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Incidence of brain metastases in patients with early HER2-positive breast cancer receiving neoadjuvant chemotherapy with trastuzumab and pertuzumab

Incidence of brain metastases in patients with early HER2-positive breast cancer receiving... www.nature.com/npjbcancer ARTICLE OPEN Incidence of brain metastases in patients with early HER2-positive breast cancer receiving neoadjuvant chemotherapy with trastuzumab and pertuzumab 1,8 1,8 7 2 2 2 3 Emanuela Ferraro , Jasmeet Singh , Sujata Patil , Pedram Razavi , Shanu Modi , Sarat Chandarlapaty , Andrea V. Barrio , 4 5 5 6 6 2 2 Rachna Malani , Ingo K. Mellinghoff , Adrienne Boire , Hannah Y. Wen , Edi Brogi , Andrew D. Seidman , Larry Norton , 2 2 Mark E. Robson and Chau T. Dang The addition of pertuzumab (P) to trastuzumab (H) and neoadjuvant chemotherapy (NAC) has decreased the risk of distant recurrence in early stage HER2-positive breast cancer. The incidence of brain metastases (BM) in patients who achieved pathological complete response (pCR) versus those who do not is unknown. In this study, we sought the incidence of BM in patients receiving HP-containing NAC as well as survival outcome. We reviewed the medical records of 526 early stage HER2- positive patients treated with an HP-based regimen at Memorial Sloan Kettering Cancer Center (MSKCC), between September 1, 2013 to November 1, 2019. The primary endpoint was to estimate the cumulative incidence of BM in pCR versus non-pCR patients; secondary endpoints included disease free-survival (DFS) and overall survival (OS). After a median follow-up of 3.2 years, 7 out of 286 patients with pCR had a BM while 5 out of 240 non-pCR patients had a BM. The 3-year DFS was significantly higher in the pCR group compared to non-pCR group (95% vs 91 %, p = 0.03) and the same trend was observed for overall survival. In our cohort, despite the better survival outcomes of patients who achieved pCR, we did not observe appreciable differences in the incidence of BM by pCR/non-pCR status. This finding suggests that the BM incidence could not be associated with pCR. Future trials with new small molecules able to cross the blood brain barrier should use more specific biomarkers rather than pCR for patients’ selection. npj Breast Cancer (2022) 8:37 ; https://doi.org/10.1038/s41523-022-00380-7 INTRODUCTION and chemotherapy in HER2-positive BC has resulted in an improvement of pathologic complete response (pCR) rate after Central nervous system (CNS) is a common site of distant NAC . Currently, the rate of BM and the predictive role of pCR on recurrence that affects prognosis and quality of life of HER2- the risk of CNS seeding is unknown in patients receiving double positive breast cancer (BC) patients . The reported cumulative blockade with trastuzumab and pertuzumab (HP) in preoperative incidence of brain metastases (BM) in HER2 positive BC is higher setting. The interest in understanding the incidence of CNS than in other subtypes suggesting that HER2 positive cancer cells 2,3 recurrence in a real-life population arises from the necessity to have a specific tropism for the CNS . The advent of different anti- shape new strategies to reduce the risk of BM in patients with HER2 agents and the implementation of local approaches such as early-stage BC. The aim of this study was to assess the incidence of stereotactic radiosurgery (SRS) has significantly improved the BM in patients receiving HP-containing NAC and to compare rates prognosis of HER2- positive BC patients with BM. However, BM still of BM stratified by pCR status. presents multiple challenges for optimal management, especially in the scenario of progression despite loco-regional therapies. New oral HER2 tyrosine kinase inhibitors (TKIs) including neratinib RESULTS and tucatinib, have demonstrated CNS activity, and have been Study population recently approved by Food and Drug Administration (FDA) in 4,5 metastatic setting . In early stage, neratinib is currently approved Overall, 533 patients with stage I-III HER2 positive breast cancer as single agent after trastuzumab-based adjuvant therapy and treated with NAC followed by surgery at MSKCC were identified. tucatinib is still under investigation in high-risk patients in Cases with a concomitant HER2 negative BC (n = 4) and combination with T-DM1 (NCT04457596). discordant HER2 status (internal versus external) (n = 3) were In stages I-III BC, the CNS recurrence rate is reported around excluded. Among the study population (n = 526), 130 patients 2–4% of patients receiving trastuzumab and/or pertuzumab- had preoperative HER2 status confirmed at MSKCC (Fig. 1). All based adjuvant treatments as first site of recurrence in a follow-up clinicopathological features are described in Table 1.ApCRwas 7–9 range of 3–5 years . Few studies have reported the rate of BM in achieved in 286/526 (54.4%) of cases, whereas 240/526 (45.6%) early-stage breast cancer patients treated with neoadjuvant had residual disease. The majority of the patients (278/286, 97% chemotherapy (NAC). The addition of pertuzumab to trastuzumab in pCR and 226/240, 94% in non-pCR group) had a poorly 1 2 Breast Cancer Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Breast Cancer Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medicine College, New York, NY, USA. Breast Cancer Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, 4 5 NY, USA. Brain Tumor Center, Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Brain Tumor Center, Human Oncology and Pathogenesis Program, Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, 7 8 NY, USA. Present address: Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA. These authors contributed equally: Emanuela Ferraro, Jasmeet Singh. email: dangc@mskcc.org Published in partnership with the Breast Cancer Research Foundation 1234567890():,; E. Ferraro et al. Fig. 1 Diagram of patients’ selection. This schema represents a consort diagram of the study and provides the patients selection based on HER2 status on biopsy and response to neoadjuvant treatment (pCR versus non-pCR). Notes: HER2+: HER2-positive, HER2−: HER2-negative, pts: patients; BC: breast cancer; bx: biopsy. differentiated breast carcinoma. The clinical stage II was the our population was 19 (range 4–58) months and 6.5 (range 6.5–17) prevalent stage at the time of diagnosis (74% and 72% in pCR months in the pCR and non-pCR group, respectively. and non-pCR groups, respectively). In both groups, most of Most of the patients had one or two brain lesions in both pCR patients received dose dense chemotherapy with doxorubicin/ and non-pCR groups, who underwent surgical resection followed cyclophosphamide followed by paclitaxel plus HP (AC-THP) as by stereotactic radiation of the tumoral bed or radiosurgery NAC (90% vs 86% in pCR and non-pCR respectively). alone. Whole brain radiation was delivered to 3 patients in the Anthracycline-free therapy with docetaxel, carboplatin plus HP pCR group and in 1 patient in the non-pCR group. One patient of (DCbHP regimen) was administered in less than 10% of cases, in the pCR group and one of the non-pCR group had an extensive both groups. A minority of patients received vinorelbine and disease with severe symptoms that did not improve after local gemcitabine, when taxane was contraindicated (Table 1). treatment. The majority of the patients received a first line Patients who achieved pCR compared to those did not, had systemic treatment for metastatic disease, except for two patients more frequently HR negative tumors (46% vs 20% P < 0.001) and who continued adjuvant HP after the local treatment (Table 3). more often had HER2 overexpression by IHC (3 + ) (94% vs 68%, The baseline characteristic of patients who developed brain BM P < 0.001). In the pCR group, the proportion of patients who were homogeneous regardless the pCR status. Eleven out of 14 received axillary dissection was lower than in the non-pCR group patients had clinical stage III disease while 3/14 stage II. In the (7% vs 35% P < 0.001). These results were consistent between pCR group, 5/7 patients had HR + /HER2 + disease while 3/7 overall patients and the subset of patients with HER2 status on patients in the non-pCR group. Only 2 patients in the pCR group pre-NAC biopsy verified at MSKCC (Table 1). and 5 patients in the non-pCR group had HR-HER2 + disease at the time of diagnosis. Disease-free survival events Survival outcomes After a median follow-up of 3.2 years (range 0.4–5.5), 36 DFS events occurred in the study population, 14 in the pCR group and Regarding survival outcomes, the 3-year DFS was 91% (95% CI 22 in the non-pCR group (Table 2). Among pCR patients with 87–95%) in the non-pCR group and 95% (95% CI 92–98%) in the pCR group (p = 0.03). The 3-years OS was 95% (95% CI 92–98) in recurrences, 4/14 had locoregional recurrence, 9/14 had distant the non-pCR group and 98% (95% CI 97–100) in the pCR group recurrence of which 7 had only BM, 1 visceral metastasis (lung) (log-rank p = 0.02) (Figs. 3 and 4). and 1 non-visceral metastasis (thoracic lymph nodes). One patient in the pCR group died of unknown cause. The loco-regional breast disease events included 2 contralateral breast cancer, 1 ipsilateral DISCUSSION lymph nodal, 1 invasive breast cancer and 1 DCIS relapses. In our cohort, the absolute rate of BM was similar between pCR Conversely, almost the totality (17/22) of DFS events of the non- and non-pCR patients, 2.4% and 2%, respectively, with the pCR group were distant relapse with 7/22 patients with visceral median follow-up of 3.2 years. The median time of BM relapse recurrence in the liver and adrenal glands, 5/22 skin and lymph was 19 versus 6.5 months in patients with pCR versus non-pCR, nodes recurrence and 5/22 with a brain only recurrence. respectively. Notably, in the pCR group, 30% of DFS events were local recurrence and almost the totality of patients with Brain metastases incidence distance recurrence had BM as first recurrence event. Conversely, There was a total of 7/286 (2.4%) BM events without other in the non-pCR group, the majority recurrence events were extracranial sites of disease in the pCR group, and 5/240 (2%) in distant relapse with extra-cranial sites of disease. A reasonable the non-pCR group after a median follow-up of 3.2 years. We did explanation of the predominance of brain relapse in patients who not observe any meaningful visual differences in the cumulative achieve pCR, could be that anti-HER2 antibodies currently used in incidence curves for BM for the two groups (Fig. 2). Among overall early stage are extremely active to clear the extracranial BM events (n = 14), 12 occurred as a first event of recurrence. In compartments from micro-metastatic disease, inducing a selec- the pCR group the totality of patients developed BM as first events tion of resistant clones with brain tropism. Patients with residual of recurrence, while in the non-pCR group 2 patients had BM as disease may have a more resistant and heterogeneous disease second event. The median time to development BM observed in with more variable clonal selection. npj Breast Cancer (2022) 37 Published in partnership with the Breast Cancer Research Foundation 1234567890():,; E. Ferraro et al. Table 1. Patients’ characteristics. Overall population MSKCC HER2-status confirmed on biopsy (n = 526) (n = 130) pCR n (%) non-pCR n (%) p-value* pCR n (%) non-pCR n (%) p-value* n = 286 (54.4) n = 240 (45.6) n = 77 (59.2) n = 53 (40.7) Median age, years (range 26–82) 50 (24-84) 50 (26-87) 0.078 50 (28-82) 49 (26-76) Menopausal status 0.2 Pre 145 (50.7) 137 (57) 38 (49) 28 (53) Post 141 (49.3) 103 (43) 39 (51) 25 (47) Clinical stage 0.010 I 16 (5.6) 3 (1) 1 (1.3) 36 (68) II 212 (74.2) 173 (72) 58 (75.3) 15 (28) III 58 (20.2) 64 (27) 18 (23.4) 2 (4) Clinical T 0.042 Tx 6 (2) 0 4 (5.2) 0 T1 47 (16.4) 23 (9.6) 6 (7.8) 3 (5.7) T2 171 (59.7) 153 (63.7) 47 (61) 38 (71.8) T3 41(14.3) 44 (18.3) 16 (20.8) 9 (16.9) T4 15 (5.2) 15 (6.3) 3 (3.9) 2 (3.8) T4d 6 (2) 5 (2.1) 1 (1.3) 1 (1.8) Lymph nodes involvement (clinical staging) 114 (39.8) 84 (35) 0.3 27 (35) 19 (35.9) N0 147 (51.5) 128 (53.4) 42 (54.5) 27 (50.9) N1 15 (5.2) 21 (8.7) 6 (7.8) 5 (9.5) N2 10 (3.5) 7 (2.9) 2 (2.7) 2 (3.7) N3 HER2 status on biopsy <0.001 IHC 3+ 268 (94) 164 (68.3) 76 (99) 27 (51) FISH amplified 18 (6) 76 (31.7) 1 (1) 26 (49) HR status on biopsy <0.001 Positive 153(54) 192 (80) 41 (52) 38 (70) Negative 133 (46) 48 (20) 36 (48) 15 (30) Histology on biopsy NA** Ductal 284 (99.3) 236 (98.3) 76 (99) 52 (99) Lobular 2 (0.7) 4 (1.7) 1 (1) 1 (1) Differentiation 0.2 Well/moderated 8 (2.7) 14 (5.8) 6 (8) 13 (24.5) Poorly differentiated 278 (97.3) 226 (94.2) 71 (92) 40 (75.5) NAC regimens 0.4 ACTHP 256 (89.5) 206 (85.8) 69 (90) 48 (90) DCbHP 18 (6.3) 22 (9.2) 3 (4) 2 (4) Other 12 (4.2) 12 (5) 5 (6) 3 (6) Type of breast surgery 0.70 Mastectomy 153(53.5) 134 (55.8) 41 (53) 32 (61) Lumpectomy 131 (45.8) 106 (44.2) 35(45) 21 (39) Axillary dissection*** 2 (0.7) 0 1 (2) 0 Type of axillary surgery <0.001 <0.001 Dissection 20 (7) 85 (35) 9 (12) 22 (42) SNLB 266 (93) 155 (65) 68 (88) 31 (58) Radiation treatment 0.009 Yes 244 (85.3) 223 (92.9) 39 (50.6) 36 (67.9) No 42 (14.7) 17 (7.1) 38 (49.4) 17 (32.1) Adjuvant anti-HER2 therapy HP 283 (99) 227 (94.6) NA 77 (100) 51 (96) HP → neratinib 0 3 (1.3) 0 0 TDM1 0 8 (3.3) 0 1 (2) Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2022) 37 E. Ferraro et al. Table 1 continued Overall population MSKCC HER2-status confirmed on biopsy (n = 526) (n = 130) pCR n (%) non-pCR n (%) p-value* pCR n (%) non-pCR n (%) p-value* n = 286 (54.4) n = 240 (45.6) n = 77 (59.2) n = 53 (40.7) H 3 (1) 2 (0.8) 1 (2) Adjuvant endocrine treatment HR+= 153 HR+= 192 NA HR+= 41 HR+= 38 AI 62 (40.5) 93 (48.4) 20 (48.7) 24 (63.2) TAM 61 (39.8) 54 (28.2) 15 (36.6) 10 (26.3) AI + LHRH 14 (9.2) 31 (16.2) 1 (2.4) 0 TAM + LHRH 1 (0.7) 7 (3.6) 0 0 No ET**** 15 (9.8) 7(3.6) 5 (12.3) 4 (10.5) Bold values indicates statistically significant p values < 0.05. L line, NAC neoadjuvant chemotherapy, ACTHP doxorubicin, cyclophosphamide, paclitaxel; trastuzumab; pertuzumab; HT hormonotherapy, DCbHP docetaxel, carboplatin, trastuzumab, pertuzumab, HR hormone receptor, AI aromatase inhibitors, TAM tamoxifen, T primary tumor, NA not applicable. *Statistical tests performed: chi-square test of independence; t-test. **NA due to small sample sizes in a category. ***In cases of Tx, the patients received just axillary dissection. These cases are not included in the statistical analysis because all the cases are related to the pCR group. ****No ET: patients with HR-positive tumors who did not receive endocrine treatments due to decline or clinical decision in case of low-ER and PR expression Table 2. Disease-free survival events: pCR versus non-pCR patients. CNS Met, no pCR CNS Met, pCR Overall population MSKCC HER2-status Non−CNS Event, no pCR Non−CNS Event, pCR (n = 526) (n = 130) pCR non-pCR pCR non-pCR n = 286 n = 240 Tot: 77 Tot: 53 DFS events 14 22 8 5 Locoregional 43 4 0 recurrence Breast 1 2 1 — Regional 2 — 2 — lymph nodes DCIS 1 1 1 — Distant recurrence 917 4 5 Brain only 7 5 3 2 Visceral disease 1 7 1 2 Non-visceral disease 1 5 0 1 Death* 12 0 0 Years from Surgery *death without prior recurrence events. Fig. 2 Cumulative incidence of CNS recurrence events stratified pCR pathological complete response, DCIS ductal carcinoma in situ. by pCR versus non-pCR. The continuous lines represent the estimated incidence of CNS events and the dashed lines the incidence of non-CNS events in non-pCR (red lines) and pCR group (blue lines), respectively. Additionally, the combination of chemotherapy and HP was associated with pCR rate of 54% and excellent survival outcome outcomes than those with non-pCR, most notably in those with compared with patients who did not achieve pCR, consistently HER2-positive hormone receptor-negative and triple negative 10–13 19,20 with literature data . Patients with HR-negative tumors and diseases . In our study, the similar BM rates between pCR and HER2 IHC 3+ were more likely to achieve pCR, as previously non-pCR groups suggest that effective therapies that cross the reported by investigators at our institution . These data were blood brain barrier are needed. Our data is consistent with the confirmed in the subgroup of patients with HER2 status results of the APHINITY trial that showed similar BM rate in the HP performed at MSKCC, suggesting reliability of the HER2 status and standard arm of 1.9% and 1.8%, respectively. of our entire population. As expected, a statistically significant In addition, there appears to be no association between NAC difference in terms of 3-year DFS and OS was observed in favor response and BM event rates although the absolute number of of the pCR group. events in our population is too small to draw conclusion. Notably, Currently, HP dual blockade plus chemotherapy has become a pooled analysis of GeparQuinto and GeparSixto , which the standard of care in patients with early stage HER2- positive included both early HER2-positive BC treated with trastuzumab BC . Several trials have demonstrated that the combination of HP or lapatinib based-regimes and triple negative tumors, showed with standard chemotherapy, can lead to a pCR rate of about 11,16–18 similar conclusions. BM as first site of metastatic disease occurred 60% . At individual level, patients with pCR have better npj Breast Cancer (2022) 37 Published in partnership with the Breast Cancer Research Foundation Cumulative Incidence of Events 0.00 0.05 0.10 0.15 0.20 0.25 0.30 E. Ferraro et al. Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2022) 37 Table 3. Description of patients with brain metastases. a b Age (yrs) Clinical stage HR status Time to BM Symptoms Brain as first site of Need of N of lesions as Local Systemic Time to 1° CNS recurrence (Y/N) hospitalization (Y/N) first BM event Treatment treatment POD or death pCR 61 cT2 N0 + 44 mo seizures and Y Y 1 Surgery Cape/Lap 19 mo visual changes and SRT 40 cT2 N1 + 35 mo cephalgia and Y Y 1 Surgery Cape/Lap 12 mo vomiting and SRT 36 cT3N2 + 14 mo ataxia, aphasia Y Y > 10 WBRT BSC 6 mo and fatigue 49 cT1N3 − 4 mo cephalgia Y Y 3 WBRT HP 2 mo 48 cT4N1 + 11 mo vertigo Y Y > 10 WBRT Cape/Lap 10 mo and nausea 66 cT4N1 + 18 mo ataxia Y N > 10 proton CSI Cape/Lap 11mo 55 cT4N1 + 19 mo aphasia Y Y 2 SRT HP NR Non-pCR 44 cT2 N3 + 15 mo ataxia Y N 1 Surgery LET +H4mo and SRT 47 cT4d N1 − 9 mo facial drop Y N 2 SRS HP 16 mo 61 cT2N1 + 19 mo ataxia Y Y 1 Surgery ANA +H7mo and SRT 48 cT4N1 − 17 mo seizures Y Y 2 Surgery Cape/Lap NR and SRT 52 cT3N1 − 6 mo vertigo Y Y 1 Surgery BSC 2 mo and SRT 47 cT3N0 + 55 mo nausea N Y 2 SRS TH 10 mo 44 cT4N2 − 14 mo cephalgia N Y > 10 WBRT THP 5 mo pCR pathological complete response, yrs years, mo months, BM brain metastases, HR hormone receptors, (+):ER and/or PR > 1%, (−): ER and/or PR < 1%, CNS central nervous system, POD progression of disease, H trastuzumab, HP trastuzumab and pertuzumab, Cape capecitabine, T paclitaxel, Lap lapatinib, ANA anastrozole, LET letrozole, SRT stereotactic radiotherapy, SRS stereotactic radiosurgery, NA not applicable, NR not reached, BSC best supportive care, WBRT whole brain radiation, proton CSI proton cranio-spinal irradiation. Age at the time of brain progression. Brain metastases symptoms suggesting need of brain radiological assessment. Need of hospitalization for the management of neurological symptoms at the time BM relapse. BM have been discovered one month after the extracranial disease (liver/chest wall). E. Ferraro et al. metastatic disease. More recently, tucatinib, a new TKI has demonstrated activity on BMs in patients with advanced pretreated HER2-positive BC and it has been FDA approved. In the phase I study , the combination of tucatinib and ado- trastuzumab emtansine led to 36% of response in BM lesions. The study of Tucatinib vs. Placebo in Combination With Capecitabine and Trastuzumab in Patients With Advanced HER2 + Breast Cancer (HER2CLIMB trial) , showed a benefit in terms of progression-free survival (PFS) and OS in patients who received tucatinib in combination with trastuzumab and capecitabine. In patients with BMs, the estimated PFS at 1 year was 24.9% (95% CI, 16.5 to 34.3) in the tucatinib-combination arm and 0% in the placebo arm. Additionally, the reported CNS-PFS was 9.9 months in the tucatinib arm versus 4.2 months in the control arm with a reduction of the risk of death by 42% in the tucatinib arm (HR: 0.58) . These data are particularly relevant, because BM still represent a source of morbidity and mortality in patients with Fig. 3 Disease-free survival stratified in pCR versus non-pCR HER2-positive BC. Indeed, with incremental improvement with groups. The red and blue curves show the estimated disease-free survival of the patients in the non-pCR group and pCR group, modern systemic treatment in reducing breast cancer recur- respectively. rences, the management of BM has become an essential component of disease control and quality of life of patients. In the treatment of early stage disease, new escalating approaches 6,9,22 have not been associated with a decrease in BMs . Clinical trials in early-stage setting should explore novel drugs and strategies that may impact on BM recurrence, including with an exploratory focus on detection of BMs in asymptomatic patients. In our cohort, patients who achieved pCR, despite the better overall outcome, seem to be still at risk of brain recurrence and for this reason, they could benefit from escalating post-neoadjuvant treatment with new TKIs as well as non-pCR patients. Moving forward, trials exploring early detection of BMs in patients with early BC could help to optimize the management of brain recurrence. To date no radiological screening is recommended by 33 34 ASCO and NCCN guidelines and potential benefit of early detection of asymptomatic BM is being explored in advanced setting (NCT03881605, NCT04030507, NCT03617341). To our knowledge, this is the first sizeable analysis of patients treated with HP-based therapy, off-study, in neoadjuvant setting Fig. 4 Overall survival stratified in pCR versus non-pCR groups. with a focus on BM recurrence. However, the study has several The red and blue curves show the estimated overall survival of the limitations including the retrospective nature, the single center patients in the non-pCR group and pCR group, respectively. setting, along with a modest number of BM events. We await a longer follow-up to see if the rate of BM increases over time in the more frequently than other distant metastases in patients with the two groups. Additionally, only a few patients with residual disease pCR (15% vs 9%), suggesting no correlation between response to received T-DM1 as adjuvant treatment, as most of the patients NAC and BM recurrence. were on adjuvant treatment before the approval of T-DM1 by the The rate of BM reported in our study was consistent with the Food and Drug Administration in this setting. The strength of our rates registered in controlled prospective trials in early stage. For 22 study is that it includes a large cohort of patients who received HP instance, in the KATHERINE trial , testing trastuzumab-DM1 based- NAC, with more than 90% receiving dose-dense AC-THP. (T-DM1) in the post-neoadjuvant setting for patients with non- Despite the inclusion of a large proportion of patients with pCR, the incidence of BM after 3-years of follow-up was 5.9% and external HER2 status, the analyses on the subgroup with MSKCC- 4.3% in patients who received T-DM1 and trastuzumab, respec- verified HER2 positivity were similar for the entire population. tively. T-DM1 as well as other anti-HER2 agents approved in the 23–27 Furthermore, this study provides a valid evidence about the treatment of early-stage BC including trastuzumab and incidence of brain recurrence after HP given preoperatively and neratinib appear to have no impact on the risk of CNS recurrence. continued after surgery. Indeed, neoadjuvant prospective trials did In the ExteNET trial , patients were treated with adjuvant not report the BM event rates separately from extra-cranial distant trastuzumab alone or sequential neratinib for one year. Regardless 35–37 recurrence events . of the assigned therapy in the trial, the rate of CNS recurrence We reported for the first time the incidence of brain recurrence was 1% in each arm, after a median follow-up of 5.2 years. in patients with pCR versus non-pCR after HP combined with Nevertheless, a recent unplanned subgroup analysis showed a chemotherapy, that seems to be not associated with response to decreased cumulative incidence of BM in neratinib arm compared NAC. However, a longer follow-up is awaited to confirm these to placebo arm in a subset of hormone receptor positive, HER2 results. Our findings support the investigation of new molecules positive BC patients who started neratinib ≤1 year from the end of 28 29 with high CNS bioavailability in early stage HER2-positive BC in adjuvant trastuzumab .With regards to lapatinib, ALTTO and order to evaluate a possible role of these agents to prevent brain NEOALTTO studies showed that lapatinib alone or in combina- recurrence. Research on specific biomarkers of CNS seeding is tion with trastuzumab in adjuvant and neoadjuvant setting did not reduce the rate of brain recurrence. crucial to better select the population that might benefit from an Due to the low CNS penetrance, bioavailability or activity of the escalating post-neoadjuvant treatment. Current data do not approved anti-HER2 compounds, the brain is a sanctuary for support pCR being one of those biomarkers. npj Breast Cancer (2022) 37 Published in partnership with the Breast Cancer Research Foundation E. Ferraro et al. METHODS patient privacy but can be made available for non-commercial use only and on reasonable request from the corresponding author. For the data sharing, an Patients’ selection agreement with the corresponding author about data usage is required. We reviewed the medical records of consecutive early stage HER2-positive breast cancer patients from the hospital cancer registry at Memorial Sloan Received: 17 March 2021; Accepted: 1 November 2021; Kettering Cancer Center (MSKCC), between September 1, 2013 to November 1, 2019. Follow-up data were obtained until June 30, 2020. We included patients with HER2-positive breast cancer who received HP in the neoadjuvant setting. Trastuzumab and pertuzumab were administered in combination with standard chemotherapy and for at least one cycle before surgery. Surgery was performed within 6 weeks after NAC. Adjuvant REFERENCES treatments, including endocrine therapy and anti-HER2 therapy, were offered 1. Lin, N. U. & Winer, E. P. Brain metastases: The HER2 paradigm. Clin. Cancer Res. 13, according to physician’s choice. Radiotherapy (RT) was offered as per 1648–1655 (2007). standard of care. HER2 positivity was defined according to ASCO-CAP 38,39 2. Kallioniemi, O. P. et al. 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Pertuzumab plus trastuzumab in combination with stan- Objectives dard neoadjuvant anthracycline-containing and anthracycline-free chemother- The primary endpoint is the incidence of BM when it was first site of apy regimens in patients with HER2-positive early breast cancer: a randomized relapse in pCR and non-CR group. The pCR was defined as absence of phase II cardiac safety study (TRYPHAENA). Ann. Oncol. 24, 2278–2284 (2013). residual invasive carcinoma in breast and axilla (ypT0/is ypN0). Disease free 12. Loibl, S. et al. Dual HER2-blockade with pertuzumab and trastuzumab in HER2- survival (DFS) and overall survival (OS) are secondary endpoints. DFS is positive early breast cancer: a subanalysis of data from the randomized phase III defined as the interval between the date of surgery and date of any breast GeparSepto trial. Ann. Oncol. 28, 497–504 (2017). 13. Swain, S. M. et al. Risk of recurrence and death in patients with early HER2-positive disease event, date of death from any cause, or, in case of non evidence of breast cancer who achieve a pathological complete response after different types disease (NED), date of last follow-up. Breast disease events included loco- of HER2-targeted therapy: a retrospective exploratory analysis. SABCS Meet. (2018). regional recurrence (ipsilateral breast recurrence of invasive carcinoma, 14. Krystel-Whittemore, M., Xu, J. & Brogi, E. Pathologic complete response rate regional-nodal recurrence, contralateral invasive breast cancer and DCIS) according to HER2 detection methods in HER2 positive breast cancer treated and distant recurrence (both CNS and non-CNS). OS, defined as the interval with neoadjuvant systemic therapy. Breast Cancer Res Treat. 177,61–66 (2019). between diagnosis date and date of death from any cause or if alive, date 15. Gradishar, W. J. et al. Breast Cancer, Version 3.2020, NCCN Clinical Practice of last follow-up, was also evaluated. Guidelines in Oncology. J. Natl. Compr. Canc. Netw. 18, 452–478 (2020). 16. Mette S, vanRamshorst et al. Neoadjuvant chemotherapy with or without Statistical analysis anthracyclines in the presence of dual HER2 blockade for HER2-positive breast The incidence of BM was estimated using the cumulative incidence cancer (TRAIN-2): a multicentre, open-label, randomised, phase 3 trial. Lancet 41 42 function and compared by pCR status using the Gray test . DFS and OS Oncol. 19, 1630–1640 (2018). were analyzed using the Kaplan-Meier method and differences assessed 17. Swain, S. M. et al. Pertuzumab, trastuzumab, and standard anthracycline- and using the log-rank test. Differences between clinicopathological features and taxane-based chemotherapy for the neoadjuvant treatment of patients with pCR status was evaluated using chi-square test and t-test. Any p-value less HER2-positive localized breast cancer (BERENICE): a phase II, open-label, multi- than 0.05 was deemed to be statistically significant. In a sensitivity analysis, all center, multinational cardiac safety study. Ann. Oncol. 29, 646–653 (2018). analyses were done on the whole population (N= 526) and on the subgroup 18. Hurvitz, S. A. et al. Neoadjuvant trastuzumab, pertuzumab, and chemotherapy of patients who had a verified HER2 status at MSKCC (N= 130). versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 19, 115–126 (2018). Reporting summary 19. Patricia, Cortazar et al. Pathological complete response and long-term clinical Further information on research design is available in the Nature Research benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 384,164–172 (2014). Reporting Summary linked to this article. 20. Spring, L. M. et al. Pathological complete response after neoadjuvant chemotherapy and impact on breast cancer recurrence and survival: a comprehensive meta- analysis. Clin. Cancer Res. (2020) https://doi.org/10.1158/1078-0432.ccr-19-3492. DATA AVAILABILITY 21. Laakmann, E. et al. Development of central nervous system metastases as a first site of metastatic disease in breast cancer patients treated in the neoadjuvant All data analyzed in this study are included in this manuscript. The data supporting trials GeparQuinto and GeparSixto. Breast Cancer Res. 21,1–8 (2019). Table 1 as well as MRI imaging data are not publicly available in order to protect Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2022) 37 E. Ferraro et al. 22. Von Minckwitz, G. et al. Trastuzumab emtansine for residual invasive HER2- ACKNOWLEDGEMENTS positive breast cancer. N. Engl. J. Med. 380, 617–628 (2019). E.F. is funded by the 2019–2020 American-Italian Cancer Foundation Post-Doctoral 23. Romond, E. H. et al. Trastuzumab plus adjuvant chemotherapy for operable HER2- Fellowship. positive breast cancer. N. Engl. J. Med. 353, 1673–1684 (2005). 24. Martine J., Piccart-Gebhart et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer martine. N. Engl. J. Med. 353, 225–237 (2005). AUTHOR CONTRIBUTIONS 25. Spielmann, M. et al. Trastuzumab for patients with axillary-node-positive breast E.F., C.T.D. and J.S. conceived the study. R.P. and S.P. contributed to the study design. cancer: results of the FNCLCC-PACS 04 trial. J. Clin. Oncol. 27,6129–6134 A.V.B. provided materials. E.F. and J.S. collected clinicopathological data. S.P. (2009). performed the statistical analysis. E.F., C.T., J.S., R.P. and S.P. drafted the manuscript. 26. Olson, E. M. et al. Incidence and risk of central nervous system metastases as site C.T.D., M.R., S.C., S.M., A.V.B., R.M., I.K.M., A.B., H.Y.W., E.B., A.D.S. and L.N. provided a of first recurrence in patients with HER2-positive breast cancer treated with critical interpretation of data. All authors reviewed the manuscript and provided the adjuvant trastuzumab. Ann. Oncol. 24, 1526–1533 (2013). final approval. E.F. and J.S. contributed equally to this work. 27. Yin, W. et al. Trastuzumab in the adjuvant treatment of HER2-positive early breast cancer patients: a meta-analysis of published randomized controlled trials. PLoS ONE 6, e21030 (2011). COMPETING INTERESTS 28. Chan, A. et al. Final efficacy results of neratinib in HER2-positive hormone P.R. received speakers’ bureau and consultancy/advisory role from Novartis, Foundation receptor-positive early-stage breast cancer from the phase III ExteNET trial. Clin. Medicine, AstraZeneca, Epic Sciences, Inivata, Natera, Tempus and contracted research Breast Cancer 21,80–91.e7 (2021). funding from Grail, Illumina, Novartis, Epic, Sciences, ArcherDx. S.M. received research 29. Piccart-Gebhart, M. et al. Adjuvant lapatinib and trastuzumab for early human support from Genentech, Daiichi-Sankyo, Astrazeneca, Seattle Genetics; speakers bureau epidermal growth factor receptor 2-positive breast cancer: Results From the from Genentech, Daiichi-Sankyo, Astrazeneca, Seattle Genetics; advisory honoraria form randomized phase III adjuvant lapatinib and/or trastuzumab treatment optimi- Macrogenics, Daiichi-Sankyo, Astrazeneca, Seattle Genetics. S.C. received contracted zation trial. J. Clin. Oncol. 34, 1034–1042 (2016). research funding from Daiichi-Sankyo, Paige.ai, Novartis, Sanofi, Lilly. A.B received a role 30. De Azambuja, E. et al. Lapatinib with trastuzumab for HER2-positive early breast in the scientific Advisory Board of Evren Scientific (unpaid); patents: Sloan Kettering cancer (NeoALTTO): Survival outcomes of a randomised, open-label, multicentre, Institute, assignee for the following United States Provisional Applications: No.: 62/ phase 3 trial and their association with pathological complete response. Lancet 258,044. November 20, 2015, No.: 10413522, awarded September 17, 2019 and No.: 63/ Oncol. 15, 1137–1146 (2014). 052,139. A.D.S received honoraria as speaker and consultant from Genentech. M.E.R 31. Borges, V. F. et al. Tucatinib combined with ado-Trastuzumab emtansine in received honoraria from Research to Practice, Intellisphere and physicians’ Education advanced ERBB2/HER2-positive metastatic breast cancer: a Phase 1b Clinical Trial. Resource, consulting or advisory role from AstraZeneca (uncompensated), Change JAMA Oncol. 4, 1214–1220 (2018). Healthcare, Daiichi-Sankyo (uncompensated), Epic Sciences (uncompensated), Merck 32. Lin, N. U. et al. Intracranial efficacy and survival with tucatinib plus trastuzumab (uncompensated), Pfizer (uncompensated) and research funding from AbbVie (institu- and capecitabine for previously treated HER2-positive breast cancer with brain tion), AstraZeneca (Institution), Invitae (Institution, in-kind), Merck (Institution) and Pfizer metastases in the HER2CLIMB trial. J. Clin. Oncol. 38, 2610–2619 (2020). (Institution). C.T.D received research funding and personal fees from Genentech/Roche 33. Ramakrishna, N. et al. Recommendations on disease management for patients and Puma Technology. The remaining authors declare no competing interests. with advanced human epidermal growth factor receptor 2–positive breast cancer and brain metastases: ASCO clinical practice guideline update. J. Clin. Oncol. 36, 2804–2807 (2018). 34. Gradishar, W. J. et al. NCCN Clinical Practice Guidelines on Oncology- Breast ADDITIONAL INFORMATION cancer. vol. version 3. (2020). Supplementary information The online version contains supplementary material 35. Gianni, L. et al. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in available at https://doi.org/10.1038/s41523-022-00380-7. patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Correspondence and requests for materials should be addressed to Chau T. Dang. Oncol. 17, 791–800 (2016). 36. Schneeweiss, A. et al. Long-term efficacy analysis of the randomised, phase II Reprints and permission information is available at http://www.nature.com/ TRYPHAENA cardiac safety study: Evaluating pertuzumab and trastuzumab plus reprints standard neoadjuvant anthracycline-containing and anthracycline-free che- motherapy regimens in patients with HER2-positive ea. Eur. J. Cancer 89,27–35 Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims (2018). in published maps and institutional affiliations. 37. Hurvitz, S. A. 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. 37, 2206–2216 (2019). Open Access This article is licensed under a Creative Commons 38. Wolff, A. C. et al. Recommendations for human epidermal growth factor receptor Attribution 4.0 International License, which permits use, sharing, 2 testing in breast. J. Clin. Oncol. 31, 3997–4013 (2013). adaptation, distribution and reproduction in any medium or format, as long as you give 39. Wolff, A. C. et al. Human epidermal growth factor receptor 2 testing in breast appropriate credit to the original author(s) and the source, provide a link to the Creative cancer: American Society of Clinical Oncology/College of American Pathologists Commons license, and indicate if changes were made. The images or other third party Clinical Practice Guideline Focused Update. Arch. Pathol. Lab. Med. 142, 1364–1382 material in this article are included in the article’s Creative Commons license, unless (2018). indicated otherwise in a credit line to the material. If material is not included in the 40. Allison, K. H. et al. Estrogen and progesterone receptor testing in breast cancer: article’s Creative Commons license and your intended use is not permitted by statutory ASCO/CAP guideline update. J. Clin. Oncol. 38, 1346–1366 (2020). regulation or exceeds the permitted use, you will need to obtain permission directly 41. Kalbfleisch, J. D. & Prentice, R. L. The Statistical Analysis of Failure Time Data. 2nd from the copyright holder. To view a copy of this license, visit http://creativecommons. Edition, John Wiley and Sons, New York. https://doi.org/10.1002/9781118032985. org/licenses/by/4.0/. (2002). 42. Gray, R. J. A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann. Stat. 16, 1141–1154 (1988). © The Author(s) 2022 npj Breast Cancer (2022) 37 Published in partnership with the Breast Cancer Research Foundation http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png npj Breast Cancer Springer Journals

Incidence of brain metastases in patients with early HER2-positive breast cancer receiving neoadjuvant chemotherapy with trastuzumab and pertuzumab

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www.nature.com/npjbcancer ARTICLE OPEN Incidence of brain metastases in patients with early HER2-positive breast cancer receiving neoadjuvant chemotherapy with trastuzumab and pertuzumab 1,8 1,8 7 2 2 2 3 Emanuela Ferraro , Jasmeet Singh , Sujata Patil , Pedram Razavi , Shanu Modi , Sarat Chandarlapaty , Andrea V. Barrio , 4 5 5 6 6 2 2 Rachna Malani , Ingo K. Mellinghoff , Adrienne Boire , Hannah Y. Wen , Edi Brogi , Andrew D. Seidman , Larry Norton , 2 2 Mark E. Robson and Chau T. Dang The addition of pertuzumab (P) to trastuzumab (H) and neoadjuvant chemotherapy (NAC) has decreased the risk of distant recurrence in early stage HER2-positive breast cancer. The incidence of brain metastases (BM) in patients who achieved pathological complete response (pCR) versus those who do not is unknown. In this study, we sought the incidence of BM in patients receiving HP-containing NAC as well as survival outcome. We reviewed the medical records of 526 early stage HER2- positive patients treated with an HP-based regimen at Memorial Sloan Kettering Cancer Center (MSKCC), between September 1, 2013 to November 1, 2019. The primary endpoint was to estimate the cumulative incidence of BM in pCR versus non-pCR patients; secondary endpoints included disease free-survival (DFS) and overall survival (OS). After a median follow-up of 3.2 years, 7 out of 286 patients with pCR had a BM while 5 out of 240 non-pCR patients had a BM. The 3-year DFS was significantly higher in the pCR group compared to non-pCR group (95% vs 91 %, p = 0.03) and the same trend was observed for overall survival. In our cohort, despite the better survival outcomes of patients who achieved pCR, we did not observe appreciable differences in the incidence of BM by pCR/non-pCR status. This finding suggests that the BM incidence could not be associated with pCR. Future trials with new small molecules able to cross the blood brain barrier should use more specific biomarkers rather than pCR for patients’ selection. npj Breast Cancer (2022) 8:37 ; https://doi.org/10.1038/s41523-022-00380-7 INTRODUCTION and chemotherapy in HER2-positive BC has resulted in an improvement of pathologic complete response (pCR) rate after Central nervous system (CNS) is a common site of distant NAC . Currently, the rate of BM and the predictive role of pCR on recurrence that affects prognosis and quality of life of HER2- the risk of CNS seeding is unknown in patients receiving double positive breast cancer (BC) patients . The reported cumulative blockade with trastuzumab and pertuzumab (HP) in preoperative incidence of brain metastases (BM) in HER2 positive BC is higher setting. The interest in understanding the incidence of CNS than in other subtypes suggesting that HER2 positive cancer cells 2,3 recurrence in a real-life population arises from the necessity to have a specific tropism for the CNS . The advent of different anti- shape new strategies to reduce the risk of BM in patients with HER2 agents and the implementation of local approaches such as early-stage BC. The aim of this study was to assess the incidence of stereotactic radiosurgery (SRS) has significantly improved the BM in patients receiving HP-containing NAC and to compare rates prognosis of HER2- positive BC patients with BM. However, BM still of BM stratified by pCR status. presents multiple challenges for optimal management, especially in the scenario of progression despite loco-regional therapies. New oral HER2 tyrosine kinase inhibitors (TKIs) including neratinib RESULTS and tucatinib, have demonstrated CNS activity, and have been Study population recently approved by Food and Drug Administration (FDA) in 4,5 metastatic setting . In early stage, neratinib is currently approved Overall, 533 patients with stage I-III HER2 positive breast cancer as single agent after trastuzumab-based adjuvant therapy and treated with NAC followed by surgery at MSKCC were identified. tucatinib is still under investigation in high-risk patients in Cases with a concomitant HER2 negative BC (n = 4) and combination with T-DM1 (NCT04457596). discordant HER2 status (internal versus external) (n = 3) were In stages I-III BC, the CNS recurrence rate is reported around excluded. Among the study population (n = 526), 130 patients 2–4% of patients receiving trastuzumab and/or pertuzumab- had preoperative HER2 status confirmed at MSKCC (Fig. 1). All based adjuvant treatments as first site of recurrence in a follow-up clinicopathological features are described in Table 1.ApCRwas 7–9 range of 3–5 years . Few studies have reported the rate of BM in achieved in 286/526 (54.4%) of cases, whereas 240/526 (45.6%) early-stage breast cancer patients treated with neoadjuvant had residual disease. The majority of the patients (278/286, 97% chemotherapy (NAC). The addition of pertuzumab to trastuzumab in pCR and 226/240, 94% in non-pCR group) had a poorly 1 2 Breast Cancer Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Breast Cancer Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medicine College, New York, NY, USA. Breast Cancer Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, 4 5 NY, USA. Brain Tumor Center, Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Brain Tumor Center, Human Oncology and Pathogenesis Program, Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, 7 8 NY, USA. Present address: Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA. These authors contributed equally: Emanuela Ferraro, Jasmeet Singh. email: dangc@mskcc.org Published in partnership with the Breast Cancer Research Foundation 1234567890():,; E. Ferraro et al. Fig. 1 Diagram of patients’ selection. This schema represents a consort diagram of the study and provides the patients selection based on HER2 status on biopsy and response to neoadjuvant treatment (pCR versus non-pCR). Notes: HER2+: HER2-positive, HER2−: HER2-negative, pts: patients; BC: breast cancer; bx: biopsy. differentiated breast carcinoma. The clinical stage II was the our population was 19 (range 4–58) months and 6.5 (range 6.5–17) prevalent stage at the time of diagnosis (74% and 72% in pCR months in the pCR and non-pCR group, respectively. and non-pCR groups, respectively). In both groups, most of Most of the patients had one or two brain lesions in both pCR patients received dose dense chemotherapy with doxorubicin/ and non-pCR groups, who underwent surgical resection followed cyclophosphamide followed by paclitaxel plus HP (AC-THP) as by stereotactic radiation of the tumoral bed or radiosurgery NAC (90% vs 86% in pCR and non-pCR respectively). alone. Whole brain radiation was delivered to 3 patients in the Anthracycline-free therapy with docetaxel, carboplatin plus HP pCR group and in 1 patient in the non-pCR group. One patient of (DCbHP regimen) was administered in less than 10% of cases, in the pCR group and one of the non-pCR group had an extensive both groups. A minority of patients received vinorelbine and disease with severe symptoms that did not improve after local gemcitabine, when taxane was contraindicated (Table 1). treatment. The majority of the patients received a first line Patients who achieved pCR compared to those did not, had systemic treatment for metastatic disease, except for two patients more frequently HR negative tumors (46% vs 20% P < 0.001) and who continued adjuvant HP after the local treatment (Table 3). more often had HER2 overexpression by IHC (3 + ) (94% vs 68%, The baseline characteristic of patients who developed brain BM P < 0.001). In the pCR group, the proportion of patients who were homogeneous regardless the pCR status. Eleven out of 14 received axillary dissection was lower than in the non-pCR group patients had clinical stage III disease while 3/14 stage II. In the (7% vs 35% P < 0.001). These results were consistent between pCR group, 5/7 patients had HR + /HER2 + disease while 3/7 overall patients and the subset of patients with HER2 status on patients in the non-pCR group. Only 2 patients in the pCR group pre-NAC biopsy verified at MSKCC (Table 1). and 5 patients in the non-pCR group had HR-HER2 + disease at the time of diagnosis. Disease-free survival events Survival outcomes After a median follow-up of 3.2 years (range 0.4–5.5), 36 DFS events occurred in the study population, 14 in the pCR group and Regarding survival outcomes, the 3-year DFS was 91% (95% CI 22 in the non-pCR group (Table 2). Among pCR patients with 87–95%) in the non-pCR group and 95% (95% CI 92–98%) in the pCR group (p = 0.03). The 3-years OS was 95% (95% CI 92–98) in recurrences, 4/14 had locoregional recurrence, 9/14 had distant the non-pCR group and 98% (95% CI 97–100) in the pCR group recurrence of which 7 had only BM, 1 visceral metastasis (lung) (log-rank p = 0.02) (Figs. 3 and 4). and 1 non-visceral metastasis (thoracic lymph nodes). One patient in the pCR group died of unknown cause. The loco-regional breast disease events included 2 contralateral breast cancer, 1 ipsilateral DISCUSSION lymph nodal, 1 invasive breast cancer and 1 DCIS relapses. In our cohort, the absolute rate of BM was similar between pCR Conversely, almost the totality (17/22) of DFS events of the non- and non-pCR patients, 2.4% and 2%, respectively, with the pCR group were distant relapse with 7/22 patients with visceral median follow-up of 3.2 years. The median time of BM relapse recurrence in the liver and adrenal glands, 5/22 skin and lymph was 19 versus 6.5 months in patients with pCR versus non-pCR, nodes recurrence and 5/22 with a brain only recurrence. respectively. Notably, in the pCR group, 30% of DFS events were local recurrence and almost the totality of patients with Brain metastases incidence distance recurrence had BM as first recurrence event. Conversely, There was a total of 7/286 (2.4%) BM events without other in the non-pCR group, the majority recurrence events were extracranial sites of disease in the pCR group, and 5/240 (2%) in distant relapse with extra-cranial sites of disease. A reasonable the non-pCR group after a median follow-up of 3.2 years. We did explanation of the predominance of brain relapse in patients who not observe any meaningful visual differences in the cumulative achieve pCR, could be that anti-HER2 antibodies currently used in incidence curves for BM for the two groups (Fig. 2). Among overall early stage are extremely active to clear the extracranial BM events (n = 14), 12 occurred as a first event of recurrence. In compartments from micro-metastatic disease, inducing a selec- the pCR group the totality of patients developed BM as first events tion of resistant clones with brain tropism. Patients with residual of recurrence, while in the non-pCR group 2 patients had BM as disease may have a more resistant and heterogeneous disease second event. The median time to development BM observed in with more variable clonal selection. npj Breast Cancer (2022) 37 Published in partnership with the Breast Cancer Research Foundation 1234567890():,; E. Ferraro et al. Table 1. Patients’ characteristics. Overall population MSKCC HER2-status confirmed on biopsy (n = 526) (n = 130) pCR n (%) non-pCR n (%) p-value* pCR n (%) non-pCR n (%) p-value* n = 286 (54.4) n = 240 (45.6) n = 77 (59.2) n = 53 (40.7) Median age, years (range 26–82) 50 (24-84) 50 (26-87) 0.078 50 (28-82) 49 (26-76) Menopausal status 0.2 Pre 145 (50.7) 137 (57) 38 (49) 28 (53) Post 141 (49.3) 103 (43) 39 (51) 25 (47) Clinical stage 0.010 I 16 (5.6) 3 (1) 1 (1.3) 36 (68) II 212 (74.2) 173 (72) 58 (75.3) 15 (28) III 58 (20.2) 64 (27) 18 (23.4) 2 (4) Clinical T 0.042 Tx 6 (2) 0 4 (5.2) 0 T1 47 (16.4) 23 (9.6) 6 (7.8) 3 (5.7) T2 171 (59.7) 153 (63.7) 47 (61) 38 (71.8) T3 41(14.3) 44 (18.3) 16 (20.8) 9 (16.9) T4 15 (5.2) 15 (6.3) 3 (3.9) 2 (3.8) T4d 6 (2) 5 (2.1) 1 (1.3) 1 (1.8) Lymph nodes involvement (clinical staging) 114 (39.8) 84 (35) 0.3 27 (35) 19 (35.9) N0 147 (51.5) 128 (53.4) 42 (54.5) 27 (50.9) N1 15 (5.2) 21 (8.7) 6 (7.8) 5 (9.5) N2 10 (3.5) 7 (2.9) 2 (2.7) 2 (3.7) N3 HER2 status on biopsy <0.001 IHC 3+ 268 (94) 164 (68.3) 76 (99) 27 (51) FISH amplified 18 (6) 76 (31.7) 1 (1) 26 (49) HR status on biopsy <0.001 Positive 153(54) 192 (80) 41 (52) 38 (70) Negative 133 (46) 48 (20) 36 (48) 15 (30) Histology on biopsy NA** Ductal 284 (99.3) 236 (98.3) 76 (99) 52 (99) Lobular 2 (0.7) 4 (1.7) 1 (1) 1 (1) Differentiation 0.2 Well/moderated 8 (2.7) 14 (5.8) 6 (8) 13 (24.5) Poorly differentiated 278 (97.3) 226 (94.2) 71 (92) 40 (75.5) NAC regimens 0.4 ACTHP 256 (89.5) 206 (85.8) 69 (90) 48 (90) DCbHP 18 (6.3) 22 (9.2) 3 (4) 2 (4) Other 12 (4.2) 12 (5) 5 (6) 3 (6) Type of breast surgery 0.70 Mastectomy 153(53.5) 134 (55.8) 41 (53) 32 (61) Lumpectomy 131 (45.8) 106 (44.2) 35(45) 21 (39) Axillary dissection*** 2 (0.7) 0 1 (2) 0 Type of axillary surgery <0.001 <0.001 Dissection 20 (7) 85 (35) 9 (12) 22 (42) SNLB 266 (93) 155 (65) 68 (88) 31 (58) Radiation treatment 0.009 Yes 244 (85.3) 223 (92.9) 39 (50.6) 36 (67.9) No 42 (14.7) 17 (7.1) 38 (49.4) 17 (32.1) Adjuvant anti-HER2 therapy HP 283 (99) 227 (94.6) NA 77 (100) 51 (96) HP → neratinib 0 3 (1.3) 0 0 TDM1 0 8 (3.3) 0 1 (2) Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2022) 37 E. Ferraro et al. Table 1 continued Overall population MSKCC HER2-status confirmed on biopsy (n = 526) (n = 130) pCR n (%) non-pCR n (%) p-value* pCR n (%) non-pCR n (%) p-value* n = 286 (54.4) n = 240 (45.6) n = 77 (59.2) n = 53 (40.7) H 3 (1) 2 (0.8) 1 (2) Adjuvant endocrine treatment HR+= 153 HR+= 192 NA HR+= 41 HR+= 38 AI 62 (40.5) 93 (48.4) 20 (48.7) 24 (63.2) TAM 61 (39.8) 54 (28.2) 15 (36.6) 10 (26.3) AI + LHRH 14 (9.2) 31 (16.2) 1 (2.4) 0 TAM + LHRH 1 (0.7) 7 (3.6) 0 0 No ET**** 15 (9.8) 7(3.6) 5 (12.3) 4 (10.5) Bold values indicates statistically significant p values < 0.05. L line, NAC neoadjuvant chemotherapy, ACTHP doxorubicin, cyclophosphamide, paclitaxel; trastuzumab; pertuzumab; HT hormonotherapy, DCbHP docetaxel, carboplatin, trastuzumab, pertuzumab, HR hormone receptor, AI aromatase inhibitors, TAM tamoxifen, T primary tumor, NA not applicable. *Statistical tests performed: chi-square test of independence; t-test. **NA due to small sample sizes in a category. ***In cases of Tx, the patients received just axillary dissection. These cases are not included in the statistical analysis because all the cases are related to the pCR group. ****No ET: patients with HR-positive tumors who did not receive endocrine treatments due to decline or clinical decision in case of low-ER and PR expression Table 2. Disease-free survival events: pCR versus non-pCR patients. CNS Met, no pCR CNS Met, pCR Overall population MSKCC HER2-status Non−CNS Event, no pCR Non−CNS Event, pCR (n = 526) (n = 130) pCR non-pCR pCR non-pCR n = 286 n = 240 Tot: 77 Tot: 53 DFS events 14 22 8 5 Locoregional 43 4 0 recurrence Breast 1 2 1 — Regional 2 — 2 — lymph nodes DCIS 1 1 1 — Distant recurrence 917 4 5 Brain only 7 5 3 2 Visceral disease 1 7 1 2 Non-visceral disease 1 5 0 1 Death* 12 0 0 Years from Surgery *death without prior recurrence events. Fig. 2 Cumulative incidence of CNS recurrence events stratified pCR pathological complete response, DCIS ductal carcinoma in situ. by pCR versus non-pCR. The continuous lines represent the estimated incidence of CNS events and the dashed lines the incidence of non-CNS events in non-pCR (red lines) and pCR group (blue lines), respectively. Additionally, the combination of chemotherapy and HP was associated with pCR rate of 54% and excellent survival outcome outcomes than those with non-pCR, most notably in those with compared with patients who did not achieve pCR, consistently HER2-positive hormone receptor-negative and triple negative 10–13 19,20 with literature data . Patients with HR-negative tumors and diseases . In our study, the similar BM rates between pCR and HER2 IHC 3+ were more likely to achieve pCR, as previously non-pCR groups suggest that effective therapies that cross the reported by investigators at our institution . These data were blood brain barrier are needed. Our data is consistent with the confirmed in the subgroup of patients with HER2 status results of the APHINITY trial that showed similar BM rate in the HP performed at MSKCC, suggesting reliability of the HER2 status and standard arm of 1.9% and 1.8%, respectively. of our entire population. As expected, a statistically significant In addition, there appears to be no association between NAC difference in terms of 3-year DFS and OS was observed in favor response and BM event rates although the absolute number of of the pCR group. events in our population is too small to draw conclusion. Notably, Currently, HP dual blockade plus chemotherapy has become a pooled analysis of GeparQuinto and GeparSixto , which the standard of care in patients with early stage HER2- positive included both early HER2-positive BC treated with trastuzumab BC . Several trials have demonstrated that the combination of HP or lapatinib based-regimes and triple negative tumors, showed with standard chemotherapy, can lead to a pCR rate of about 11,16–18 similar conclusions. BM as first site of metastatic disease occurred 60% . At individual level, patients with pCR have better npj Breast Cancer (2022) 37 Published in partnership with the Breast Cancer Research Foundation Cumulative Incidence of Events 0.00 0.05 0.10 0.15 0.20 0.25 0.30 E. Ferraro et al. Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2022) 37 Table 3. Description of patients with brain metastases. a b Age (yrs) Clinical stage HR status Time to BM Symptoms Brain as first site of Need of N of lesions as Local Systemic Time to 1° CNS recurrence (Y/N) hospitalization (Y/N) first BM event Treatment treatment POD or death pCR 61 cT2 N0 + 44 mo seizures and Y Y 1 Surgery Cape/Lap 19 mo visual changes and SRT 40 cT2 N1 + 35 mo cephalgia and Y Y 1 Surgery Cape/Lap 12 mo vomiting and SRT 36 cT3N2 + 14 mo ataxia, aphasia Y Y > 10 WBRT BSC 6 mo and fatigue 49 cT1N3 − 4 mo cephalgia Y Y 3 WBRT HP 2 mo 48 cT4N1 + 11 mo vertigo Y Y > 10 WBRT Cape/Lap 10 mo and nausea 66 cT4N1 + 18 mo ataxia Y N > 10 proton CSI Cape/Lap 11mo 55 cT4N1 + 19 mo aphasia Y Y 2 SRT HP NR Non-pCR 44 cT2 N3 + 15 mo ataxia Y N 1 Surgery LET +H4mo and SRT 47 cT4d N1 − 9 mo facial drop Y N 2 SRS HP 16 mo 61 cT2N1 + 19 mo ataxia Y Y 1 Surgery ANA +H7mo and SRT 48 cT4N1 − 17 mo seizures Y Y 2 Surgery Cape/Lap NR and SRT 52 cT3N1 − 6 mo vertigo Y Y 1 Surgery BSC 2 mo and SRT 47 cT3N0 + 55 mo nausea N Y 2 SRS TH 10 mo 44 cT4N2 − 14 mo cephalgia N Y > 10 WBRT THP 5 mo pCR pathological complete response, yrs years, mo months, BM brain metastases, HR hormone receptors, (+):ER and/or PR > 1%, (−): ER and/or PR < 1%, CNS central nervous system, POD progression of disease, H trastuzumab, HP trastuzumab and pertuzumab, Cape capecitabine, T paclitaxel, Lap lapatinib, ANA anastrozole, LET letrozole, SRT stereotactic radiotherapy, SRS stereotactic radiosurgery, NA not applicable, NR not reached, BSC best supportive care, WBRT whole brain radiation, proton CSI proton cranio-spinal irradiation. Age at the time of brain progression. Brain metastases symptoms suggesting need of brain radiological assessment. Need of hospitalization for the management of neurological symptoms at the time BM relapse. BM have been discovered one month after the extracranial disease (liver/chest wall). E. Ferraro et al. metastatic disease. More recently, tucatinib, a new TKI has demonstrated activity on BMs in patients with advanced pretreated HER2-positive BC and it has been FDA approved. In the phase I study , the combination of tucatinib and ado- trastuzumab emtansine led to 36% of response in BM lesions. The study of Tucatinib vs. Placebo in Combination With Capecitabine and Trastuzumab in Patients With Advanced HER2 + Breast Cancer (HER2CLIMB trial) , showed a benefit in terms of progression-free survival (PFS) and OS in patients who received tucatinib in combination with trastuzumab and capecitabine. In patients with BMs, the estimated PFS at 1 year was 24.9% (95% CI, 16.5 to 34.3) in the tucatinib-combination arm and 0% in the placebo arm. Additionally, the reported CNS-PFS was 9.9 months in the tucatinib arm versus 4.2 months in the control arm with a reduction of the risk of death by 42% in the tucatinib arm (HR: 0.58) . These data are particularly relevant, because BM still represent a source of morbidity and mortality in patients with Fig. 3 Disease-free survival stratified in pCR versus non-pCR HER2-positive BC. Indeed, with incremental improvement with groups. The red and blue curves show the estimated disease-free survival of the patients in the non-pCR group and pCR group, modern systemic treatment in reducing breast cancer recur- respectively. rences, the management of BM has become an essential component of disease control and quality of life of patients. In the treatment of early stage disease, new escalating approaches 6,9,22 have not been associated with a decrease in BMs . Clinical trials in early-stage setting should explore novel drugs and strategies that may impact on BM recurrence, including with an exploratory focus on detection of BMs in asymptomatic patients. In our cohort, patients who achieved pCR, despite the better overall outcome, seem to be still at risk of brain recurrence and for this reason, they could benefit from escalating post-neoadjuvant treatment with new TKIs as well as non-pCR patients. Moving forward, trials exploring early detection of BMs in patients with early BC could help to optimize the management of brain recurrence. To date no radiological screening is recommended by 33 34 ASCO and NCCN guidelines and potential benefit of early detection of asymptomatic BM is being explored in advanced setting (NCT03881605, NCT04030507, NCT03617341). To our knowledge, this is the first sizeable analysis of patients treated with HP-based therapy, off-study, in neoadjuvant setting Fig. 4 Overall survival stratified in pCR versus non-pCR groups. with a focus on BM recurrence. However, the study has several The red and blue curves show the estimated overall survival of the limitations including the retrospective nature, the single center patients in the non-pCR group and pCR group, respectively. setting, along with a modest number of BM events. We await a longer follow-up to see if the rate of BM increases over time in the more frequently than other distant metastases in patients with the two groups. Additionally, only a few patients with residual disease pCR (15% vs 9%), suggesting no correlation between response to received T-DM1 as adjuvant treatment, as most of the patients NAC and BM recurrence. were on adjuvant treatment before the approval of T-DM1 by the The rate of BM reported in our study was consistent with the Food and Drug Administration in this setting. The strength of our rates registered in controlled prospective trials in early stage. For 22 study is that it includes a large cohort of patients who received HP instance, in the KATHERINE trial , testing trastuzumab-DM1 based- NAC, with more than 90% receiving dose-dense AC-THP. (T-DM1) in the post-neoadjuvant setting for patients with non- Despite the inclusion of a large proportion of patients with pCR, the incidence of BM after 3-years of follow-up was 5.9% and external HER2 status, the analyses on the subgroup with MSKCC- 4.3% in patients who received T-DM1 and trastuzumab, respec- verified HER2 positivity were similar for the entire population. tively. T-DM1 as well as other anti-HER2 agents approved in the 23–27 Furthermore, this study provides a valid evidence about the treatment of early-stage BC including trastuzumab and incidence of brain recurrence after HP given preoperatively and neratinib appear to have no impact on the risk of CNS recurrence. continued after surgery. Indeed, neoadjuvant prospective trials did In the ExteNET trial , patients were treated with adjuvant not report the BM event rates separately from extra-cranial distant trastuzumab alone or sequential neratinib for one year. Regardless 35–37 recurrence events . of the assigned therapy in the trial, the rate of CNS recurrence We reported for the first time the incidence of brain recurrence was 1% in each arm, after a median follow-up of 5.2 years. in patients with pCR versus non-pCR after HP combined with Nevertheless, a recent unplanned subgroup analysis showed a chemotherapy, that seems to be not associated with response to decreased cumulative incidence of BM in neratinib arm compared NAC. However, a longer follow-up is awaited to confirm these to placebo arm in a subset of hormone receptor positive, HER2 results. Our findings support the investigation of new molecules positive BC patients who started neratinib ≤1 year from the end of 28 29 with high CNS bioavailability in early stage HER2-positive BC in adjuvant trastuzumab .With regards to lapatinib, ALTTO and order to evaluate a possible role of these agents to prevent brain NEOALTTO studies showed that lapatinib alone or in combina- recurrence. Research on specific biomarkers of CNS seeding is tion with trastuzumab in adjuvant and neoadjuvant setting did not reduce the rate of brain recurrence. crucial to better select the population that might benefit from an Due to the low CNS penetrance, bioavailability or activity of the escalating post-neoadjuvant treatment. Current data do not approved anti-HER2 compounds, the brain is a sanctuary for support pCR being one of those biomarkers. npj Breast Cancer (2022) 37 Published in partnership with the Breast Cancer Research Foundation E. Ferraro et al. METHODS patient privacy but can be made available for non-commercial use only and on reasonable request from the corresponding author. For the data sharing, an Patients’ selection agreement with the corresponding author about data usage is required. We reviewed the medical records of consecutive early stage HER2-positive breast cancer patients from the hospital cancer registry at Memorial Sloan Received: 17 March 2021; Accepted: 1 November 2021; Kettering Cancer Center (MSKCC), between September 1, 2013 to November 1, 2019. Follow-up data were obtained until June 30, 2020. We included patients with HER2-positive breast cancer who received HP in the neoadjuvant setting. Trastuzumab and pertuzumab were administered in combination with standard chemotherapy and for at least one cycle before surgery. Surgery was performed within 6 weeks after NAC. Adjuvant REFERENCES treatments, including endocrine therapy and anti-HER2 therapy, were offered 1. Lin, N. U. & Winer, E. P. Brain metastases: The HER2 paradigm. Clin. Cancer Res. 13, according to physician’s choice. Radiotherapy (RT) was offered as per 1648–1655 (2007). standard of care. HER2 positivity was defined according to ASCO-CAP 38,39 2. Kallioniemi, O. P. et al. 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Pathological complete response after neoadjuvant chemotherapy and impact on breast cancer recurrence and survival: a comprehensive meta- analysis. Clin. Cancer Res. (2020) https://doi.org/10.1158/1078-0432.ccr-19-3492. DATA AVAILABILITY 21. Laakmann, E. et al. Development of central nervous system metastases as a first site of metastatic disease in breast cancer patients treated in the neoadjuvant All data analyzed in this study are included in this manuscript. The data supporting trials GeparQuinto and GeparSixto. Breast Cancer Res. 21,1–8 (2019). Table 1 as well as MRI imaging data are not publicly available in order to protect Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2022) 37 E. Ferraro et al. 22. Von Minckwitz, G. et al. Trastuzumab emtansine for residual invasive HER2- ACKNOWLEDGEMENTS positive breast cancer. N. Engl. J. Med. 380, 617–628 (2019). E.F. is funded by the 2019–2020 American-Italian Cancer Foundation Post-Doctoral 23. Romond, E. H. et al. Trastuzumab plus adjuvant chemotherapy for operable HER2- Fellowship. positive breast cancer. N. Engl. J. Med. 353, 1673–1684 (2005). 24. Martine J., Piccart-Gebhart et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer martine. N. Engl. J. Med. 353, 225–237 (2005). AUTHOR CONTRIBUTIONS 25. Spielmann, M. et al. Trastuzumab for patients with axillary-node-positive breast E.F., C.T.D. and J.S. conceived the study. R.P. and S.P. contributed to the study design. cancer: results of the FNCLCC-PACS 04 trial. J. Clin. Oncol. 27,6129–6134 A.V.B. provided materials. E.F. and J.S. collected clinicopathological data. S.P. (2009). performed the statistical analysis. E.F., C.T., J.S., R.P. and S.P. drafted the manuscript. 26. Olson, E. M. et al. Incidence and risk of central nervous system metastases as site C.T.D., M.R., S.C., S.M., A.V.B., R.M., I.K.M., A.B., H.Y.W., E.B., A.D.S. and L.N. provided a of first recurrence in patients with HER2-positive breast cancer treated with critical interpretation of data. All authors reviewed the manuscript and provided the adjuvant trastuzumab. Ann. Oncol. 24, 1526–1533 (2013). final approval. E.F. and J.S. contributed equally to this work. 27. Yin, W. et al. Trastuzumab in the adjuvant treatment of HER2-positive early breast cancer patients: a meta-analysis of published randomized controlled trials. PLoS ONE 6, e21030 (2011). COMPETING INTERESTS 28. Chan, A. et al. Final efficacy results of neratinib in HER2-positive hormone P.R. received speakers’ bureau and consultancy/advisory role from Novartis, Foundation receptor-positive early-stage breast cancer from the phase III ExteNET trial. Clin. Medicine, AstraZeneca, Epic Sciences, Inivata, Natera, Tempus and contracted research Breast Cancer 21,80–91.e7 (2021). funding from Grail, Illumina, Novartis, Epic, Sciences, ArcherDx. S.M. received research 29. Piccart-Gebhart, M. et al. Adjuvant lapatinib and trastuzumab for early human support from Genentech, Daiichi-Sankyo, Astrazeneca, Seattle Genetics; speakers bureau epidermal growth factor receptor 2-positive breast cancer: Results From the from Genentech, Daiichi-Sankyo, Astrazeneca, Seattle Genetics; advisory honoraria form randomized phase III adjuvant lapatinib and/or trastuzumab treatment optimi- Macrogenics, Daiichi-Sankyo, Astrazeneca, Seattle Genetics. S.C. received contracted zation trial. J. Clin. Oncol. 34, 1034–1042 (2016). research funding from Daiichi-Sankyo, Paige.ai, Novartis, Sanofi, Lilly. A.B received a role 30. De Azambuja, E. et al. Lapatinib with trastuzumab for HER2-positive early breast in the scientific Advisory Board of Evren Scientific (unpaid); patents: Sloan Kettering cancer (NeoALTTO): Survival outcomes of a randomised, open-label, multicentre, Institute, assignee for the following United States Provisional Applications: No.: 62/ phase 3 trial and their association with pathological complete response. Lancet 258,044. November 20, 2015, No.: 10413522, awarded September 17, 2019 and No.: 63/ Oncol. 15, 1137–1146 (2014). 052,139. A.D.S received honoraria as speaker and consultant from Genentech. M.E.R 31. Borges, V. F. et al. Tucatinib combined with ado-Trastuzumab emtansine in received honoraria from Research to Practice, Intellisphere and physicians’ Education advanced ERBB2/HER2-positive metastatic breast cancer: a Phase 1b Clinical Trial. Resource, consulting or advisory role from AstraZeneca (uncompensated), Change JAMA Oncol. 4, 1214–1220 (2018). Healthcare, Daiichi-Sankyo (uncompensated), Epic Sciences (uncompensated), Merck 32. Lin, N. U. et al. Intracranial efficacy and survival with tucatinib plus trastuzumab (uncompensated), Pfizer (uncompensated) and research funding from AbbVie (institu- and capecitabine for previously treated HER2-positive breast cancer with brain tion), AstraZeneca (Institution), Invitae (Institution, in-kind), Merck (Institution) and Pfizer metastases in the HER2CLIMB trial. J. Clin. Oncol. 38, 2610–2619 (2020). (Institution). C.T.D received research funding and personal fees from Genentech/Roche 33. Ramakrishna, N. et al. Recommendations on disease management for patients and Puma Technology. The remaining authors declare no competing interests. with advanced human epidermal growth factor receptor 2–positive breast cancer and brain metastases: ASCO clinical practice guideline update. J. Clin. Oncol. 36, 2804–2807 (2018). 34. Gradishar, W. J. et al. NCCN Clinical Practice Guidelines on Oncology- Breast ADDITIONAL INFORMATION cancer. vol. version 3. (2020). Supplementary information The online version contains supplementary material 35. Gianni, L. et al. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in available at https://doi.org/10.1038/s41523-022-00380-7. patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Correspondence and requests for materials should be addressed to Chau T. Dang. Oncol. 17, 791–800 (2016). 36. Schneeweiss, A. et al. Long-term efficacy analysis of the randomised, phase II Reprints and permission information is available at http://www.nature.com/ TRYPHAENA cardiac safety study: Evaluating pertuzumab and trastuzumab plus reprints standard neoadjuvant anthracycline-containing and anthracycline-free che- motherapy regimens in patients with HER2-positive ea. Eur. J. Cancer 89,27–35 Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims (2018). in published maps and institutional affiliations. 37. Hurvitz, S. A. 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. 37, 2206–2216 (2019). Open Access This article is licensed under a Creative Commons 38. Wolff, A. C. et al. Recommendations for human epidermal growth factor receptor Attribution 4.0 International License, which permits use, sharing, 2 testing in breast. J. Clin. Oncol. 31, 3997–4013 (2013). adaptation, distribution and reproduction in any medium or format, as long as you give 39. Wolff, A. C. et al. Human epidermal growth factor receptor 2 testing in breast appropriate credit to the original author(s) and the source, provide a link to the Creative cancer: American Society of Clinical Oncology/College of American Pathologists Commons license, and indicate if changes were made. The images or other third party Clinical Practice Guideline Focused Update. Arch. Pathol. Lab. Med. 142, 1364–1382 material in this article are included in the article’s Creative Commons license, unless (2018). indicated otherwise in a credit line to the material. If material is not included in the 40. Allison, K. H. et al. Estrogen and progesterone receptor testing in breast cancer: article’s Creative Commons license and your intended use is not permitted by statutory ASCO/CAP guideline update. J. Clin. Oncol. 38, 1346–1366 (2020). regulation or exceeds the permitted use, you will need to obtain permission directly 41. Kalbfleisch, J. D. & Prentice, R. L. The Statistical Analysis of Failure Time Data. 2nd from the copyright holder. To view a copy of this license, visit http://creativecommons. Edition, John Wiley and Sons, New York. https://doi.org/10.1002/9781118032985. org/licenses/by/4.0/. (2002). 42. Gray, R. J. A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann. Stat. 16, 1141–1154 (1988). © The Author(s) 2022 npj Breast Cancer (2022) 37 Published in partnership with the Breast Cancer Research Foundation

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