Part of this work was presented at the San Antonio Breast Cancer Symposium in December 2020.
Docetaxel/carboplatin/trastuzumab/pertuzumab (TCHP) regimen is frequently used to treat early and locally advanced human epidermal growth factor receptor 2 (HER2)–positive breast cancer (BC) in neoadjuvant setting. However, large-scaled real-world evidence did not exist.
We retrospectively reviewed medical records of patients with early or locally advanced HER2-positive BC who underwent neoadjuvant TCHP followed by curative surgery at Samsung Medical Center between January 2016 and August 2020.
Of 447 patients, 316 (70.7%) received breast-conserving surgery and 131 (29.3%) received total mastectomy. In terms of neoadjuvant chemotherapy response, pathologic complete response (pCR) and residual cancer burden (RCB) score were analyzed. The rate of pCR was 64% a class of RCB 0 was observed in 65% of cases, RCB class I in 12%, RCB class II in 14%, and RCB class III in 2%. The 3-year event-free survival rate was 90.6%, BC with pCR occurred in 92.8%, and BC with non-pCR in 86.3% (p=0.016). In terms of distant metastasis, the 3-year distant recurrence-free survival rate was 93.5%; BC with pCR occurred in 95.9% and BC with non-pCR in 89.2% (p=0.013). Mucositis (85.2%), pain (83.2%), and diarrhea (70.5%) were the most common non-hematologic adverse events. In terms of hematologic adverse events, anemia (89.9%) was the most commonly observed adverse events followed by thrombocytopenia (29.8%).
Neoadjuvant TCHP therapy had a pCR rate of 64% and a 3-year event-free survival of 90% in real world experience. In terms of toxicity profile, anemia was frequently observed and adequate management including occasional transfusion was required.
Anti–human epidermal growth factor receptor-2 (HER2) monoclonal antibody, trastuzumab improved survival of patients with early and advanced HER2-positive breast cancer (BC) [
The addition of pertuzumab to trastuzumab and cytotoxic chemotherapy significantly improved overall survival in HER2-positive metastatic BC [
As neoadjuvant therapy, pertuzumab added to trastuzumab and cytotoxic chemotherapy improved pCR and patient survival [
Among clinical trials with pertuzumab for early or locally advanced HER2-positive BC, the TRYPHAENA clinical trial was designed to evaluate the safety and efficacy of pertuzumab and trastuzumab in combination with anthracycline- or carboplatin-based neoadjuvant chemotherapy (NAC) in HER2-positive BC [
Recent advance of adjuvant treatment strategy suggested that trastuzumab emtansine (T-DM1) significantly improved 3-year DFS in HER2-positive BC which did not achieved pCR after NAC compared with trastuzumab treatment despite several toxicities [
Here, we report our clinical experience with BC patients treated with neoadjuvant TCHP followed by curative surgery. Comprehensive analysis of the efficacy and safety of the neoadjuvant TCHP regimen were performed in real world experience (RWE).
We retrospectively reviewed electronic medical records of patients with early or locally advanced HER2-positive BC who underwent neoadjuvant TCHP chemotherapy followed by curative surgery at Samsung Medical Center between January 2016 and August 2020. We included patients diagnosed with clinical stage II to IIIC BC by diagnostic examinations (breast ultrasonography and/or magnetic resonance imaging, chest and abdomino-pelvic computed tomography (CT) scan, bone scan, and/or positron emission tomography–CT scans, if indicated). Stage was based on American Joint Committee on Cancer (AJCC) 7th edition. Patients who received previous BC surgery due to local recurrence after curative surgery or who underwent palliative surgery were excluded. In the event of bilateral BC, one BC that required NAC was selected.
Patients received six cycles of TCHP neoadjuvant therapy. The study drugs were administered intravenously once every 3 weeks. Details of administration method were described in previous article [
Pathologists determined BC histology and receptor status (estrogen receptor [ER], progesterone receptor [PR], and HER2) according to hematoxylin and eosin and immunohistochemical (IHC) staining. ER and PR positivity were defined as Allred score in the range of 3–8 according to IHC staining with antibodies to ER (Immunotech, Marseille, France) and PR (Novocastra, Newcastle upon Tyne, UK), respectively. HER2 status was evaluated using the appropriate antibody (DAKO, Carpinteria, CA) and/or silver
After surgery, pathologic response to NAC was determined as pCR or residual cancer burden (RCB) [
EFS was defined as the elapsed time from date of curative surgery to detection of local or distant tumor recurrence. We also included contralateral or ipsilateral DCIS as an observed event. Distant recurrence-free survival (DRFS) was defined as the elapsed time from date of curative surgery to detection of distant metastasis. Overall survival (OS) was defined as the duration between curative surgery and death. DRFS and OS were analyzed using the Kaplan-Meier method. Cox proportional-hazard regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Two-tailed p-values < 0.05 were considered statistically significant, and IBM SPSS Statistics ver. 21 (IBM Corp., Armonk, NY) was used for analysis of all data.
Between February 2016 and August 2019, 1,840 BC patients received NAC followed by curative surgery. Among these patients, those with HER2-positive BC numbered 539 (38.0%), and the TCHP regimen was used in 447 (24.3%) (
Of 447 patients, 279 (62.4%) received breast-conserving surgery (BCS) with sentinel lymph node biopsy (SLNB), 43 (9.6%) received BCS with axillary lymph node dissection (ALND), 83 (18.6%) opted for total mastectomy (TM) with SLNB, and 42 (9.4%) underwent TM with ALND. When axillary lymph node metastasis was suspected, fine needle aspiration was performed at the time of BC diagnosis. We confirmed axillary lymph node metastases pathologically in 172 patients. Of these 172 patients, ALND was performed in 47 (27.3%). Twenty-eight patients (16.3%) had axillary lymph node metastasis at the time of curative surgery.
In terms of NAC response, we evaluated pathologic response at the time of curative surgery. This evaluation included pCR and RCB score. The rate of pCR was 64% and differed according to hormone receptor status (p < 0.001), clinical stage (p=0.028), and histologic grade (p=0.010) (
In multivariate analysis of the associations between baseline characteristics and pCR status, hormone receptor negativity was positively related to pCR (HR, 0.36; 95% CI, 0.24 to 0.56; p=0.001) whereas pre-menopausal status and advanced clinical stage were oppositely (HR, 1.91; 95% CI, 1.27 to 2.95; p=0.004 and HR, 2.62; 95% CI, 1.36 to 5.07; p=0.004, respectively) (
We ceased data acquisition in December 2020, and the median follow-up duration was 36 months. During follow-up, 33 events have occurred, 24 cases of distant metastasis and nine of local recurrence. The 3-year EFS rate was 90.6%, BC with pCR occurred in 92.8%, and BC with non-pCR in 86.3% (p=0.016) (
We also analyzed the association between survival rate and RCB class (
The effects of key characteristics on EFS were shown in
Mucositis (85.2%), pain (83.2%), and diarrhea (70.5%) were the most common non-hematologic adverse events (
Five patients (1.1%) did not complete six cycles of neoadjuvant TCHP chemotherapy. Two patients (0.4%) only received three cycles, four cycles in two patients (0.4%) and five cycles in one patient (0.2%). RDIs of docetaxel and carboplatin were 0.965 and 0.876, respectively (
In terms of cardiac toxicity, median left ventricle ejection fraction (LVEF) at baseline echocardiography was 65.6 (interquartile range, 62 to 69) and 64.0 (interquartile range, 60 to 67). We observed ejection fraction (EF) decrease in 257 patients during NAC and more than 10% decrease of EF was observed in 88 patients. However, no patients underwent significant declines in LVEF (≥ 10% points from baseline to < 50%) and symptomatic left ventricle systolic dysfunction (
After curative surgery, patients received adjuvant targeted agents per the established protocol. In BC patients achieving pCR, 96.5% received adjuvant trastuzumab; 3.5% received the trastuzumab and pertuzumab combination. In BC patients without pCR, adjuvant trastuzumab was used in 88.8% of patients, the trastuzumab and pertuzumab combination in 7.5%, and T-DM1 in 3.7%.
Of 447 patients, 411 (91.9%) patients received adjuvant radiotherapy (RTx) after curative surgery and 258 patients (62.8%) of patients received adjuvant RTx were performed in our institute. We evaluated the relationship between the radiation dose and pCR status. In this analysis, patients who achieved pCR received less radiation dose compared with patients without pCR (p < 0.001) (
We evaluated the efficacy and safety profile of neoadjuvant TCHP chemotherapy in real world practice. pCR rate was 64% and 3-year EFS was 90.6%. In terms of adverse events (AEs), approximately 90% of patients experienced anemia. Mucositis, pain, and diarrhea were the most frequently observed non-hematologic AEs.
This result was compatible with that of the TRYPHAENA clinical trial [
We analyzed the incidence of down-staging in terms of axillary lymph node status, one of the advantages of NAC. Approximately 72.7% of patients experienced down-staging in terms of axillary node evaluation. Moreover, we performed further subgroup analysis to find the factors associated with pCR and survival. Hormone receptor negativity, low clinical stage (stage IIA–IIIA), and post-menopausal status were favorable to pCR. In terms of survival, clinical stage and pCR affected the EFS. Interestingly, hormone receptor negativity increased pCR rate but negatively affected EFS although statistical significance was marginal (p=0.055). Previous studies have suggested that hormone receptor-negative, HER2-positive BC had higher pCR rate compared with hormone receptor-positive, HER2-positive BC, whereas progression-free survival (PFS) was longer in hormone receptor-positive, HER2-positive BC rather than hormone receptor-negative, HER2-positive BC according to the NeoSphere trial.
Moreover, clinical stage significantly affected survival regardless of pCR status. This result suggests that negative hormone receptor status with initially high clinical stage BC has increased disease recurrence even though pCR had been achieved. Longer-term follow-up is warranted to confirm our suggestion.
In terms of AEs, there are s differences between our clinical experience and what was observed in clinical trial [
RDI of docetaxel decreased during NAC. Especially patients over 60 years of age received less dose of docetaxel compared with whom under 60 years of age. This result suggested that elderly patient had high risk of serious AEs and dose reduction would be needed. Therefore, physicians should carefully examine elderly patients with underlying disease during NAC with TCHP regimen. In terms of carboplatin, we initially decreased the dosage of carboplatin in patients who had risk factors of renal impairment or emesis. Therefore, the dose intensity of carboplatin in the first cycle was low despite the high proportion of young patients.
The combination of docetaxel, pertuzumab, and trastuzumab is used for metastatic HER2-positive BC as first-line treatment; its efficacy was demonstrated in the CLEOPATRA clinical trial [
Approximately 90% of patients in the TRYPAENA trial received the scheduled number of cycles of docetaxel and carboplatin [
Although this study s retrospective analysis of neoadjuvant TCHP chemotherapy, the sample size is relatively large, and details of AEs are described. Neoadjuvant TCHP regimen is now popularly used for HER2-positive BC and therefore RWE of this regimen may be useful as treatment reference. In contrast with previous clinical trial, we focused on the factors affecting the efficacy of NAC and NAC-related AEs rather than cardiac toxicity. Relatively short follow-up duration is limitation of our study and long-term follow-up would be warranted.
In conclusion, neoadjuvant TCHP therapy had a pCR rate of 64% and a 3-year EFS of 90% in RWE. In terms of toxicity profile, anemia was frequently observed and adequate management including occasional transfusion was required.
Supplementary materials are available at Cancer Research and Treatment website (
This study was reviewed and approved by the Institutional Review Board (IRB) of Samsung Medical Center, Seoul, Korea (IRB No. 2019-04-021). The requirement for informed consent was waived due to the use of medical records with retrospective clinical data.
Conceived and designed the analysis: Kim SW, Park YH.
Collected the data: Kim JY, Nam SJ, Lee JE, Yu J, Chae BJ, Lee SK, Ryu JM, Ahn JS, Im YH, Kim SW, Park YH.
Contributed data or analysis tools: Kim JY, Ahn JS, Im YH, Kim SW, Park YH.
Performed the analysis: Kim JY.
Wrote the paper: Kim JY, Park YH.
YHP reports grants from Pfizer, AstraZeneca, Novartis, Merck, Roche, and Eisai. All other authors declare no competing interests.
Pathologic complete response (pCR) according to hormone receptor (HR) status (A), clinical stage (B), and histologic grade (C).
Multivariate analysis of factors affecting to pathologic complete response (pCR) (A) and event-free survival (EFS) (B). CI, confidence interval; HG, histologic grade; NG, nuclear grade.
Event-free survival (A), distant recurrence-free survival (B), and overall survival (C) according to pathologic complete response (pCR) or non-pCR.
Clinicopathological characteristics of patients
Characteristic | No. (%) (n=447) |
---|---|
49 (19–80) | |
< 40 | 75 (16.8) |
≥ 40 and < 50 | 166 (47.1) |
≥ 50 and < 60 | 157 (35.1) |
≥ 60 | 49 (11.0) |
447 (100) | |
Pre-menopause | 258 (57.7) |
Post-menopause | 187 (41.8) |
Unknown | 2 (0.5) |
Yes | 66 (14.8) |
No | 381 (85.2) |
2A | 112 (25.1) |
2B | 132 (29.5) |
3A | 133 (29.8) |
3B | 5 (1.1) |
3C | 65 (14.5) |
BCS with SLNB | 279 (62.4) |
BCS with ALND | 43 (9.6) |
TM with SLNB | 83 (18.6) |
TM with ALND | 42 (9.4) |
BRCA1 alteration | 0 |
BRCA2 alteration | 3 (2.3) |
IDC | 402 (89.9) |
IDC with ILC | 11 (2.5) |
Micropapillary | 21 (4.7) |
Others | 13 (2.9) |
1 | 3 (0.7) |
2 | 216 (48.3) |
3 | 225 (50.3) |
Unknown | 3 (0.7) |
1 | 0 |
2 | 189 (42.3) |
3 | 257 (57.5) |
Unknown | 1 (0.2) |
ER+/PR+ | 141 (31.5) |
ER+/PR− | 71 (15.9) |
ER−/PR+ | 3 (0.7) |
ER−/PR− | 231 (51.7) |
Unknown | 1 (0.2) |
AJCC, American Joint Committee on Cancer; ALND, axillary lymph node dissection; BCS, breast-conserving surgery; ER, estrogen receptor; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma; PR, progesterone receptor; SLNB, sentinel lymph node biopsy; TM, total mastectomy including nipple sparing mastectomy.
Adverse events for neoadjuvant TCHP chemotherapy
Adverse event | All grade | ≥ Grade 3 |
---|---|---|
302 (67.6) | 26 (5.8) | |
129 (27.8) | 13 (2.9) | |
327 (70.5) | 14 (3.1) | |
115 (25.7) | 1 (0.2) | |
149 (33.3) | 2 (0.4) | |
108 (24.2) | 2 (0.4) | |
92 (20.6) | 0 | |
50 (11.2) | 1 (0.2) | |
Albumin | 49 (11.0) | 0 |
Bilirubin, total | 29 (6.5) | 0 |
AST | 240 (53.7) | 5 (1.1) |
ALT | 281 (62.9) | 6 (1.3) |
ALP | 137 (30.6) | 0 |
381 (85.2) | 1 (0.2) | |
242 (54.1) | 3 (0.7) | |
270 (60.4) | 3 (0.7) | |
372 (83.2) | 1 (0.2) | |
Anemia | 402 (89.9) | 32 (7.2) |
RBC transfusion | 90 (20.1) | 0 |
Leukopenia | 95 (21.3) | 6 (1.3) |
Neutropenia | 108 (24.2) | 24 (5.4) |
Febrile neutropenia | 0 | 9 (2.0) |
Thrombocytopenia | 133 (29.8) | 5 (1.1) |
PLT transfusion | 6 (1.3) | 0 |
Values are presented as number (%). ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; PLT, platelet; RBC, red blood cell; TCHP, docetaxel/carboplatin/trastuzumab/pertuzumab.