The proper use of anthracycline-containing regimens in combination with anti-HER2-targeted therapy in a neoadjuvant setting for patients with HER2-positive breast cancer has not been resolved. Regimens preceded by anthracyclines have become the standard of care, and although the order has no significant impact on HER2-negative breast cancer, it is inconclusive as to whether a taxane-first sequence would have a similar effect on HER2-positive breast cancer. The present study aimed to investigate the benefit of a taxane-first sequence and of adriamycin and cyclophosphamide (AC) in patients with non-clinical complete response (non-cCR) to pertuzumab, trastuzumab and docetaxel (PTD). The present single-center prospective observational study was performed to investigate PTD followed by AC, and aimed to clarify the cCR rate after PTD alone and the pathological clinical response (pCR) rate after subsequent AC in patients without cCR after PTD alone. A total 24 patients were analyzed; of these, 14 achieved pCR (pCR rate, 58.3%). While four of 14 patients (28.6%) in the intention-to-treat population achieved pCR, nine of 14 patients (64.3%) achieved pCR with AC but not cCR after PTD. The median tumor reduction rate after four cycles of PTD was 58.9% (range, 20.8-100%) in all 24 patients, whereas the reduction rate after PTD-AC was 76.9% (range, 31.1-100%). Cardiac serious adverse events occurred in three patients (12.5%). In conclusion, a high pCR rate was observed for the taxane-first sequence. Patients were highly responsive to PTD, but some cases achieved additional antitumor effects after AC, which resulted in pCR without cCR after PTD alone. Since cardiotoxicity remains a significant problem, a higher risk-benefit treatment strategy is required to aim for AC omission. Trial registration number: UMIN000046338, name of registry: UMIN-CTR, date of registration: December 10, 2021.
HER2-positive breast cancer was originally a subtype with a poor prognosis due to its aggressiveness, but improvements in anti-HER2 therapy have dramatically reduced the frequency of recurrence and have prolonged overall survival (
This prospective observational study was conducted at a single institute to investigate PTD followed by AC as a preoperative chemotherapy in patients with HER2-positive breast cancer and intended to estimate tumor reduction after PTD alone or after both PTD and AC. The planned study period was from April 2019 to in July 2022, and the registration period was from March 2019 to July 2021. Key inclusion criteria are: HER2-positive breast cancer diagnosed pathologically HER2 3+ by immunohistochemistry or positive results on in situ hybridization if HER2 2+ by immunohistochemistry; patients indicated to receive neoadjuvant chemotherapy; an Eastern Cooperative Oncology Group Performance Status of 0 or 1. Key exclusion criteria were patients with other active cancers that required treatment, those with heart failure (EF <60%), and those whose inclusion was determined to be inappropriate by the investigators. Magnetic resonance imaging (MRI) and ultrasound (US) were used to assess the maximum tumor diameter for breast lesions at baseline, after PTD, and after both PTD and AC; the maximum tumor diameter was measured in accordance with RECIST ver.1.1. If cancer lesions on images were not solitary tumors, the maximum diameter of the area including all lesions was defined as a viable lesion. Contrast-enhanced computed tomography and ultrasound were used to assess the shape and short axis diameter of the axillary lymph node (AxLN).
To assess the primary breast tumor, MRI was evaluated with frequency-selective fat suppression (e-THRIVE) and maximum intensity projection imaging, and the contrast effect range was judged as a viable lesion (Ingenia 3.0T Omega HP release 5.41, Philips Healthcare). Ultrasound was performed by laboratory technicians, who reported the imaging data in clinical documents using Aplio 700, Aplio a550 (Canon) and LOGIQ E9 (GE Healthcare Japan). If a low echoic area with no blood flow was observed with apparent discrepancies compared with MRI images, MRI findings were preferred over US findings. Pathological findings included the diameter of remnant lesions in the surgical pathology report prepared by pathologists, who were blinded to the patient information in this study.
The primary endpoint was the pCR rate after PTD followed by AC, which was defined as ypT0/is and ypN0. Secondary endpoints were tumor reduction rate and clinical complete response (cCR) during PTD treatment, AC treatment, and the sequential full regimen (PTD-AC), and safety, especially cardiotoxicity, at 1 year after surgery. Left ventricular ejection fraction (LVEF) was measured by echocardiography, and the same methods were used for each individual patient throughout the study (
The study protocol was approved by the Clinical Trial Center of Sapporo Medical University, Japan (approval no. 302-237), was conducted in accordance with The Declaration of Helsinki and the Ethical Principles for Medical Research Involving Human Subjects, and is registered with UMIN-CTR (UMIN000046338). We complied with the latest editions of the ‘Declaration of Helsinki of the World Medical Association’ and the ‘Ethical Guidelines for Medical Research Involving Human Subjects’ (Ministry of Health, Labour and Welfare) with which all medical research involving human subjects must comply. The consent documents approved by the review committee were given to the subjects (approval no. 302-237), and consent was obtained in writing of the subject's own free will after sufficient explanation.
As for the regimen protocol of PTD, patients were given intravenous Pmab on day 1 for three weeks of every cycle; the starting loading dose was 840 mg, which decreased to 420 mg in subsequent cycles. Then, patients were administered Tmab on day 1 of every cycle at a dose of 8 mg/kg, which decreased to 6 mg/kg. Finally, patients were administered docetaxel on day 1 of every cycle at a dose of 75 mg/m2 after which they were given 6.6 mg of dexamethasone and 0.75 mg of palonosetron. Those drugs were given to patients for four cycles.
As for the subsequent four cycles of AC, patients were given 60 mg/m2 of doxorubicin and 600 mg/m2 of cyclophosphamide on day 1 for three weeks of every cycle. Aprepitant at 125 mg was also given intravenously on day 1 and a decreased dose of 80 mg was given orally on days 2 and 3; 1 mg of granisetron was also given intravenously on day 1.
If the AxLNs were clinically negative and this was discovered before the preoperative treatment, sentinel lymph-node biopsy (SLNB) was performed, while axillary lymph-node dissection (ALND) was performed in cases of clinically positive AxLNs in patients who underwent either mastectomy or partial mastectomy. After surgery, tri-weekly Pmab and Tmab were administered to each patient. During the study period, 1-year trastuzumab emtansine (T-DM1) as a postoperative treatment was covered by insurance in Japan in accordance with the KATHERINE trial (
Descriptive statistics were used to describe the baseline characteristics. Mann-Whitney U test was performed for the reduction rate of PTD, AC, and PTD-AC in those with and without ER positivity. Odds ratios and 95% confidence intervals for pCR for each clinicopathologic factor were calculated by nominal logistic analysis. All statistical analyses were performed using JMP 15.1.0 (SAS Institute Inc., Cary NC, USA).
In total, 25 eligible patients were registered, but one patient declined surgery and was thus ineligible. Therefore, this analysis included 24 patients who were administered PTD-AC for NAC. One patient underwent surgery after 4 cycles of PTD with no AC because of a severe cardiac AE. The baseline patient characteristics are summarized in
Adjuvant therapy was indicated in all patients; one year of Pmab + Tmab was given to 22 patients and one year of T-DM1 was given to 2 patients, which was available at the hospital as a postoperative treatment. Thereafter, irradiation was indicated after adjuvant therapy in eight patients and was intended for the preserved breast after partial mastectomy or was intended as post-mastectomy radiotherapy (PMRT).
Overall, 23 of 24 patients (%) achieved 85% or more relative dose intensity (RDI) of the planned eight treatment cycles. Four patients had dose reductions but maintained RDI above 85%, while the other 19 patients achieved 100% RDI without dose reductions or discontinuation.
The median tumor reduction rate after 4 cycles of PTD was 58.9% (20.8-100%) in all 24 patients, 58.3% (20.8-100%) in patients with ER-positive breast cancer, and 67.6% (31.3-100%) in patients with ER-negative breast cancer (P=0.4733;
As shown in
We conducted an exploratory study in which we analyzed recurrent events. We found that there were no recurrent events over a median follow-up of 22.8 (6.8-37.2) months. The selected adjuvant therapy is described below. Two patients were planned to receive 14 cycles of adjuvant T-DM1, 21 patients were to receive 14 cycles of Tmab + Pmab, and 1 patient was to receive 14 cycles of Tmab. However, the planned adjuvant treatment could not be completed because two patients receiving Tmab + Pmab and one patient receiving Tmab discontinued the treatment because of cardiotoxicity.
The incidence of treatment-related adverse events (AEs) is summarized in
As for cardiac safety, in this study, the median observation period for the evaluation of cardiac function (by echocardiography) was 22.0 (range, 3.0-34.3) months. Severe AEs were observed in three cases described below (3/24; 12.5%). One patient had severe mitral regurgitation (grade 3) without significant LVEF reduction two months after the day neoadjuvant chemotherapy (NAC) was initiated, and accordingly, she did not receive anthracycline-containing regimens (#10). Two patients had significant LVEF reductions of 10% or more but <50% from baseline, and they also had symptomatic LVSD (grade 3) at 9.9 and 11.5 months after starting NAC. Both patients experienced LVSD during adjuvant systemic therapy (Tmab + Pmab); the former required intensive care and had a moderate outcome, and the latter also had a moderate outcome but received only oral medication. Those three patients discontinued the planned treatment.
This study was conducted as a single-center prospective observational study with a PTD-first sequence. We investigated the effect of PTD alone and the additional effects of anthracycline-containing regimens. As for perioperative systemic therapy, regimens preceded by anthracyclines have become the standard of care, and although the order makes no significant difference in safety and efficacy (
In this study, 14 patients in the intention-to-treat population achieved pCR at a rate of 58.3%. There were four cases of cCR with PTD alone, which resulted in pCR at surgery. In contrast, there were also cases of pCR due to AC after non-cCR (9/14 patients; 64.3%), which indicated the possibility of an additional effect of AC administered later. In the NeoSphere study, pCR was defined as the absence of invasive neoplastic cells on microscopic examination of the PBT at surgery, and in that study, the pCR rate of the PTD group was 45.8% (
In the NAC setting, trials omitting anthracycline have been reported, although most protocols use carboplatin instead of anthracycline. In the TRAIN-2 study, the pCR rate was similar [the difference was -1.5% between the anthracycline and the non-anthracycline groups; 95% CI (-11-8), P=0.95(
Pivotal studies on the prognostic improvement effect of adding Pmab or other antiHER2 drugs, in the treatment regimen have been reported. The combination of Tmab with Pmab improves invasive disease-free survival (IDFS) in adjuvant chemotherapy for HER2-positive breast cancer (
A meta-analysis of the diagnostic performance of MRI in HER2-positive breast cancer received NAC revealed a positive predictive value (PPV) of 62.0-94.6% for non-pCR (residual disease) diagnostic, a negative predictive value (NPV) of 34.9-72%, and sensitivity of 47-90% (
According to the combination of US, there was no difference between MRI and US accuracy [P=0.15, (
Although the limitations in detecting residual lesions due to PTD, should be noted, diagnoses made by MRI/US are performed with a certain degree of accuracy in daily practice. Recently, pCR/NAC diagnosis using core needle biopsy or vacuum-assisted biopsy improves NPV and resulted in a favorable false-negative rate (
Regarding cardiac disorders, the cardiotoxicity of anthracycline administration in addition to that of anti-HER2 therapy is a problem that should not be underestimated. In this study, AEs other than cardiotoxicity did not differ significantly from those previously reported. However, LVSD was observed in two patients, and one patient experienced severe mitral regurgitation but no significant LVEF reduction. The results showed a higher frequency of LVSD events of any grade (3/24; 12.5%) than TRYPHAENA (
A limitation of this prospective observational study is the small number of cases, because of the low frequency of HER2-positive rates, 10-20% of all breast cancers (
In conclusion, we again found that the pCR rate and response rate to PTD were high but that some cases experienced an additional effect of AC, which resulted in pCR. As cardiotoxicity remains a significant problem, further research on the risk-benefit treatment strategy is needed to target the omission of AC or for selection of patients expecting an additional AC effect. For taxane-first sequences, a high pCR rate was observed, although it should be noted that the frequency of cardiac AEs could not be ignored.
Not applicable.
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
HS, GK, DK, HK, TO and IT conceived and planned in detail the present study. YK, FS, NN and TH extracted the entirety of patient data and performed the data construction and put the data into a form that could be entered into statistical software. AW, KS and SU performed analysis and interpretation of the patient data with HS. DK, HK and TO revised it critically for important intellectual content. IT provided overall supervision and gave final approval to the publishable version. All authors read and approved the final manuscript. HS and GK confirm the authenticity of all the raw data.
This study adhered to ethical tenets of The Declaration of Helsinki and Ethical Principles for Medical Research Involving Human Subjects, was approved by the Clinical Trial Center of Sapporo Medical University, Japan, and is registered with UMIN-CTR (UMIN000046338). The consent documents approved by the review committee were given to the subjects (302-237), and consent was obtained in writing of the subject's own free will after sufficient explanation.
Patients provided written informed consent for publication.
The authors declare that they have no competing interests.
Waterfall plot sorted by PTD reduction rate and clinical and pathological findings during NAC. cCR was observed in 8 of 24 patients with primary breast tumors after sequential PTD-AC, while pCR was observed in 14 of 24 patients. Notably, four patients achieved apparent cCR, and all four patients achieved pCR after PTD alone. IDC, invasive ductal carcinoma; ER, estrogen receptor; PgR, progesterone receptor; NAC, neoadjuvant chemotherapy; cCR, clinical complete response; pCR, pathological complete response; AC, adriamycin and cyclophosphamide; PTD, pertuzumab, trastuzumab and docetaxel; ILC, invasive lobular carcinoma; muc, mucinous carcinoma.
Baseline patients' characteristics (n=24).
Characteristic | Values |
---|---|
Median age, years (range) | 54.5 (39-76) |
cT, 1/2/≥3 | 4/17/3 |
cN, 0/≥1 | 12/12 |
ER, positive/negative | 15/9 |
PgR, positive/negative | 12/12 |
HER2, 3+/2+ and ISH-positive | 23/1 |
NG, 1-2/3 | 18/6 |
Median Ki67, % (range) | 32 (14-90) |
Breast surgery, mastectomy/partial mastectomy | 19/5 |
Axillary surgery, SLNB/ALND after SLNB/ALND | 11/1/12 |
Adjuvant therapy, 1 year of Pmab + Tmab/1 y of T-DM1 | 22/2 |
Radiotherapy, yes/no | 8/16 |
ER, estrogen receptor; PgR, progesterone receptor; NG, nuclear grade; SLNB, sentinel lymph node biopsy; ALND, axillary lymph node dissection; Pmab, pertuzumab; Tmab, trastuzumab; T-DM1, trastuzumab emtansine.
Clinical and pathological findings on axillary lymph nodes during NAC.
Case no. | ||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Clinical and pathological findings | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 | 17 | 18 | 19 | 20 | 21 | 22 | 23 | 24 |
Primary breast tumor | ||||||||||||||||||||||||
cT of main tumor baseline | 2 | 2 | 1c | 3 | 2 | 2 | 2 | 2 | 1c | 2 | 2 | 2 | 3 | 2 | 2 | 2 | 2 | 2 | 1c | 4 | 1c | 2 | 2 | 2 |
cT of main tumor after PTD | 1c | 2 | 1c | 2 | 1c | 2 | 2 | 1b | 1b | 1c | 1c | 1b | 1c | 1c | 1b | 1c | 1c | 1b | 1c | 1b | 0 | 0 | 0 | 0 |
ypT | 1b | 1b | 0 | 1c | 2 | 0 | 1mi | 0 | 1c | 0 | is | 0 | 1mi | 0 | is | 1b | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Main tumor reduction rate PTD | 0.21 | 0.28 | 0.31 | 0.38 | 0.42 | 0.44 | 0.46 | 0.52 | 0.53 | 0.53 | 0.55 | 0.58 | 0.6 | 0.63 | 0.65 | 0.68 | 0.71 | 0.71 | 0.77 | 0.87 | 1 | 1 | 1 | 1 |
Main tumor reduction rate PTD-AC | 1 | 0.31 | 1 | 0.83 | 0.58 | 0.54 | 0.54 | 0.71 | 0.57 | 1 | 0.62 | 0.58 | 0.73 | 0.63 | 0.77 | 0.68 | 1 | 1 | 0.77 | Skip | 1 | 1 | 1 | 1 |
Clinical findings of AxLN | ||||||||||||||||||||||||
Swelling AxLN number | 0 | 0 | 0 | 2 | 0 | 1 | 0 | 1 | 2 | 0 | 0 | 1 | 1 | 4 | 0 | 5 | 0 | 6 | 1 | 1 | 1 | 0 | 0 | 0 |
AxLN FNA | - | - | - | m | - | m | - | m | m | - | - | m | m | - | m | - | m | m | m | - | - | - | ||
cN baseline | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 1 | 1 | 0 | 0 | 1 | 1 | 1 | 0 | 1 | 0 | 3 | 1 | 2 | 1 | 0 | 0 | 0 |
cN after PTD | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Short diameter of the largest AxLN | ||||||||||||||||||||||||
Minor axis of AxLN before NAC, mm | 37 | 15 | 20 | 23 | ||||||||||||||||||||
Minor axis of AxLN after PTD, mm | 32 | |||||||||||||||||||||||
Minor axis of AxLN after PTD-AC, mm | 15 | |||||||||||||||||||||||
Pathological findings of AxLN | ||||||||||||||||||||||||
Results of SLNB for cN0 | ||||||||||||||||||||||||
SLNB positive node number | 0 | 0 | 0 | - | 1 | - | 0 | - | - | 0 | 0 | - | - | - | 0 | - | 0 | - | - | - | - | 0 | 0 | 0 |
SLNB total number | 2 | 1 | 1 | - | 1 | - | 1 | - | - | 2 | 1 | - | - | - | 1 | - | 1 | - | - | - | - | 1 | 1 | 2 |
Results of final LN status including ALND | ||||||||||||||||||||||||
Pathological positive AxLN number | - | - | - | 1 | 3 | 0 | - | 0 | 3 | - | - | 1 | 0 | 0 | - | 0 | - | 0 | 2 | 0 | 0 | - | - | - |
ypN | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 1mi | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
Details of lymph-node metastasis and treatment effects corresponding to the above cases. After PTD-AC, a remnant AxLN metastatic nest was observed in 5 of 12 cN-positive patients, and in all of these patients, the short axis diameter of AxLNs was less than 15 mm, and there were no findings suggestive of malignancy, such as focal thickening of the cortex or disappearance of the lymph-node hilum. Moreover, breast tumors in two patients disappeared, but residual metastases remained in the AxLN, which resulted in non-pCR. cN positivity in 12 patients was diagnosed follows: 10 patients by FNA; 1 who did not undergo FNA but had a clinically apparent metastatic node because of large swelling in 6 AxLNs; and 1 patient had insufficient tissue but had a clinically apparent metastatic node because of swelling in four LNs. Tis, ductal carcinoma in situ; T1mi, micro metastasis; AxLN, axillary lymph node; AxLN, axillary lymph node; FNA, fine needle aspiration; NAC, neoadjuvant chemotherapy; SLNB, sentinel lymph node biopsy; ALND, axillary lymph node dissection; skip, AC was skipped in case #20 because of severe adverse event. -, No metastasis; m: metastasis;
†, No FNA but clinically apparent metastatic node.
‡, Insufficient specimens but clinically apparent metastatic node because of many swelling LNs.
*, Short diameter of 15 mm or less and no abnormalities on imaging.
Breakdown of pathologic findings.
Pathological findings | ypT | ypN | Number (n=24) |
---|---|---|---|
pCR | ypT0 | ypN0 | 12 |
ypTis | ypN0 | 2 | |
non-pCR | ypT1mi | ypN0 | 2 |
ypT1 | ypN0 | 3 | |
ypT2 | ypN0 | 0 | |
ypT0 | ypN1mi | 1 | |
ypT0 | ypN1 | 1 | |
ypTis | ypN1 | 0 | |
ypT1mi | ypN1 | 0 | |
ypT1 | ypN1 | 2 | |
ypT2 | ypN1 | 1 |
There were 14 cases of pCR as defined in this study, 12 cases of ypT0ypN0, and 2 cases of ypTisypN0. In two cases, the PBT disappeared, but AxLN metastases remained. pCR, pathological complete response; PBT, primary breast tumor; AxLN, axillary lymph node.
Univariate analysis for pCR.
Clinicopathological factors | Odds ratio | 95% CI | P-value |
---|---|---|---|
cT (≥cT2 vs. cT1) | 2.33 | 0.24-23.57 | 0.4491 |
cN (≥cN1 vs. cN0) | 1.00 | 0.18-5.63 | 1.0000 |
ER (negative vs. positive) | 2.33 | 0.39-19.44 | 0.3630 |
PgR (negative vs. positive) | 5.00 | 0.84-42.54 | 0.0781 |
NG (3 vs. 1-2) | - | - | - |
Ki67 (≥20% vs. <20%) | 4.00 | 0.27-109.96 | 0.3115 |
pCR, pathological complete response; 95% CI, 95% confidence interval; ER, estrogen receptor; PgR, progesterone receptor; NG, nuclear grade.
Summary of adverse events in patients.
Adverse event | Total | Grade 1-2 | Grade ≥3 |
---|---|---|---|
Blood and lymphatic system disorders | |||
Neutropenia | 4 | 2 | 2 |
Anemia | 1 | 1 | 0 |
Febrile neutropenia | 3 | - | 3 |
Cardiac disorders | |||
Left ventricular systolic disfunction | 2 |
- | 2 |
Mitral valve disorder | 1 | 0 | 1 |
General disorders and administration site conditions | |||
Fatigue | 8 | 8 | 0 |
Peripheral edema | 6 | 6 | 0 |
Mucosal inflammation | 0 | 0 | 0 |
Fever | 2 | 2 | 0 |
Skin and subcutaneous tissue disorders | |||
Alopecia | 24 | 24 | 0 |
Rash | 9 | 9 | 0 |
Nail disorder | 3 | 3 | 0 |
Pruritus | 2 | 2 | 0 |
Dry skin | 1 | 1 | 0 |
Skin hyperpigmentation | 1 | 1 | 0 |
Palmer-plantar erythrodysesthesia syndrome | 12 | 12 | 0 |
Pruritus | 2 | 2 | 0 |
Gastrointestinal disorders | |||
Diarrhea | 10 | 10 | 0 |
Nausea | 13 | 13 | 0 |
Vomiting | 1 | 1 | 0 |
Constipation | 2 | 2 | 0 |
Abdominal pain | 1 | 1 | 0 |
Mucositis oral | 2 | 2 | 0 |
Metabolism and nutrition disorders | |||
Anorexia | 2 | 2 | 0 |
Nervous system disorders | |||
Headache | 2 | 2 | 0 |
Peripheral motor neuropathy | 1 | 1 | 0 |
Peripheral sensory neuropathy | 4 | 4 | 0 |
Dysgeusia | 3 | 3 | 0 |
Musculoskeletal and connective tissue disorders | |||
Myalgia | 2 | 2 | 0 |
Arthralgia | 2 | 2 | 0 |
Respiratory, thoracic and mediastinal disorders | |||
Cough | 2 | 2 | 0 |
Other adverse events | |||
Cystitis noninfective | 1 | 1 | 0 |
Shingles | 2 | 2 | 0 |
Middle ear inflammation | 1 | 1 | 0 |
aOne patient with LVEF reduction over 10% was non-symptomatic.