Neoadjuvant Trastuzumab, Pertuzumab, and Docetaxel vs Trastuzumab Emtansine in Patients With ERBB2-Positive Breast Cancer: A Phase 2 Randomized Clinical Trial | Breast Cancer | JAMA Oncology | JAMA Network
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Visual Abstract. Neoadjuvant Trastuzumab, Pertuzumab, and Docetaxel vs Trastuzumab Emtansine in Patients With ERBB2-positive Breast Cancer
Neoadjuvant Trastuzumab, Pertuzumab, and Docetaxel vs Trastuzumab Emtansine in Patients With ERBB2-positive Breast Cancer
Figure 1.  Patient Flow in the Trial (CONSORT)
Patient Flow in the Trial (CONSORT)

In the group of patients randomized to receive standard treatment, 2 patients withdrew consent and 2 received a diagnosis of disseminated disease after randomization and before the start of treatment. One patient receiving treatment with trastuzumab emtansine received all preoperative treatment but withdrew consent before surgery and underwent surgery elsewhere.

Figure 2.  Subgroup Analysis of Baseline Clinical and Tumor Characteristics at Baseline in Relation to Pathologic Complete Response
Subgroup Analysis of Baseline Clinical and Tumor Characteristics at Baseline in Relation to Pathologic Complete Response

Odds ratios (ORs) were estimated using logistic regression. ERBB 2+ indicates intermediate expression of ERBB2 (formerly HER2); ERBB 3+, marked expression of ERBB2; ER, estrogen receptor; PR, progesterone receptor; and TIL, tumor-infiltrating lymphocyte.

Figure 3.  Event-Free Survival After a Median Follow-up of 40.4 Monthsa
Event-Free Survival After a Median Follow-up of 40.4 Monthsa

Events were defined as progression during neoadjuvant therapy, local-regional or distant recurrence, contralateral breast cancer, any other malignant neoplasm, or death of any cause, whatever appears first. One patient in the investigational group withdrew consent shortly before surgery and has, therefore, been excluded from the analysis.

aRange, 2.2-66.5 months.

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    Original Investigation
    June 24, 2021

    Neoadjuvant Trastuzumab, Pertuzumab, and Docetaxel vs Trastuzumab Emtansine in Patients With ERBB2-Positive Breast Cancer: A Phase 2 Randomized Clinical Trial

    Author Affiliations
    • 1Breast Cancer Center, Karolinska University Hospital, Stockholm, Sweden
    • 2Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
    • 3Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
    • 4Department of Oncology, South Hospital, Stockholm, Sweden
    • 5Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden
    • 6Department of Pathology, Skåne University Hospital, Lund, Sweden
    • 7Department of Oncology, Uppsala University Hospital, Uppsala, Sweden
    • 8Department of Immunology, Genetics and Pathology, Uppsala University Hospital, Uppsala, Sweden
    • 9Department of Oncology, Southern Älvsborg Hospital, Borås, Sweden
    • 10Department of Oncology, Sahlgrenska University Hospital, Göteborg, Sweden
    • 11Department of Radiation Sciences, Oncology Unit, Umeå University Hospital, Umeå, Sweden
    • 12Department of Oncology, Sundsvall Hospital, Sundsvall, Sweden
    • 13Department of Oncology, Örebro University Hospital, Örebro, Sweden
    • 14Department of Oncology, St Göran Hospital, Stockholm, Sweden
    • 15Department of Radiology, Karolinska University Hospital, Stockholm, Sweden
    • 16Department of Nuclear Medicine, Karolinska University Hospital, Stockholm, Sweden
    • 17Central Trial Office, Clinical Trial Unit, Karolinska University Hospital, Stockholm, Sweden
    JAMA Oncol. 2021;7(9):1360-1367. doi:10.1001/jamaoncol.2021.1932
    Key Points

    Question  Is the efficacy of the present standard combination of docetaxel, trastuzumab, and pertuzumab different from that of trastuzumab emtansine as neoadjuvant therapy for ERBB2-positive breast cancer?

    Findings  In this primary analysis of the randomized phase 2 PREDIX HER2 trial, combination docetaxel, trastuzumab, and pertuzumab had similar pathologic complete response when compared with trastuzumab emtansine.

    Meaning  In selected patients with ERBB2 (formerly HER2)-positive breast cancer, neoadjuvant treatment can be de-escalated with trastuzumab emtansine monotherapy.

    Abstract

    Importance  Trastuzumab emtansine (T-DM1) is presently approved for treatment of advanced breast cancer and after incomplete response to neoadjuvant therapy, but the potential of T-DM1 as monotherapy is so far unknown.

    Objective  To assess pathologic complete response (pCR) to standard neoadjuvant therapy of combination docetaxel, trastuzumab, and pertuzumab (DTP) vs T-DM1 monotherapy in patients with ERBB2 (formerly HER2)-positive breast cancer.

    Design, Setting, and Participants  This randomized phase 2 trial, conducted at 9 sites in Sweden, enrolled 202 patients between December 1, 2014, and October 31, 2018. Participants were 18 years or older, with ERBB2-positive tumors larger than 20 mm and/or verified lymph node metastases. Analysis was performed on an intention-to-treat basis.

    Interventions  Patients were randomized to receive 6 cycles of DTP (standard group) or T-DM1 (investigational group). Crossover was recommended at lack of response or occurrence of intolerable toxic effects. Assessment with fluorine 18–labeled fluorodeoxyglucose (18F-FDG) positron emission tomography combined with computed tomography (PET-CT) was performed at baseline and after 2 and 6 treatment cycles.

    Main Outcome and Measures  Pathologic complete response, defined as ypT0 or Tis ypN0. Secondary end points were clinical and radiologic objective response; event-free survival, invasive disease-free survival, distant disease-free survival, and overall survival; safety; health-related quality of life (HRQoL); functional and biological tumor characteristics; and frequency of breast-conserving surgery.

    Results  Overall, 202 patients were randomized; 197 (99 women in the standard group [median age, 51 years (range, 26-73 years)] and 98 women in the investigational group [median age, 53 years (range, 28-74 years)]) were evaluable for the primary end point. Pathologic complete response was achieved in 45 patients in the standard group (45.5%; 95% CI 35.4%-55.8%) and 43 patients in the investigational group (43.9%; 95% CI 33.9%-54.3%). The difference was not statistically significant (P = .82). In a subgroup analysis, the pCR rate was higher in hormone receptor–negative tumors than in hormone receptor–positive tumors in both treatment groups (45 of 72 [62.5%] vs 45 of 125 [36.0%]). Three patients in the T-DM1 group experienced progression during therapy. In an exploratory analysis, tumor-infiltrating lymphocytes at 10% or more (median) estimated pCR significantly (odds ratio, 2.76; 95% CI, 1.42-5.36; P = .003). Response evaluation with 18F-FDG PET-CT revealed a relative decrease of maximum standardized uptake value by equal to or greater than 68.7% (median) was associated with pCR (odds ratio, 6.74, 95% CI, 2.75-16.51; P < .001).

    Conclusions and Relevance  In this study, treatment with standard neoadjuvant combination DTP was equal to T-DM1.

    Trial Registrations  ClinicalTrials.gov Identifier: NCT02568839; EudraCT number: 2014-000808-10

    Introduction

    Neoadjuvant therapy has become the standard of care in early-stage ERBB2 (formerly HER2)-positive breast cancer, owing to the high rates of pathologic complete response (pCR) with the combination of chemotherapy with ERBB2-targeting agents, and the high correlation of pCR with long-term outcomes in this tumor subtype.1,2 Several trials have established that the addition of pertuzumab to trastuzumab (dual blockade) and chemotherapy statistically significantly improves the likelihood to achieve pCR.3 The neoadjuvant strategy was further supported by the results of the KATHERINE trial showing that if pCR is not achieved, adjuvant treatment with trastuzumab emtansine (T-DM1) statistically significantly improves event-free survival (EFS).4

    Recent efforts5-8 have focused on de-escalation of neoadjuvant therapy in ERBB2-positive breast cancer to decrease acute and long-term toxic effects without compromising outcomes. The noninferiority of anthracycline-free regimens combining dual blockade, a taxane, and carboplatin has been shown in studies to have pCR rates exceeding 60%, especially in hormone receptor–negative disease.5,6 Using T-DM1 has also been investigated as a de-escalation strategy in the KRISTINE study comparing combination dual blockade, a taxane, and carboplatin with the combination of T-DM1 and pertuzumab.7 Demonstrating a favorable toxic effect profile, T-DM1 resulted in a lower pCR rate and higher risk of local-regional progression before surgery.8

    Neoadjuvant Response-Guided Treatment of HER2 Positive Breast Cancer (PREDIX HER2) is a randomized phase 2 trial comparing neoadjuvant trastuzumab, pertuzumab, and docetaxel (standard treatment) vs T-DM1 monotherapy (investigational treatment). The trial has a translational focus with sequential biopsies, blood collection, and positron emission tomography (PET) scans. Here, we report the primary efficacy analysis, health-related quality of life (HRQoL) results, and the exploratory analysis of tumor-infiltrating lymphocytes (TILs) and longitudinal PET evaluation.

    Methods
    Study Design and Participants

    PREDIX HER2 is a randomized, multicenter, open-label, phase 2 trial conducted at 9 study sites in Sweden between December 1, 2014, and October 31, 2018. Eligible patients were women and men 18 years or older with ERBB2-positive tumors larger than 20 mm and/or morphologically verified lymph node metastases, left ventricular ejection fraction of 55% or more, and Eastern Cooperative Oncology Group performance status of 0 or 1. ERBB2 positivity was defined by a score of 2+ or 3+ by immunohistochemistry and amplification with an ERBB2 to CEP17-ratio of 2.0 or more, or 4 or more ERBB2 copies with a ratio less than 2.0 by in situ hybridization. Patients with up to 2 distant metastases could be included provided that the lesions were amenable to radical local treatment after breast surgery. Exclusion criteria were clinically significant cardiac, hepatic, renal, or psychiatric disorders or a history of other malignant neoplasms within the last 5 years, except for adequately treated basal or squamous cell carcinoma of the skin or in situ carcinoma of the cervix. The study was conducted according to the Declaration of Helsinki9 and the principles of Good Clinical Practice and approved by the Regional Ethical Committee in Stockholm and the Swedish Medical Product Agency. All patients provided written informed consent. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline. The trial protocol is available in Supplement 1.

    Randomization

    Patients were randomized in a 1:1 ratio; randomization was conducted at the Central Trial Office at Karolinska University Hospital by a web-based procedure (TENALEA) using random permuted blocks (block size of 2 or 4), stratified by participating sites. Patients were randomly assigned to receive 6 courses of docetaxel, subcutaneous trastuzumab, and pertuzumab or T-DM1 every 3 weeks.

    Procedures

    Treatment consisted of either 6 courses of docetaxel (first dose, 75 mg/m2, then 100 mg/m2), subcutaneous trastuzumab (600 mg), and pertuzumab (loading dose, 840 mg, then 420 mg), or 6 courses of T-DM1 (3.6 mg/kg). Patients in the standard group received bone marrow support with filgrastim per standard of care. Dose adjustments for toxic effects are in eTable 1 in Supplement 2. The protocol recommended that patients switch to the opposite treatment in case of lack of response (no change or progressive disease) or intolerable adverse events.

    Response evaluations included mammography and ultrasonography or magnetic resonance imaging after the second, fourth, and sixth cycles; fluorine 18–labeled fluorodeoxyglucose (18F-FDG) PET combined with computed tomography (CT) was a protocol-defined optional procedure performed at baseline and repeated after the second and last cycles. To reduce exposure to radiation, the procedure was confined to the thorax, including the regional lymph nodes.

    All patients had breast cancer surgery 3 to 4 weeks after termination of the neoadjuvant treatment. Patients with clinically and radiologically negative lymph node status underwent sentinel node biopsy before the start of neoadjuvant therapy. In patients with node metastases verified by biopsy, axillary node dissection was performed in connection with breast surgery.

    Postoperatively, patients received 2 (standard group) or 4 (investigational group) courses of adjuvant treatment with epirubicin (90-100 mg/m2) and cyclophosphamide (600 mg/m2). Thereafter, 11 courses of adjuvant subcutaneous trastuzumab (600 mg) were administered to patients in both treatment groups.

    Core biopsies were obtained at baseline and after the second cycle; tumor tissue was preserved from the surgical resection specimens. Blood samples were collected at baseline and alongside the second, fourth, and sixth cycles; 3 months after surgery; and then repeated in connection with yearly follow-up visits for 5 years.

    Tumor type, grade, proliferation, ERBB2 status, estrogen receptor status, and progesterone receptor status were determined on the baseline core biopsy from the primary site. Tumors were regarded as hormone receptor–positive if estrogen receptors or progesterone receptors were present in 10% or more of tumor cells. Proliferation was determined by immunohistochemistry using Ki67. Stromal TILs were evaluated on hematoxylin and eosin–stained full-face sections, by a pathologist (J.H.) blinded to the treatment allocation, as the percentage of tumor stroma covered by infiltrating lymphocytes, in accordance with the recommendations of the International TILs Working Group.10

    Health-related quality of life was assessed using the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire C30 and the breast cancer–specific EORTC-BR23 questionnaire.11,12 Patients were asked to complete the HRQoL forms at baseline before randomization and after 2, 4 and 6 courses of treatment; 3 months after surgery; and at the yearly follow-up visits.

    Outcomes

    The primary end point was pCR to primary medical treatment, defined as absence of invasive carcinoma in the breast and axillary lymph nodes, while residual ductal carcinoma in situ was accepted (ypT0 or Tis ypN0). Secondary end points were: clinical and radiologic objective response; EFS, invasive disease-free survival, distant disease-free survival, and overall survival; safety; HRQoL; functional and biological tumor characteristics; and frequency of breast-conserving surgery.

    Statistical Analysis

    The sample size was based on an explorative design: assuming a pCR after 6 cycles in 50% of cases in the standard group, and to detect an absolute difference in pCR by 20% between the 2 treatment alternatives, with a 2-sided significance level of P < .10 and a power of 80%, a total of 166 patients were required in a balanced design. The target sample size was set to 200 patients, to account for a presumed 20% failure rate in the predefined tissue-based correlative analyses. The level of significance was set to P < .05 in all other tests except for analysis of HRQoL, where a significance level of P < .01 was used to take multiple testing of the scales into account. All efficacy analyses were performed in the intention-to-treat population. Median follow-up time was calculated using the reversed Kaplan-Meier method, with follow-up times calculated for patients still alive.

    Categorical variable differences between groups were tested using the χ2 test of independence or Fisher exact test when appropriate. Differences in continuous variables were tested using the Mann-Whitney test. The association between pCR and treatment was estimated using logistic regression. Tests of interaction between treatment and clinical factors were performed by including product terms into regression models. Results from the logistic regression models are presented as odds ratios (ORs) and 95% CIs.

    In the analysis of EFS, time was calculated from the date of randomization to dates of progression, local-regional recurrence, distant recurrence, contralateral breast cancer, distant recurrence, or death, whichever occurs first. Event-free survival was calculated using the Kaplan-Meier method and differences between groups were assessed using the log-rank test. The effect of treatment on time to failure was estimated using Cox proportional hazards regression and results are presented as hazard ratios and 95% CIs.

    Linear regression including the baseline scores was used in the analysis of HRQoL. All statistical analyses were performed using Stata Statistical Software, release 16 (StataCorp LLC).

    Results
    Patient Characteristics

    Between December 1, 2014, and October 31, 2018, 202 patients were enrolled. After randomization but before the start of treatment, 2 patients withdrew consent and 2 patients received a diagnosis of disseminated disease, all in the standard treatment group, and were not included in the intention-to-treat population (Figure 1). One patient in the investigational group withdrew consent after neoadjuvant treatment. Thus, 99 women in the standard group (median age, 51 years [range, 26-73 years]) and 98 women in the investigational group (median age, 53 years [range, 28-74 years]) contributed to the efficacy analysis for pCR (eTable 2 in Supplement 2). Baseline characteristics were balanced between the 2 treatment groups. However, 13 patients were included based on 4 to 6 ERBB2 copies by results of in situ hybridization and an ERBB2 to CEP17 ratio of less than 2.0; 11 of those patients were assigned to the standard group (P = .02).

    Ninety-two patients in the standard group and 94 in the investigational group received all 6 courses of neoadjuvant treatment as scheduled. Seventeen patients switched from standard treatment to T-DM1, 4 owing to stable disease and 13 owing to grade 3 or higher toxic effects or the patient’s refusal to continue the assigned treatment because of adverse effects. Nine patients switched from T-DM1 to standard treatment, 4 owing to stable disease, 3 owing to tumor progression, and 2 owing to grade 3 or higher toxic effects.

    Efficacy

    Pathologic complete response was achieved in 88 of the 197 patients (44.7%): 45 in the standard group (45.5%; 95% CI 35.4%-55.8%) and 43 in the investigational group (43.9%; 95% CI 33.9%-54.3%), a nonsignificant mean difference of 1.6% (95% CI 0.53%-1.65%; P = .82). Residual ductal carcinoma in situ was found in 21 of the 88 patients (23.9%). In a subgroup analysis, the pCR rate was higher in hormone receptor–negative tumors than in hormone receptor–positive tumors in both treatment groups (45 of 72 [62.5%] vs 45 of 125 [36.0%]). Pathologic complete response was more frequent in patients with hormone receptor–negative disease (all patients, 45 of 72 [62.5%]; standard group, 22 of 33 [66.7%]; and investigational group, 23 of 39 [59.0%]) than in those with hormone receptor–positive tumors (all patients, 45 of 125 [36.0%]; standard group, 24 of 66 [36.4%]; and investigational group, 21 of 59 [35.6%]; P = .001). Among the 13 patients with “equivocal” ERBB2 status, only 1 patient in the standard group achieved pCR, while none in the investigational group achieved pCR; a sensitivity analysis excluding these 13 patients had no significant impact regarding pCR. Subgroup analyses demonstrated no statistically significant differences between the groups related to pCR (Figure 2). Fifty patients in each treatment group had breast-conserving surgery, and 50 in the standard group and 48 in the investigational group had modified radical mastectomy; 19 of these patients combined radical mastectomy with immediate prosthetic reconstruction.

    At the cutoff date for this analysis in December 2020, the median follow-up time from randomization was 40.4 months (range, 2.2-66.5 months). Event-free survival was not significantly different between the treatment groups (χ2 = 0.85 [95% CI, 0.60-4.13]; P = .36; Figure 3). Among 17 events (8.6%), 3 were due to local progression of the primary breast tumor during neoadjuvant treatment, all in the investigational group. Postoperative events included 4 patients (2.0%) with a diagnosis of local-regional relapse, 4 patients (2.0%) with contralateral breast cancer, and 5 patients (2.5%) with distant metastases. One death unrelated to cancer or study therapy was reported for a woman treated with T-DM1. A sensitivity analysis excluding all patients who had been crossed over to the opposite treatment did not significantly change the outcome regarding pCR and EFS. Two of the 7 patients with oligometastatic disease at diagnosis developed new distant metastases during follow-up, both in the T-DM1 group.

    Safety

    A total of 198 patients received at least 1 dose of study treatment and were evaluated for safety. In general, T-DM1 was better tolerated, with a higher frequency of grade 3 and 4 adverse events in the standard group vs the investigational group (39 of 99 [39.4%] vs 10 of 99 [10.1%]), including neutropenic fever (26 of 99 [26.3%] vs 3 of 99 [3.0%]). The most frequently reported adverse events in the standard group were diarrhea, mucositis, exanthema, and sensory neuropathy; T-DM1 was associated with headache, mucositis, sensory neuropathy, and increase of liver transaminases, which were of grade 1 and 2 for most patients. A total of 38 patients in the standard group had dose reductions of docetaxel and 11 patients in the investigational group had dose reductions of T-DM1. No deaths occurred during the study treatment.

    HRQoL

    The response rate for the HRQoL questionnaires was 99.0% (196 of 198) at baseline and 86.9% (172 of 198) after the sixth cycle. There were no differences in HRQoL between the 2 groups at baseline (eFigure 1 and eFigure 2 in Supplement 2). Results after 6 courses of treatment revealed statistically significant differences favoring the investigational group on 13 of the EORTC quality of life questionnaire C30 and BR23 variables. Three months after surgery, however, statistically significant differences in favor of the standard group were found for 6 variables. No other between-group differences were found, except for lower levels of breast symptoms in patients treated with T-DM1. At 1-year follow-up, HRQoL levels were similar to baseline levels for most variables in both groups.

    TILs

    Baseline biopsies for central assessment of stromal TILs were available in 172 patients (87.3% of the study participants). The percentage of stromal TILs was used as a dichotomous variable, with a median of 10% as a cutoff point. Patients with TILs less than 10% had a significantly lower pCR rate compared with those with TILs of 10% or more (18 of 65 [27.7%] vs 55 of 107 [51.4%]; OR, 2.76; 95% CI, 1.42-5.36; P = .003, adjusted for treatment group). The odds to achieve pCR were higher in patients with hormone receptor–negative tumors (OR, 4.06; 95% CI, 1.25-13.19; P = .02), with a pCR rate of 68.9% (31 of 45) in those with TILs of 10% or more vs 35.3% (6 of 17) in those with TILs less than 10%. In patients with hormone receptor–positive tumors, corresponding pCR rates were 38.7% (24 of 62) in those with TILs of 10% or more and 25.0% (12 of 48) in those with TILs less than 10% (OR, 1.89; 95% CI, 0.83-4.34; P = .13).

    Sequential 18F-FDG PET Combined With CT

    Functional imaging using 18F-FDG PET combined with CT was an optional protocol-described procedure performed at 4 of the 9 participating study sites, resulting in longitudinal and prospective PET and CT data from 108 patients. The relative change of the maximum standardized uptake value from baseline to cycle 2, Δrel [C2-BL], was assessed as a factor associated with pCR. Using the median decrease by the relative change of the maximum standardized uptake value from baseline to cycle 2 of 68.7% as a cutoff, a decrease of the maximum standardized uptake value equal to or greater than 68.7% was associated with pCR in 57.4% of patients (31 of 54) compared with 16.7% of patients (9 of 54) with a decrease less than 68.7% (OR, 6.74; 95% CI, 2.75-16.51; P < .001).

    Discussion

    The concept of treatment de-escalation has been previously described in an adjuvant single-group trial of paclitaxel plus trastuzumab for patients with tumors of 3 cm or smaller, with 67% of luminal ERBB2-positive tumors demonstrating few adverse effects and high rates of disease-free survival (93.3%) and local recurrence-free survival (98.6%) at 7 years of follow-up.13

    To our knowledge, PREDIX HER2 is the first controlled, prospective, randomized clinical trial that compares neoadjuvant T-DM1 given as monotherapy with an approved standard of care in ERBB2-positive breast cancer with docetaxel for 6 courses together with dual antibody blockade. Six courses of T-DM1 resulted in a pCR rate of 43.9%, similar to that in the standard treatment group (45.5%) and in line with the pCR rates achieved historically with the combination of cytotoxic chemotherapy and ERBB2-targeting antibodies.4 Patients treated with T-DM1 in PREDIX HER2 had a markedly lower frequency of adverse effects, especially grade 3 and 4 adverse effect, and significantly better HRQoL during the neoadjuvant treatment, compared with the standard therapy group. However, 1 year after surgery, HRQoL was similar between the study groups, most likely owing to the longer postoperative chemotherapy after T-DM1.

    The efficacy of neoadjuvant T-DM1 presented here is in the same range previously reported in the KRISTINE trial (44.4%), in which T-DM1 was given together with pertuzumab.7 Although co-administration of the 2 drugs does not have a negative impact on their pharmacokinetics14 and preclinical models have suggested synergistic effects of the combination,15 the phase 3 trial MARIANNE in patients with advanced breast cancer did not demonstrate an improvement of progression-free survival or overall survival by adding pertuzumab to T-DM1.16 Similarly, in a neoadjuvant treatment trial of patients with hormone receptor–positive, ERBB2-positive breast cancer, addition of endocrine therapy to T-DM1 did not improve pCR rates.17 These studies support the administration of T-DM1 monotherapy, as in the PREDIX HER2 trial.

    At a median follow-up time of 40.4 months (3.4 years), EFS events did not differ between the treatment groups. Three patients had local progression during neoadjuvant treatment in the T-DM1 group, as also seen previously in a small subset of patients in the KRISTINE trial.8 Early identification of patients with intrinsic resistance to T-DM1 and switching to standard treatment, as done in PREDIX HER2, may be a way to circumvent early local-regional failure and inferior results with T-DM1. Thus, the results reported here can have important clinical implications by demonstrating that de-escalation with T-DM1 or newer antibody-drug conjugates may be feasible with appropriate patient selection and early identification of nonresponders who may be rescued by switching to another treatment.

    Initial explorative analyses indicate that a strong early metabolic response shown on results of 18F-FDG PET combined with CT was significantly correlated with pCR in both treatment groups, in concordance with data on patients treated with trastuzumab and pertuzumab18 or chemotherapy.19-21 Similarly, baseline stromal TILs of 10% or more were a factor associated with pCR, particularly in patients with hormone receptor–negative tumors. Further validation is needed to demonstrate if the combination of biomarkers is useful to select patients for a safe neoadjuvant treatment de-escalation.

    Limitations

    This study has limitations. First, patients with equivocal ERBB2 status according to the definition used when the trial was launched in December 2014 were included; according to the updated 2018 American Society of Clinical Oncology and College of American Pathologists guidelines, these patients would be considered as ERBB2 negative.22 However, a sensitivity analysis excluding the 13 patients with low ERBB2 expression showed no significant difference regarding pCR and EFS. Further analysis of ERBB2 protein, RNA levels, and amplification status will shed light on whether these and patients with lower levels of ERBB2 amplification respond differentially to the 2 study treatments. Second, the protocol-specified treatment switch in 26 patients could have affected the observed efficacy outcomes, but the efficacy analysis is based on the intention-to-treat principle, which reduces the risk for potential biases, and a sensitivity analysis excluding these patients did not affect the results significantly. Third, all patients received postoperative chemotherapy and the patients in the investigational group received 4 cycles vs 2 cycles in the standard group, which may affect the long-term outcome, but not the primary efficacy end point of the study. Fourth, the size of the study was moderate and the EFS analysis and all correlative analyses should be considered exploratory and hypothesis generating. Our findings need to be confirmed by larger randomized trials.

    Conclusions

    The first report from the PREDIX HER2 trial shows that standard neoadjuvant treatment with docetaxel, trastuzumab, and pertuzumab was equivalent to T-DM1 monotherapy, while T-DM1 demonstrated a more favorable toxic effect profile. With appropriate patient selection and dynamic therapy adaptation based on early response assessment, T-DM1 may have the potential to become a successful strategy for treatment de-escalation.

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    Article Information

    Accepted for Publication: April 15, 2021.

    Published Online: June 24, 2021. doi:10.1001/jamaoncol.2021.1932

    Correction: This article was corrected on August 12, 2021, to fix errors in the Abstract and Results.

    Corresponding Author: Thomas Hatschek, MD, Breast Cancer Center, Karolinska University Hospital Solna, 171 76 Stockholm, Sweden (thomas.hatschek@ki.se).

    Author Contributions: Dr Hatschek had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Hatschek, Pekar, Lindman, Einbeigi, Carlsson, Grybäck, Johansson, Brandberg, Bergh.

    Acquisition, analysis, or interpretation of data: Hatschek, Foukakis, Bjöhle, Lekberg, Fredholm, Elinder, Bosch, Lindman, Schiza, Einbeigi, Adra, Andersson, Carlsson, Dreifaldt, Isaksson-Friman, Agartz, Azavedo, Grybäck, Hellström, Johansson, Maes, Zerdes, Hartman, Brandberg, Bergh.

    Drafting of the manuscript: Hatschek, Foukakis, Pekar, Agartz, Hellström, Johansson, Brandberg, Bergh.

    Critical revision of the manuscript for important intellectual content: Hatschek, Foukakis, Bjöhle, Lekberg, Fredholm, Elinder, Bosch, Lindman, Schiza, Einbeigi, Adra, Andersson, Carlsson, Dreifaldt, Isaksson-Friman, Azavedo, Grybäck, Johansson, Maes, Zerdes, Hartman, Brandberg, Bergh.

    Statistical analysis: Foukakis, Azavedo, Johansson.

    Obtained funding: Hatschek.

    Administrative, technical, or material support: Hatschek, Foukakis, Fredholm, Bosch, Pekar, Carlsson, Agartz, Grybäck, Hellström, Maes, Zerdes, Hartman, Bergh.

    Supervision: Hatschek, Foukakis, Bosch, Adra, Hellström, Bergh.

    Conflict of Interest Disclosures: Dr Foukakis reported receiving grants and personal fees from Pfizer (institutional); and personal fees from Novartis, Veracyte, Exact Sciences, Affibody, and Wolters Kluwer outside the submitted work. Dr Bosch reported serving on the advisory boards for Pfizer and Novartis; and receiving grants from Roche outside the submitted work. Dr Lindman reported receiving grants from Roche; and personal fees from Lilly, Daiichi, and Novartis outside the submitted work. Dr Hartman reported receiving personal fees from Roche, Novartis, Eli Lilly, Pfizer, and Merck; and grants from Cepheid; and being cofounder of Stratipath AB outside the submitted work. Dr Bergh reported receiving grants from AstraZeneca (institutional), Merck (institutional), Amgen (institutional), Bayer (institutional), Roche (institutional), Pfizer (institutional), and Sanofi (institutional); and payment to Asklepios Medicin Hb from UpToDate outside the submitted work. No other disclosures were reported.

    Funding/Support: This study was supported by grants from Region Stockholm, Karolinska Institutet including Cancer Research KI, the Swedish Research Council, the Swedish Cancer Society, the Research Funds at Radiumhemmet, and Roche Sweden.

    Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Data Sharing Statement: See Supplement 3.

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