The Evolving Role of Neoadjuvant Therapy for Operable Breast Cancer

Authors: Laura M. Spring MD1,2, Yael Bar MD1, and Steven J. Isakoff MD, PhD1,2
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  • 1 Massachusetts General Hospital Cancer Center, and
  • | 2 Harvard Medical School, Boston, Massachusetts.

The role of neoadjuvant therapy (NAT) for localized breast cancer has evolved tremendously over the past several years. Currently, NAT is the preferred option for high-risk early triple-negative (TN) and HER2-positive (HER2+) breast cancers and is indicated for some estrogen receptor–positive (ER+) breast cancers. In addition to traditional absolute indications for NAT, relative indications such as the assessment of outcomes at the time of surgery and guidance of treatment escalation and de-escalation have greatly evolved in recent years. Pathologic complete response (pCR) and the Residual Cancer Burden (RCB) index are highly prognostic for disease recurrence and survival, mainly in patients with TN or HER2+ disease. Furthermore, post-NAT escalation strategies have been shown to improve long-term outcomes of patients who do not achieve pCR. Additionally, by allowing the direct assessment of drug effect on the tumor, the neoadjuvant setting has become an attractive setting for the exploration of novel agents and the identification of predictive biomarkers. Neoadjuvant trial design has also evolved, using adaptive treatment approaches that enable treatment de-escalation or escalation based on response. However, despite multiple practice-changing neoadjuvant trials and the addition of various new agents to the neoadjuvant setting for early breast cancer, many key questions remain. For example, patient selection for neoadjuvant immunotherapy in TN breast cancer, de-escalation methods in HER2+ breast cancer, and the use of gene expression profiles to guide NAT recommendations in ER+ breast cancer. This article reviews the current approach for NAT in localized breast cancer as well as evolving NAT strategies, the key remaining challenges, and the ongoing work in the field.

Use of neoadjuvant therapy (NAT) for operable breast cancer has increased significantly over the past several years. Initially, interest in NAT centered around operability and improving eligibility for breast-conserving surgery.1 Later, the neoadjuvant setting became recognized as a human in vivo system to explore predictive biomarkers, surrogate endpoints, and the efficacy of therapies including novel agents, making it an attractive setting for drug development.2 More recently, indications for NAT have evolved to recognize its critical role in guiding escalation and de-escalation of subsequent therapy, particularly in triple-negative breast cancer (TNBC) and HER2-positive (HER2+) breast cancer.

Assessment of outcomes at the time of surgery, such as pathologic complete response (pCR, most commonly defined as ypT0/isN0) and the Residual Cancer Burden (RCB) index, have been shown to be highly prognostic surrogates for disease-free survival (DFS) and overall survival (OS) on an individual patient level.35 More recently, the neoadjuvant trial design has evolved to offer earlier assessment of response, with an increasing interest in adaptive designs. This review examines the evolving role of NAT for operable breast cancer.

Neoadjuvant Approach in TNBC

Current Approach

NAT is currently the preferred approach for the majority of patients with early TNBC at least 2 cm in diameter or node-positive, whereas up-front surgery is generally reserved for smaller, node-negative tumors.6 The RCB index and pCR are highly prognostic in patients with TNBC.35 Additionally, postneoadjuvant treatment escalation improves long-term outcomes for patients with TNBC with residual disease following NAT.7,8 Cytotoxic polychemotherapy remains the mainstay of NAT for early TNBC. Compared with early non-TNBC subtypes in which the use of anthracyclines has been greatly reduced, anthracycline- and taxane-based regimens remain the standard for most patients with localized TNBC.9,10 The addition of the platinum agent carboplatin to neoadjuvant chemotherapy (NACT) was consistently shown to increase pCR rates in multiple clinical trials.1113 According to a meta-analysis of 9 randomized trials, the incorporation of carboplatin significantly increased pCR rates from 37% to 52%.14 However, no significant difference in event-free survival (EFS) was observed, and increased rates of hematologic toxicities and treatment delays or discontinuations were observed.14 Despite the proven and robust pCR improvement, the routine incorporation of carboplatin for patients with TNBC was not recommended by many clinical guidelines due to uncertainty regarding the translation of this improvement to long-term survival benefit.15,16 Recently presented post hoc analysis from the phase III BrighTNess study showed significant and clinically meaningful EFS benefit with the addition of carboplatin to anthracycline- and taxane-based regimens (hazard ratio [HR], 0.57; P=.018).17 Furthermore, in a recent meta-analysis of 6 trials which reported long-term outcomes, platinum-based NACT was associated with a significant increased EFS (HR, 0.70) and a nonsignificant 18% reduction in the risk of death (HR, 0.82).18 Interestingly, a platinum-based regimen was included in the pivotal KEYNOTE-522 trial.19

The immunogenic nature of early TNBC, together with the emerging role of immune checkpoint inhibitors (ICIs) in the metastatic setting, paved the road for a series of clinical trials examining the efficacy of ICIs in combination with NACT.1929 In the phase III KEYNOTE-522 study, high-risk patients with early TNBC were randomized to receive either neoadjuvant pembrolizumab (a PD-1 inhibitor) or placebo in combination with NACT.19 An additional 9 cycles of adjuvant pembrolizumab or placebo were administered after surgery. The addition of pembrolizumab to NACT significantly improved pCR rates by 7.4% (63.0% vs 55.6%) and the 3-year EFS rate by 7.7% (84.5% vs 76.8%; HR, 0.63).30 Based on the positive co-primary endpoints, the FDA approved pembrolizumab for the treatment of high-risk early TNBC, setting a new standard-of-care for these patients.

In the IMpassion031 trial, addition of the PD-L1 inhibitor atezolizumab to NACT significantly increased pCR rates by 17% (41% to 58%; P=.004).27 Although the study was not powered to detect changes in EFS, at the time of data cutoff there was a numeric nonsignificant EFS advantage in favor of the atezolizumab group (HR, 0.76).27 In the GeparNuevo study, addition of the PD-L1 inhibitor durvalumab to NACT failed to significantly improve pCR rates.28 However, the secondary endpoints of 3-year invasive DFS, distant DFS, and OS were all significantly improved (HR, 0.54, 0.37, and 0.26, respectively), and notably durvalumab was not continued in the adjuvant setting in this trial.31

Remaining Challenges and Evolving Treatment Strategies

As new neoadjuvant drug combinations are emerging, patient selection for the different NAT regimens, particularly for immunotherapy, remains a key challenge. Approximately 35% to 40% of patients with TNBC achieve pCR with a standard anthracycline- and taxane-based NACT alone.32 Considering the risk for lifelong toxicity, in patients treated with curative intent there is a need to better identify the subpopulations most likely to benefit from the addition of immunotherapy. Both in the KEYNOTE-522 and the IMpassion031 trials, the magnitude of improvement in pCR rates was higher in patients with node-positive disease than in those with node-negative disease (KEYNOTE-522: 20.6% vs 6.2% and IMpassion031: 26% vs 9% improvement in patients with node-positive vs node-negative disease, respectively).19,27 Accordingly, one could consider sparing neoadjuvant immunotherapy in some lower-risk patients eligible for those studies, such as patients with T2N0 disease, or exploring an early adaptive approach in which immunotherapy is not used unless the response to initial NACT is subpar.

In contrast to the metastatic setting, in which PD-L1 serves as a predictive biomarker for ICI therapy, improvement in pCR rates following neoadjuvant ICI was regardless of PD-L1 status.19,2528 Moreover, PD-L1, tumor-infiltrating lymphocytes (TILs), and specific immune gene signatures were predictive for response in both the ICI and the chemotherapy-only arms, and thereby did not differentiate between the groups.19,27,31,33 Interestingly, the binary immuno-oncology (IO) score (DetermaIO test, Oncocyte Corporation), based on a 27-gene IO signature,34 has been associated with pCR in patients with TNBC treated with neoadjuvant immunotherapy and chemotherapy.35 Recently, the IO score was found to be predictive for neoadjuvant immunotherapy benefit over chemotherapy alone in a post hoc biomarkers analysis of the NeoTRIPaPDL1 study.36 Nevertheless, identifying new predictive biomarkers for response to neoadjuvant immunotherapy remains an urgent need.

Another key open question is whether adjuvant immunotherapy is needed for patients with pCR. In both the KEYNOTE-522 and the IMpassion031 trials, additional immunotherapy was given after surgery regardless of pCR status.19,27 In the KEYNOTE-522 trial, patients who achieved pCR had a relatively good 3-year EFS regardless of treatment arm (94.4% and 92.5% in the pembrolizumab and placebo arms, respectively).30 That, together with the positive long-term outcomes from the GeparNuevo study, which did not include an adjuvant component, suggest that adjuvant immunotherapy may not be essential if a pCR is achieved.31 This question will be addressed by the upcoming OptimICE-pCR study. A complementary question is about determining the best approach for patients who do not achieve pCR.

In KEYNOTE-522, patients in the pembrolizumab arm who did not achieve pCR had a 3-year EFS of 67.4% compared with 56.8% in the placebo arm.30 Despite the improvement, these results still reflect a very poor prognosis. Both adjuvant capecitabine (CREATE-X trial) and adjuvant olaparib (OlympiA trial, BRCA-mutated patients) significantly increased DFS in patients with early TNBC who did not achieve pCR, and both drugs are the current standard for such patients.7,8 Because safety data from the metastatic setting do exist for the combination of ICI with either capecitabine or a PARP inhibitor,3739 treatment combinations for patients who did not achieve a pCR is a reasonable option. However, further studies are needed to determine the optimal adjuvant treatment for these patients.

Different chemotherapy backbones were used in combination with ICI in the different studies (Table 1). Whether, and to what extent, the results of these trials are affected by the choice of chemotherapy regimen remains to be determined. Nevertheless, due to the likelihood of long-term substantial toxicity, there is a strong incentive to reduce anthracycline use in patients with TNBC who are treated with curative intent. In the recently published phase II NeoSTOP trial, an anthracycline-free neoadjuvant regimen (carboplatin and docetaxel) was compared with a standard anthracycline- and taxane-based regimen in patients with early TNBC. The pCR and pCR+ RCB-1 rates were 54% and 67%, respectively, in both arms.40 Further, the ongoing NeoPACT trial is evaluating the combination of pembrolizumab with the same anthracycline-free NACT (ClinicalTrials.gov identifier: NCT03639948). These encouraging results, along with others,41 warrant further evaluation of anthracycline-free neoadjuvant regimens for patients with TNBC.

Table 1.

Selected Neoadjuvant Practice Changing and Thought-Provoking Clinical Trials

Table 1.

Similar to ICIs, additional drugs found to be effective in the metastatic setting are now being evaluated in the neoadjuvant setting for TNBC. PARP inhibitors are effective for the treatment of patients with germline BRCA-mutated HER2-negative (HER2−) breast cancer in both the metastatic and the adjuvant/postneoadjuvant setting.8,42,43 Several attempts have been made to evaluate the role of PARP inhibitors in the neoadjuvant setting.12,4446 Of special interest is the single-arm phase II NeoTALA trial, in which a neoadjuvant single-agent talazoparib was given to 61 patients with BRCA-mutated TNBC, resulting in an impressive pCR rate of 49.2% (in the intent-to-treat population).45,47 The TROP2-directed antibody–drug conjugate sacituzumab govitecan is FDA-approved for the treatment of metastatic TNBC.48 Current ongoing trials are evaluating the role of sacituzumab govitecan in the neoadjuvant (NeoSTAR, NCT04230109) and postneoadjuvant settings (SASCIA, NCT04595565; ASPRIA, NCT04434040).

Neoadjuvant Approach in HER2± Breast Cancer

Current Approach

The neoadjuvant approach is the current preferred approach for localized HER2+ breast cancer that is ≥T2 or node-positive.6 Achievement of pCR is a strong surrogate marker of superior long-term outcomes in HER2+ disease, particularly estrogen receptor–negative (ER−)/HER2+ disease.3,4,49 Multiple trials have established that the addition of trastuzumab to chemotherapy significantly increases pCR rates.5053 Dual inhibition with pertuzumab and trastuzumab has resulted in improved pCR rates, leading to FDA approval of pertuzumab in the neoadjuvant setting with trastuzumab and chemotherapy for HER2+ locally advanced, inflammatory, or early-stage breast cancer (either >2 cm in diameter or node-positive).54,55

In the NeoSphere trial, the pCR rate with docetaxel/trastuzumab/pertuzumab (THP) was significantly higher compared with trastuzumab/docetaxel (45.8% vs 29%, P=.0141).54 In the other 2 study arms, pertuzumab/docetaxel and pertuzumab/trastuzumab demonstrated inferior pCR rates. Importantly, no additional cardiotoxicity was observed in the arms with dual HER2 blockade. Although the study was not powered to assess long-term outcomes, the addition of pertuzumab to trastuzumab/docetaxel also improved DFS.56 In NeoSphere, patients also received an adjuvant anthracycline-based regimen (FEC [5-fluorouracil/epirubicin/cyclophosphamide]). In the United States, doxorubicin/cyclophosphamide (AC) given in a dose-dense fashion is typically used instead of FEC. This led many to adopt a neoadjuvant regimen consisting of AC followed by (or preceded by) the THP regimen, with docetaxel often substituted by weekly paclitaxel for improved tolerability.

The role of anthracyclines in the neoadjuvant treatment of HER2+ breast cancer has been a topic of discussion, given the increasing interest in de-escalation and limiting the long-term consequences of curative therapy. The TRYPHAENA and BERENICE trials studied neoadjuvant dual HER2 inhibition with standard anthracycline and nonanthracycline chemotherapy regimens.55,57 Results revealed high pCR rates overall, regardless of inclusion of an anthracycline, with pCR rates between 57% and 66%, and up to 84% in the ER− subgroup.55,57 Similarly, the TRAIN-2 study reported similar rates of pCR, EFS, and OS using anthracycline and nonanthracycline regimens in combination with pertuzumab and trastuzumab.58,59 Based on the reassuring results regarding eliminating anthracyclines, the combination of docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP), which was evaluated in the TRYPHAENA study, emerged as a common standard neoadjuvant regimen and led to a change in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer to preferentially recommend anthracycline-free regimens in the management of HER2+ breast cancer.6

Remaining Challenges and Evolving Treatment Strategies

De-escalation has been a major theme in the management of localized HER2+ breast cancer. Trials have explored chemotherapy-free regimens in the neoadjuvant space, including the NeoSphere trial as previously discussed. The WSG-ADAPT trial evaluated the efficacy of 12 weeks of neoadjuvant pertuzumab and trastuzumab ± paclitaxel in the ER− subgroup, and demonstrated an impressive pCR rate of 90.5% with dual HER2 blockade plus paclitaxel, and a pCR rate of 36.3% without chemotherapy.60 The KRISTINE trial studied neoadjuvant T-DM1 + pertuzumab compared with TCHP, with the T-DM1/pertuzumab arm resulting in lower pCR rates (44.4% vs 55.7%; P=.02) and a higher risk of locoregional progression events before surgery.61,62 The ongoing EA1181/CompassHER2 pCR study is further studying taxane + trastuzumab/pertuzumab (HP) regimens in the neoadjuvant setting (ClinicalTrials.gov identifier: NCT04266249) to evaluate outcomes following a de-escalated neoadjuvant regimen omitting carboplatin. The DAPHNe study evaluated neoadjuvant paclitaxel + HP and reported 56.7% of patients achieved pCR, of whom 98.2% adhered to a de-escalated antibody-only adjuvant regimen.63 Although overall it is clear that chemotherapy plus dual anti-HER2 blockade is superior to dual anti-HER2 blockade without chemotherapy, the pCR rates in the chemotherapy-free regimens are intriguing and suggest there is a patient subset in which chemotherapy may be safely avoided. Increasing literature has highlighted that HER2+ breast cancer is heterogenous,64 and ultimately a practical pathologic assessment of heterogeneity is needed to identify patients who will do well with anti-HER2 therapy alone.

Escalation strategies are also being explored, largely for patients with residual disease following neoadjuvant therapy. The current standard for residual disease is to switch to T-DM1 based on the KATHERINE study, which demonstrated a reduction in risk of recurrence or death by 50% with adjuvant T-DM1 than with trastuzumab alone.65 The DESTINY-Breast05 trial is comparing T-DM1 versus trastuzumab deruxtecan in the residual disease setting (NCT04622319). Toxicity will need to be carefully considered in this curative setting. The CompassHER2-RD trial is evaluating the addition of tucatinib to T-DM1 in a randomized study (NCT04457596). Tucatinib is a small molecule anti-HER2 tyrosine kinase inhibitor with established activity against brain metastases, and it would be a major advancement for patients if earlier use of this agent resulted in fewer central nervous system recurrences.

Neoadjuvant Approach in ER+/HER2− Breast Cancer

Current Approach

Although NAT is standard for stage II to III TNBC and HER2+ breast cancer, the treatment approach can be challenging in estrogen receptor–positive (ER+)/HER2− localized breast cancer, in which chemosensitivity is not as robust as the other clinical subtypes.66 In contrast to the other clinical subtypes, the rates of pCR are low and the presence of residual disease does not carry the same degree of prognostic significance given the vital role of adjuvant endocrine therapy.3,4 Accordingly, presence of residual disease following NAT in ER+/HER2− localized breast cancer is not necessarily an indication to change the adjuvant systemic therapy plan. Overall, there are challenges in both patient selection and choice of therapy for the neoadjuvant approach in ER+/HER2− disease. Whether to administer NAT for ER+/HER2− operable breast cancer requires multidisciplinary discussion to best determine whether up-front surgery or NAT is most appropriate.

Both chemotherapy and endocrine therapy are NAT options for ER+/HER2− localized breast cancer. Neoadjuvant endocrine therapy (NET) is associated with similar response rates as neoadjuvant combination chemotherapy, but with lower toxicity.6668 However, patient selection is a key factor and, in general, NET is underused.69 Initially the NET approach was primarily used to treat elderly patients with ER+ breast cancer, particularly those considered not to be good candidates for chemotherapy or surgery.70 More data exist for the neoadjuvant endocrine approach in postmenopausal women compared with premenopausal women.66,70,71 Among postmenopausal women, it is well established that aromatase inhibitors are more effective than tamoxifen.66,72,73 Several studies have explored combination approaches with endocrine therapy and targeted therapy. For example, studies adding CDK4/6 inhibition to NET have consistently demonstrated superior Ki67 suppression compared with endocrine therapy alone, but have not demonstrated a difference in clinical response.7478

Remaining Challenges and Evolving Treatment Strategies

In the adjuvant setting, the use of gene expression profiles (GEPs) are well established to guide chemotherapy use. When chemotherapy is not clearly indicated, options include up-front surgery or attempting to obtain a GEP using the diagnostic biopsy, which has not yet become standard of care. Notably, the adjuvant RxPONDER trial did not demonstrate a statistically significant benefit of adjuvant chemotherapy among postmenopausal women diagnosed with 1 to 3 positive nodes and an Oncotype DX recurrence score ≤25.79 It is therefore difficult to justify using NACT for downstaging in such patients, though the extent of lymph node involvement can be challenging to assess clinically. Overall, although additional data are needed to better understand the role of GEPs in the neoadjuvant setting, NET is an attractive option for postmenopausal women when downstaging is needed. In contrast, there is mounting evidence that high GEP scores are associated with higher response rates to NACT.80,81 There are fewer data examining the relationship between GEPs and NET. Retrospective studies suggest higher response rates to NET are seen among patients with low to intermediate recurrence scores compared with high scores.8284

Overall, GEPs offer great potential to tailor treatment recommendations in the neoadjuvant setting as well as to standard clinicopathologic characteristics. Ultimately, an adaptive approach may be best for patients with intermediate scores on GEPs. For example, data from the IMPACT trial among other studies suggest that 2- to 4-week tumor Ki67 expression on endocrine therapy is predictive of long-term outcomes.85 The phase III neoadjuvant ALTERNATE trial randomized postmenopausal women with localized ER+ invasive breast cancer to either anastrozole, fulvestrant, or its combination to assess a biomarker-driven treatment strategy to identify women with a low risk of disease recurrence.86 On-treatment biopsies during NET were performed and patients with Ki67 >10% were switched to chemotherapy. In the WSG-ADAPT HER2−/ER+ study, a short 3-week course of preoperative endocrine therapy with evaluation of GEP on the pretreatment core biopsy and change in Ki67 identified patients for whom endocrine therapy alone was sufficient, allowing for patient selection for escalation or de-escalation strategies.87 Such strategies allow early assessment of endocrine-responsive versus endocrine-unresponsive disease, which can aid in personalizing therapy and avoiding unnecessary chemotherapy in some situations.

Future State and Evolving Clinical Trial Designs

Despite a multitude of practice-changing trials in recent years (Table 1), many key questions surrounding NAT for localized breast cancer remain. Ongoing trials (Table 2) are exploring several important questions, including the integration of novel agents, the use of predictive biomarkers, and escalation/de-escalation strategies. Use of pCR as a primary endpoint for neoadjuvant trials remains common, especially for HER2+ and TNBC. For TNBC and HER2+ breast cancer (particularly ER−/HER2+), pCR remains a powerful biomarker. Although trial-level analyses, which allow comparison of different treatments, have not validated pCR as a surrogate endpoint for improved long-term outcomes,3,88,89 it is important to note that most neoadjuvant trials are powered for pCR and not for measures of long-term outcomes. The KEYNOTE-522 trial for TNBC featured dual primary endpoints of both pCR and EFS,19 and although this required a larger sample size, the approach set the stage for a more rapid approval of pembrolizumab. Based on the trial design, it remains unknown whether adjuvant pembrolizumab is needed for patients who achieve a pCR. A meta-analysis demonstrated that for patients achieving a pCR, the survival benefit is maintained whether adjuvant chemotherapy was received.4 It is currently unknown whether conclusions regarding pCR can be applied to immunotherapy and other novel therapies. It will be critical for future trials with ICIs to consider de-escalation when pCR is achieved in order to prevent overtreatment.

Table 2.

Select Ongoing Neoadjuvant and Postneoadjuvant Studies

Table 2.

I-SPY 2 is a multicenter, randomized, phase II trial with multiple arms and pCR as the primary endpoint.90 The trial utilizes an adaptive strategy that allows changes to the trial as results are learned using Bayesian methods, rather than relying on a static statistical plan, and predictions are made for success in the confirmatory phase III setting.91 One of the major strengths of the I-SPY 2 approach is its ability to triage promising new therapies and novel combinations in a relatively short time frame.92 The I-SPY 2 platform highlights many of the strengths of the neoadjuvant setting for drug development.

Blood-based biomarkers may also change the interpretation of pCR in the future through the identification of minimal residual disease with circulating tumor DNA (ctDNA).93 A number of studies are looking at the predictive and prognostic potential of ctDNA in the neoadjuvant setting. As sensitivity improves, change in ctDNA has the potential to be used in an adaptive treatment approach early during the course of NAT to guide whether a change in approach is needed, which offers a number of advantages compared with the traditional neoadjuvant approach (Figure 1). To date, image assessments and biopsies (such as to assess Ki67) have been used for adaptive strategies.

Figure 1.
Figure 1.

Current and evolving neoadjuvant therapy trial designs. (A) Traditional neoadjuvant trials randomize all therapy preoperatively, followed by standard subtype-specific adjuvant therapy regardless of pathologic response. (B) Postneoadjuvant/residual disease trials deliver standard therapy preoperatively, with standard subtype-specific adjuvant therapy for lower-risk patients (those with pCR) and randomized adjuvant therapy in higher-risk patients (those without pCR). (C) Adaptive neoadjuvant trials deliver a short-course neoadjuvant therapy preoperatively and then rely on tissue-, blood-, or imaging-based biomarker analysis to risk-stratify patients and randomize to de-escalated or escalated further neoadjuvant therapy. Blue and orange squares represent cycles of hypothetical randomized therapy trial arms.

Abbreviations: NAT, neoadjuvant therapy; pCR, pathologic complete response; RCB, Residual Cancer Burden.

Citation: Journal of the National Comprehensive Cancer Network 20, 6; 10.6004/jnccn.2022.7016

For ER+/HER2− localized breast cancer, efforts must focus both on patient selection for the neoadjuvant approach and on treatment selection (NET vs NACT). Use of GEPs on diagnostic specimens is likely to play an increasing role. Strategies to improve use of NET for appropriate patients are also needed, and adaptive trials such as ALTERNATE and the WSG-ADAPT HER2−/ER+ study are setting the stage.

Conclusions

NAT for localized breast cancer has evolved remarkably over the past several years. The neoadjuvant approach is also now well established as an efficient setting for rapid development and triage of novel therapies for patients with breast cancer. Optimization of escalation and de-escalation strategies, and adaptive treatment approaches based on response and biomarkers, will be needed to further advance the field and continue to improve outcomes for patients with breast cancer.

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Submitted for publication February 2, 2022; accepted for publication March 28, 2022.

Disclosures: Dr. Spring has disclosed receiving consulting fees from Novartis and Puma Technology, and institutional research funding from Merck & Co., Inc. and Phillips. Dr. Isakoff has disclosed receiving consulting fees from Seagen, Novartis, Puma Technologies, and Paxman; and institutional research funding from Genentech, AbbVie, OncoPep, Inc., Merck & Co., Inc., and AstraZeneca. Dr. Bar has disclosed no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors.

Funding: Research reported in this publication was supported by the NCI of the NIH under award number K12CA087723 (L.M. Spring) and a grant from NCCN (L.M. Spring).

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Correspondence: Steven J. Isakoff, MD, PhD, Massachusetts General Hospital Cancer Center, Harvard Medical School, 55 Fruit Street, BHX.231, Boston, MA 02114. Email: sisakoff@mgh.harvard.edu
  • View in gallery

    Current and evolving neoadjuvant therapy trial designs. (A) Traditional neoadjuvant trials randomize all therapy preoperatively, followed by standard subtype-specific adjuvant therapy regardless of pathologic response. (B) Postneoadjuvant/residual disease trials deliver standard therapy preoperatively, with standard subtype-specific adjuvant therapy for lower-risk patients (those with pCR) and randomized adjuvant therapy in higher-risk patients (those without pCR). (C) Adaptive neoadjuvant trials deliver a short-course neoadjuvant therapy preoperatively and then rely on tissue-, blood-, or imaging-based biomarker analysis to risk-stratify patients and randomize to de-escalated or escalated further neoadjuvant therapy. Blue and orange squares represent cycles of hypothetical randomized therapy trial arms.

    Abbreviations: NAT, neoadjuvant therapy; pCR, pathologic complete response; RCB, Residual Cancer Burden.

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