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.3–5 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.3–5 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.11–13 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.19–29 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.19,25–28 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,37–39 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.
Selected Neoadjuvant Practice Changing and Thought-Provoking Clinical Trials
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.12,44–46 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.50–53 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.66–68 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.74–78
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.82–84
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.
Select Ongoing Neoadjuvant and Postneoadjuvant Studies
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.
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
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
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.
References
- 1.↑
Rastogi P, Anderson SJ, Bear HD, et al. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project protocols B-18 and B-27. J Clin Oncol 2008;26:778–785.
- 2.↑
Bardia A, Baselga J. Neoadjuvant therapy as a platform for drug development and approval in breast cancer. Clin Cancer Res 2013;19:6360–6370.
- 3.↑
Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 2014;384:164–172.
- 4.↑
Spring LM, Fell G, Arfe A, et al. Pathological complete response after neoadjuvant chemotherapy and impact on breast cancer recurrence and survival: a comprehensive meta-analysis. Clin Cancer Res 2020;26:2838–2848.
- 5.↑
Symmans WF, Wei C, Gould R, et al. Long-term prognostic risk after neoadjuvant chemotherapy associated with residual cancer burden and breast cancer subtype. J Clin Oncol 2017;35:1049–1060.
- 7.↑
Masuda N, Lee SJ, Ohtani S, et al. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med 2017;376:2147–2159.
- 8.↑
Tutt ANJ, Garber JE, Kaufman B, et al. Adjuvant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer. N Engl J Med 2021;384:2394–2405.
- 9.↑
Hurvitz SA, McAndrew NP, Bardia A, et al. A careful reassessment of anthracycline use in curable breast cancer. NPJ Breast Cancer 2021;7:134.
- 10.↑
Blum JL, Flynn PJ, Yothers G, et al. Anthracyclines in early breast cancer: the ABC trials-USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology). J Clin Oncol 2017;35:2647–2655.
- 11.↑
Sikov WM, Berry DA, Perou CM, et al. Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). J Clin Oncol 2015;33:13–21.
- 12.↑
Loibl S, O’Shaughnessy J, Untch M, et al. Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial. Lancet Oncol 2018;19:497–509.
- 13.↑
von Minckwitz G, Schneeweiss A, Loibl S, et al. Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lancet Oncol 2014;15:747–756.
- 14.↑
Poggio F, Bruzzone M, Ceppi M, et al. Platinum-based neoadjuvant chemotherapy in triple-negative breast cancer: a systematic review and meta-analysis. Ann Oncol 2018;29:1497–1508.
- 15.↑
Gradishar WJ, Anderson BO, Abraham J, et al. Breast Cancer, Version 3.2020, NCCNClinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2020;18:452–478.
- 16.↑
Korde LA, Somerfield MR, Carey LA, et al. Neoadjuvant chemotherapy, endocrine therapy, and targeted therapy for breast cancer: ASCO guideline. J Clin Oncol 2021;39:1485–1505.
- 17.↑
Geyer CE, Sikov WM, Huober J, et al. Long-term efficacy and safety of addition of carboplatin with or without veliparib to standard neoadjuvant chemotherapy in triple-negative breast cancer: 4-year follow-up data from BrighTNess, a randomized phase III trial. Ann Oncol 2022; 33:384–394.
- 18.↑
Poggio F, Tagliamento M, Ceppi M, et al. Adding a platinum agent to neoadjuvant chemotherapy for triple-negative breast cancer: the end of the debate. Ann Oncol 2022;33:347–349.
- 19.↑
Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for early triple- negative breast cancer. N Engl J Med 2020;382:810–821.
- 20.↑
Bianchini G, Balko JM, Mayer IA, et al. Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease. Nat Rev Clin Oncol 2016;13:674–690.
- 21.↑
Bianchini G, De Angelis C, Licata L, et al. Treatment landscape of triple-negative breast cancer - expanded options, evolving needs. Nat Rev Clin Oncol 2022;19:91–113.
- 22.↑
Loi S, Drubay D, Adams S, et al. Tumor-infiltrating lymphocytes and prognosis: a pooled individual patient analysis of early-stage triple- negative breast cancers. J Clin Oncol 2019;37:559–569.
- 23.↑
Denkert C, von Minckwitz G, Darb-Esfahani S, et al. Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy. Lancet Oncol 2018;19:40–50.
- 24.↑
Emens LA, Adams S, Barrios CH, et al. First-line atezolizumab plus nab-paclitaxel for unresectable, locally advanced, or metastatic triple- negative breast cancer: IMpassion130 final overall survival analysis. Ann Oncol 2021;32:983–993.
- 25.↑
Emens LA, Molinero L, Loi S, et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer: biomarker evaluation of the IMpassion130 study. J Natl Cancer Inst 2021;113:1005–1016.
- 26.↑
Cortes J, Cescon DW, Rugo HS, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet 2020;396:1817–1828.
- 27.↑
Mittendorf EA, Zhang H, Barrios CH, et al. Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. Lancet 2020;396:1090–1100.
- 28.↑
Loibl S, Untch M, Burchardi N, et al. A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: clinical results and biomarker analysis of GeparNuevo study. Ann Oncol 2019;30:1279–1288.
- 29.↑
Gianni L, Huang CS, Egle D, et al. Pathologic complete response (pCR) to neoadjuvant treatment with or without atezolizumab in triple negative, early high-risk and locally advanced breast cancer. NeoTRIPaPDL1 Michelangelo randomized study [abstract]. Cancer Res 2020;80:Abstract GS3–04.
- 30.↑
Schmid P, Cortes J, Dent R, et al. Event-free survival with pembrolizumab in early triple-negative breast cancer. New Engl J Med 2022; 386:556–567.
- 31.↑
Loibl S, Schneeweiss A, Huober JB, et al. Durvalumab improves long-term outcome in TNBC: results from the phase II randomized GeparNUEVO study investigating neodjuvant durvalumab in addition to an anthracycline/taxane based neoadjuvant chemotherapy in early triple-negative breast cancer (TNBC) [abstract]. J Clin Oncol 2021;39 (Suppl):Abstract 506.
- 32.↑
Liedtke C, Mazouni C, Hess KR, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol 2008;26:1275–1281.
- 33.↑
Loibl S, Sinn BV, Karn T, et al. mRNA signatures predict response to durvalumab therapy in triple negative breast cancer (TNBC) – results of the translational biomarker programme of the neoadjuvant double-blind placebo controlled GeparNuevo trial [abstract]. Cancer Res 2019;79(4_Suppl):Abstract PD2–07.
- 34.↑
Nielsen TJ, Ring BZ, Seitz RS, et al. A novel immuno-oncology algorithm measuring tumor microenvironment to predict response to immunotherapies. Heliyon 2021;7:e06438.
- 35.↑
Iwase T, Blenman KRM, Li X, et al. A Novel immunomodulatory 27-gene signature to predict response to neoadjuvant immunochemotherapy for primary triple-negative breast cancer. Cancers (Basel) 2021;13:4839.
- 36.↑
Bianchini G, Dugo M, Huang CS, et al. Predictive value of gene-expression profiles (GEPs) and their dynamics during therapy in the NeoTRIPaPDL1 trial [abstract]. Ann Oncol 2021;32:S1283–1284. Abstract LBA12.
- 37.↑
Shah AN, Flaum L, Helenowski I, et al. Phase II study of pembrolizumab and capecitabine for triple negative and hormone receptor-positive, HER2-negative endocrine-refractory metastatic breast cancer. J Immunother Cancer 2020;8:e000173.
- 38.↑
Vinayak S, Tolaney SM, Schwartzberg L, et al. Open-label clinical trial of niraparib combined with pembrolizumab for treatment of advanced or metastatic triple-negative breast cancer. JAMA Oncol 2019;5:1132–1140.
- 39.↑
Domchek SM, Postel-Vinay S, Im SA, et al. Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): an open-label, multicentre, phase 1/2, basket study. Lancet Oncol 2020;21:1155–1164.
- 40.↑
Sharma P, Kimler BF, O’Dea A, et al. Randomized phase II trial of anthracycline-free and anthracycline-containing neoadjuvant carboplatin chemotherapy regimens in stage I-III triple-negative breast cancer (NeoSTOP). Clin Cancer Res 2021;27:975–982.
- 41.↑
Zhang L, Wu Z, Lin Y, et al. Neoadjuvant docetaxel + carboplatin versus epirubicin+cyclophosphamide followed by docetaxel in triple-negative, early-stage breast cancer (NeoCART): results from a multicenter, randomized controlled, open-label, phase II trial [abstract]. J Clin Oncol 2020;38(Suppl):Abstract 586.
- 42.↑
Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med 2017;377:523–533.
- 43.↑
Litton JK, Rugo HS, Ettl J, et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med 2018;379:753–763.
- 44.↑
Rugo HS, Olopade OI, DeMichele A, et al. Adaptive randomization of veliparib-carboplatin treatment in breast cancer. N Engl J Med 2016;375:23–34.
- 45.↑
Litton JK, Scoggins ME, Hess KR, et al. Neoadjuvant talazoparib for patients with operable breast cancer with a germline BRCA pathogenic variant. J Clin Oncol 2020;38:388–394.
- 46.↑
Han H, Liu MC, Hamilton E, et al. Pilot neoadjuvant study of niraparib in HER2-negative, BRCA-mutated resectable breast cancer [abstract]. Cancer Res 2020;80:Abstract P3-11-03.
- 47.↑
Litton JK, Beck JT, Jones JM, et al. Neoadjuvant talazoparib in patients with germline BRCA1/2 (gBRCA1/2) mutation-positive, early HER2-negative breast cancer (BC): results of a phase 2 study [abstract]. J Clin Oncol 2021;39(Suppl):Abstract 505.
- 48.↑
Bardia A, Mayer IA, Vahdat LT, et al. Sacituzumab govitecan-hziy in refractory metastatic triple-negative breast cancer. N Engl J Med 2019;380:741–751.
- 49.↑
Broglio KR, Quintana M, Foster M, et al. Association of pathologic complete response to neoadjuvant therapy in HER2-positive breast cancer with long-term outcomes: a meta-analysis. JAMA Oncol 2016;2:751–760.
- 50.↑
Buzdar AU, Ibrahim NK, Francis D, et al. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol 2005;23:3676–3685.
- 51.↑
Untch M, Fasching PA, Konecny GE, et al. Pathologic complete response after neoadjuvant chemotherapy plus trastuzumab predicts favorable survival in human epidermal growth factor receptor 2-overexpressing breast cancer: results from the TECHNO trial of the AGO and GBG study groups. J Clin Oncol 2011;29:3351–3357.
- 52.↑
Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet 2010;375:377–384.
- 53.↑
Untch M, Rezai M, Loibl S, et al. Neoadjuvant treatment with trastuzumab in HER2-positive breast cancer: results from the GeparQuattro study. J Clin Oncol 2010;28:2024–2031.
- 54.↑
Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 2012;13:25–32.
- 55.↑
Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2- positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol 2013;24:2278–2284.
- 56.↑
Gianni L, Pienkowski T, Im YH, et al. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol 2016;17:791–800.
- 57.↑
Swain SM, Ewer MS, Viale G, et al. Pertuzumab, trastuzumab, and standard anthracycline- and taxane-based chemotherapy for the neoadjuvant treatment of patients with HER2-positive localized breast cancer (BERENICE): a phase II, open-label, multicenter, multinational cardiac safety study. Ann Oncol 2018;29:646–653.
- 58.↑
van Ramshorst MS, van der Voort A, van Werkhoven ED, et al. Neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2 blockade for HER2-positive breast cancer (TRAIN-2): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2018;19:1630–1640.
- 59.↑
van der Voort A, van Ramshorst MS, van Werkhoven ED, et al. Three-year follow-up of neoadjuvant chemotherapy with or without anthracyclines in the presence of dual ERBB2 blockade in patients with ERBB2-positive breast cancer: a secondary analysis of the TRAIN-2 randomized, phase 3 trial. JAMA Oncol 2021;7:978–984.
- 60.↑
Nitz UA, Gluz O, Christgen M, et al. De-escalation strategies in HER2-positive early breast cancer (EBC): final analysis of the WSG-ADAPT HER2+/HR- phase II trial: efficacy, safety, and predictive markers for 12 weeks of neoadjuvant dual blockade with trastuzumab and pertuzumab ± weekly paclitaxel. Ann Oncol 2017;28:2768–2772.
- 61.↑
Hurvitz SA, Martin M, Symmans WF, et al. Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol 2018;19:115–126.
- 62.↑
Hurvitz SA, Martin M, Jung KH, et al. Neoadjuvant trastuzumab emtansine and pertuzumab in human epidermal growth factor receptor 2-positive breast cancer: three-year outcomes from the phase III KRISTINE study. J Clin Oncol 2019;37:2206–2216.
- 63.↑
Waks AG, Desai NV, Li T, et al. A prospective trial of treatment de-escalation following neoadjuvant paclitaxel/trastuzumab/pertuzumab in HER2-positive breast cancer. NPJ Breast Cancer 2022;8:63.
- 64.↑
Filho OM, Viale G, Stein S, et al. Impact of HER2 heterogeneity on treatment response of early-stage HER2-positive breast cancer: phase II neoadjuvant clinical trial of T-DM1 combined with pertuzumab. Cancer Discov 2021;11:2474–2487.
- 65.↑
von Minckwitz G, Huang CS, Mano MS, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med 2019;380:617–628.
- 66.↑
Spring LM, Gupta A, Reynolds KL, et al. Neoadjuvant endocrine therapy for estrogen receptor-positive breast cancer: a systematic review and meta-analysis. JAMA Oncol 2016;2:1477–1486.
- 67.↑
Alba E, Calvo L, Albanell J, et al. Chemotherapy (CT) and hormonotherapy (HT) as neoadjuvant treatment in luminal breast cancer patients: results from the GEICAM/2006-03, a multicenter, randomized, phase-II study. Ann Oncol 2012;23:3069–3074.
- 68.↑
Semiglazov VF, Semiglazov VV, Dashyan GA, et al. Phase 2 randomized trial of primary endocrine therapy versus chemotherapy in postmenopausal patients with estrogen receptor-positive breast cancer. Cancer 2007;110:244–254.
- 69.↑
Chiba A, Hoskin TL, Heins CN, et al. Trends in neoadjuvant endocrine therapy use and impact on rates of breast conservation in hormone receptor-positive breast cancer: a National Cancer Data Base study. Ann Surg Oncol 2017;24:418–424.
- 70.↑
Sella T, Weiss A, Mittendorf EA, et al. Neoadjuvant endocrine therapy in clinical practice: a review. JAMA Oncol 2021;7:1700–1708.
- 71.↑
Masuda N, Sagara Y, Kinoshita T, et al. Neoadjuvant anastrozole versus tamoxifen in patients receiving goserelin for premenopausal breast cancer (STAGE): a double-blind, randomised phase 3 trial. Lancet Oncol 2012;13:345–352.
- 72.↑
Smith IE, Dowsett M, Ebbs SR, et al. Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: the Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) multicenter double-blind randomized trial. J Clin Oncol 2005;23:5108–5116.
- 73.↑
Ellis MJ, Coop A, Singh B, et al. Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: evidence from a phase III randomized trial. J Clin Oncol 2001;19:3808–3816.
- 74.↑
Prat A, Saura C, Pascual T, et al. Ribociclib plus letrozole versus chemotherapy for postmenopausal women with hormone receptor-positive, HER2-negative, luminal B breast cancer (CORALLEEN): an open-label, multicentre, randomised, phase 2 trial. Lancet Oncol 2020;21:33–43.
- 75.↑
Chow LWC, Morita S, Chow CYC, et al. Neoadjuvant palbociclib on ER+ breast cancer (N007): clinical response and EndoPredict’s value. Endocr Relat Cancer 2018;25:123–130.
- 76.↑
Ma CX, Gao F, Luo J, et al. NeoPalAna: neoadjuvant palbociclib, a cyclin-dependent kinase 4/6 inhibitor, and anastrozole for clinical stage 2 or 3 estrogen receptor-positive breast cancer. Clin Cancer Res 2017;23:4055–4065.
- 77.↑
Hurvitz SA, Martin M, Press MF, et al. Potent cell-cycle inhibition and upregulation of immune response with abemaciclib and anastrozole in neoMONARCH, phase II neoadjuvant study in HR+/HER2- breast cancer. Clin Cancer Res 2020;26:566–580.
- 78.↑
Cottu P, D’Hondt V, Dureau S, et al. Letrozole and palbociclib versus chemotherapy as neoadjuvant therapy of high-risk luminal breast cancer. Ann Oncol 2018;29:2334–2340.
- 79.↑
Kalinsky K, Barlow WE, Gralow JR, et al. 21-gene assay to inform chemotherapy benefit in node-positive breast cancer. N Engl J Med 2021;385:2336–2347.
- 80.↑
Gianni L, Zambetti M, Clark K, et al. Gene expression profiles in paraffin-embedded core biopsy tissue predict response to chemotherapy in women with locally advanced breast cancer. J Clin Oncol 2005;23:7265–7277.
- 81.↑
Whitworth P, Beitsch P, Mislowsky A, et al. Chemosensitivity and endocrine sensitivity in clinical luminal breast cancer patients in the prospective Neoadjuvant Breast Registry Symphony Trial (NBRST) predicted by molecular subtyping. Ann Surg Oncol 2017;24:669–675.
- 82.↑
Ueno T, Masuda N, Yamanaka T, et al. Evaluating the 21-gene assay Recurrence Score® as a predictor of clinical response to 24 weeks of neoadjuvant exemestane in estrogen receptor-positive breast cancer. Int J Clin Oncol 2014;19:607–613.
- 83.↑
Akashi-Tanaka S, Shimizu C, Ando M, et al. 21-Gene expression profile assay on core needle biopsies predicts responses to neoadjuvant endocrine therapy in breast cancer patients. Breast 2009;18:171–174.
- 84.↑
Iwata H, Masuda N, Yamamoto Y, et al. Validation of the 21-gene test as a predictor of clinical response to neoadjuvant hormonal therapy for ER+, HER2-negative breast cancer: the TransNEOS study. Breast Cancer Res Treat 2019;173:123–133.
- 85.↑
Dowsett M, Smith IE, Ebbs SR, et al. Prognostic value of Ki67 expression after short-term presurgical endocrine therapy for primary breast cancer. J Natl Cancer Inst 2007;99:167–170.
- 86.↑
Ma CX, Suman VJ, Leitch AM, et al. ALTERNATE: neoadjuvant endocrine treatment (NET) approaches for clinical stage II or III estrogen receptor-positive HER2-negative breast cancer (ER+ HER2- BC) in postmenopausal (PM) women: Alliance A011106 [abstract]. J Clin Oncol 2020;38(Suppl):Abstract 504.
- 87.↑
Harbeck N, Gluz O, Kuemmel S, et al. Endocrine therapy alone in patients with intermediate or high-risk luminal early breast cancer (0-3 lymph nodes), recurrence score <26 and Ki67 response after preoperative endocrine therapy: primary outcome results from the WSG-ADAPT HR+/HER2- trial [abstract]. Presented at the 2020 San Antonio Breast Cancer Symposium; December 8–11, 2020. Abstract GS4–04.
- 88.↑
Berruti A, Amoroso V, Gallo F, et al. Pathologic complete response as a potential surrogate for the clinical outcome in patients with breast cancer after neoadjuvant therapy: a meta-regression of 29 randomized prospective studies. J Clin Oncol 2014;32:3883–3891.
- 89.↑
Conforti F, Pala L, Sala I, et al. Evaluation of pathological complete response as surrogate endpoint in neoadjuvant randomised clinical trials of early stage breast cancer: systematic review and meta-analysis. BMJ 2021;375:e066381.
- 90.↑
Barker AD, Sigman CC, Kelloff GJ, et al. I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy. Clin Pharmacol Ther 2009;86:97–100.
- 91.↑
Harrington D, Parmigiani G. I-SPY 2—a glimpse of the future of phase 2 drug development? N Engl J Med 2016;375:7–9.
- 92.↑
Carey LA, Winer EP. I-SPY 2—toward more rapid progress in breast cancer treatment. N Engl J Med 2016;375:83–84.
- 93.↑
Earl H, Provenzano E, Abraham J, et al. Neoadjuvant trials in early breast cancer: pathological response at surgery and correlation to longer term outcomes - what does it all mean? BMC Med 2015;13:234.
- 94.
Kim HJ, Noh WC, Lee ES, et al. Efficacy of neoadjuvant endocrine therapy compared with neoadjuvant chemotherapy in pre-menopausal patients with oestrogen receptor-positive and HER2-negative, lymph node-positive breast cancer. Breast Cancer Res 2020;22:54.
- 95.
Johnston S, Puhalla S, Wheatley D, et al. Randomized phase II study evaluating palbociclib in addition to letrozole as neoadjuvant therapy in estrogen receptor-positive early breast cancer: PALLET trial. J Clin Oncol 2019;37:178–189.
- 96.
Smith I, Robertson J, Kilburn L, et al. Long-term outcome and prognostic value of Ki67 after perioperative endocrine therapy in postmenopausal women with hormone-sensitive early breast cancer (POETIC): an open-label, multicentre, parallel-group, randomised, phase 3 trial. Lancet Oncol 2020;21:1443–1454.
- 97.
Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet Oncol 2014;15:640–647.
- 98.
Schneeweiss A, Chia S, Hickish T, et al. Long-term efficacy analysis of the randomised, phase II TRYPHAENA cardiac safety study: evaluating pertuzumab and trastuzumab plus standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer. Eur J Cancer 2018;89:27–35.
- 99.
Harbeck N, Gluz O, Christgen M, et al. De-escalation strategies in human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (BC): final analysis of the West German Study Group adjuvant dynamic marker-adjusted personalized therapy trial optimizing risk assessment and therapy response prediction in early BC HER2- and hormone receptor-positive phase II randomized trial-efficacy, safety, and predictive markers for 12 weeks of neoadjuvant trastuzumab emtansine with or without endocrine therapy (ET) versus trastuzumab plus ET. J Clin Oncol 2017;35:3046–3054.
- 100.
Loibl S, Weber KE, Timms KM, et al. Survival analysis of carboplatin added to an anthracycline/taxane-based neoadjuvant chemotherapy and HRD score as predictor of response-final results from GeparSixto. Ann Oncol 2018;29:2341–2347.
- 101.
Oliveira M, Saura C, Nuciforo P, et al. FAIRLANE, a double-blind placebo-controlled randomized phase II trial of neoadjuvant ipatasertib plus paclitaxel for early triple-negative breast cancer. Ann Oncol 2019;30:1289–1297.
- 102.
Fasching PA, Link T, Hauke J, et al. Neoadjuvant paclitaxel/olaparib in comparison to paclitaxel/carboplatinum in patients with HER2-negative breast cancer and homologous recombination deficiency (GeparOLA study). Ann Oncol 2021;32:49–57.
