007 |
| NeoSphere | Trastuzumab + docetaxel Pertuzumab + trastuzumab + docetaxel Pertuzumab + trastuzumab Pertuzumab + docetaxel |
29%∗ 45.8%∗ 16.8% 24% ∗ P = 0.0140 |
21.5% 39.3% 11.2% 17.7% |
| CHER-LOB | (Paclitaxel → FEC) + trastuzumab (Paclitaxel → FEC) + lapatinib (Paclitaxel → FEC) + trastuzumab + lapatinib |
25% 26.3% 46.7% P = 0.019 |
|
| TBCRC 006 | Lapatinib + traztusumab | 27% | |
| TRYPHAENA | (FEC → docetaxel) + trastuzumab + pertuzumab FEC → (docetaxel + trastuzumab + pertuzumab) Carboplatin + trastuzumab + pertuzumab |
61.6% 57.3% 66.2% |
50.7% 45.3% 51.9% |
| NSABP B-41 | AC → paclitaxel + trastuzumab AC → paclitaxel + lapatinib AC → paclitaxel + trastuzumab + lapatinib |
52.5%∗ 53.2% 62%∗ ( P = 0.095)∗ |
49.4%∗ 47.4% 60.2%∗ ( P = 0.056)∗ |
AC , Adriamycin cyclophosphamide; FEC , fluorouracil, epirubicin, cyclophosphamide; pCR , pathological complete response.
The improved pCR rate (as a proxy for improved survival outcome and reduced local regional recurrence [LRR] rates) with the addition of pertuzumab to standard therapy led to accelerated drug approval in the neoadjuvant setting by the US Food and Drug Administration.
Another promising anti-HER2-directed therapy, T-DM1 or ado-trastuzumab emtansine, has been used in advanced HER2-positive breast cancer although it is not currently used as standard first-line therapy. T-DM1 consists of trastuzumab linked to emtansine, allowing for targeting to the HER2 receptor with intracellular delivery of toxic chemotherapy. In the neoadjuvant setting, T-DM1 has been studied in the phase II Women’s Healthcare Study Group-Adjuvant Dynamic marker-Adjusted Personalized Therapy (WSG-ADAPT) HER2+/ HR+ trial. This randomised study of 376 patients found pCR rates of 40.5% for T-DM1 alone, 41.5% for T-DM1 and endocrine therapy and 15.1% for trastuzumab with endocrine therapy ( P < 0.001). This finding is very interesting considering that lower pCR rates for chemotherapy and anti-HER2 therapy have been reported in HER2-positive ER-positive disease when compared to ER-negative disease.
In patients with stage I HER2-positive breast cancer an abbreviated course of systemic therapy (Taxol and Herceptin) has been described. For this reason, in patients with clinical T1 N0 HER2-positive breast cancer, while candidates for neoadjuvant therapy, an initial surgery approach determines pathologic stage and their candidacy for this regimen. Others prefer the neoadjuvant approach for any patient likely to get chemotherapy and anti-HER2 therapy because they prescribe a shortened 6-month course of trastuzumab in patients who achieve a pathological CR. The portfolio of HER-2 neoadjuvant clinical trials most strongly illustrates the utility of the neoadjuvant platform to identify targeted therapies in particular populations to achieve improved clinical outcomes.
In contemporary clinical practice, patients with stage II or III HER2-positive breast cancer are likely to be offered chemotherapy and trastuzumab and pertuzumab in the neoadjuvant setting. These tumours demonstrate the highest rates of pCR. Upfront surgery may be considered to de-escalate chemotherapy with stage I HER2-positive breast cancer.
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