The total cohort was 594 patients. 499 (84%) of patients had external HER2 testing done on their breast biopsy prior to receiving NAST at MSKCC. 456 (77%) and 138 (23%) received antracycline-taxane and taxane based chemotherapy, respectively, during NAST. Overall, 587 (99%) received trastuzumab and pertuzumab (HP) and 7 (1%) received trastuzumab alone. NAST was completed by 563 (95%) of patients. Baseline patient characteristics are summarized in [Table 1].
Table 1 - Baseline patient characteristics
|
Total cohort (n = 594)
|
Median age (IQR) - yrs
|
54 (41 – 59)
|
Female sex – n (%)
|
590 (99.3)
|
Race or ethnic group - n (%)
White
Black
Asian
Other
Unknown
|
375 (63.1)
81 (13.6)
90 (15.2)
22 (3.7)
26 (4.4)
|
Menopausal status - n (%)
Pre
Post
|
313 (53)
277 (47)
|
Histology - n (%)
IDC
ILC
Mixed IDC and ILC
Other
|
565 (95.1)
22 (3.7)
4 (0.7)
3 (0.5)
|
Tumor grade - n (%)
1
2
3
|
2 (0.3)
129 (21.7)
463 (77.9)
|
Clinical stage - n (%)
I
II
III
|
13 (2.2)
473 (79.6)
108 (18.2)
|
Pre op HR status - n (%)
Positive
Negative
|
407 (68.5)
187 (31.5)
|
Pre op HER2 status - n (%)
IHC 0-1+, FISH amplified
IHC 2+, FISH amplified
IHC 3+
|
7 (1.1)
135 (22.7)
452 (76.1)
|
NACT received
AC-THP
DCbHP
THP
Other
|
450 (75.8)
72 (12.1)
59 (9.9)
13 (2.2)
|
Abbreviations: Doxorubicin/Cyclophosphamide-Paclitaxel/Trastuzumab/Pertuzumab (AC-THP); Docetaxel/Carboplatin/Trastuzumab/Pertuzumab (DCbHP); Hormone receptor (HR); Fluorescence in situ hybridisation (FISH); Human epidermal growth factor receptor 2 (HER2); Immunohistochemistry (IHC); Interquartile range (IQR); Invasive ductal carcinoma (IDC); Invasive lobular carcinoma (ILC); Neoadjuvant systemic therapy (NAST); Number (n); Paclitaxel/Trastuzumab/Pertuzumab (THP). Percentages may not total 100 because of rounding.
In 594 patients, pCR (ypT0/isN0) was achieved in 325 (55%) and RD was seen in 269 (45%) patients. In 269 patients with RD, 45 (17%) did not have HER2 retesting and were excluded from the final analysis. This was mainly due to insufficient residual tissue for retesting or if the initial breast biopsy had HER2 testing done internally at our center. In the remaining 224 patients, 143 (64%) retained HER2(+) and 81 (36%) were HER2(-) [Figure 1]. The 81 patients with HER2(-) RD had pre op HER2 status of IHC 0/FISH amplified, 1+/FISH amplified, IHC 2+/FISH amplified and IHC 3+ in 1 (1%), 4 (5%), 38 (47%) and 38 (47%) respectively. Postoperatively, the 81 patients with HER2(-) RD were IHC 0, 1+ and 2+/FISH non amplified in 21 (26%), 42 (52%) and 18 (22%) patients respectively; 69 (85%) were HR(+) and 12 (15%) were HR(-).
For the 325 patients who achieved pCR, 295 (91%) successfully completed a year of HER2 targeted therapy with HP. Cardiotoxicity and early recurrence were the main reason for those who discontinued with 9 (2.8%) having symptomatic left ventricular ejection fraction (LVEF) decline, 5 (1.5%) having asymptomatic LVEF decline and 2 (0.6%) having early recurrence. In the 143 patients with HER2(+) RD, adjuvant T-DM1, HP, trastuzumab alone and no HER2 directed therapy were initiated in 121 (85%), 16 (11%), 1 (1%) and 5 (3%) of patients, respectively. In the 81 patients with HER2(-) RD, adjuvant T-DM1, HP, trastuzumab alone and no HER2 directed therapy were initiated in 45 (56%), 27 (33%), 3 (4%) and 6 (7%) of patients, respectively.
Out of the 224 patients with HER2 tested RD, 166 (74%) received T-DM1. In the 166 patients who received T-DM1, 124 (75%) completed the full course of therapy, 30 (18%) discontinued T-DM1 but completed a full year of HER2 targeted therapy with (27 received HP and 3 received trastuzumab alone) and 12 (7%) discontinued T-DM1 with no further HER2 targeted therapy.
Toxicity was the main reason for the patients who discontinued T-DM1 (39/42), with peripheral neuropathy, fatigue and cardiotoxicity being the most common toxicity in 23 (59%), 7 (18%) and 4 (10%) of patients respectively. The adjuvant therapies received by patients with RD are summarized in [Table 2]. The update of the KATHERINE trial regarding outcomes of adjuvant T-DM1 in HER2(-) RD patients was published in Sept 2022 [7], and thus this knowledge would not have been available during the treatment timeframe of our cohort.
Table 2 - Adjuvant therapies for patients with residual disease
|
HER2(+) RD (n = 143)
|
HER2(-) RD (n=81)
|
Adj HER2 targeted therapy - n (%)
T-DM1
HP
H
Not received
|
121 (84.6)
16 (11.2)
1 (0.6)
5 (3.5)
|
45 (55.6)
27 (33.3)
3 (3.7)
6 (7.4)
|
Reason for not receiving adj T-DM1 - n (%)
Patient declined
ypT1aN0 or ypT1miN0 RD
Unsure of benefit in HER2(-) RD
Prior toxicity from NAST
Prolonged surgical complications
Short interval recurrence
|
11 (7.8)
5 (3.5)
NA
5 (3.5)
NA
1 (0.7)
|
13 (16)
9 (11.1)
7 (8.6)
5 (6.1)
1 (1.2)
1 (1.2)
|
Endocrine therapy - n (%)
AI
AI + LHRH
Tamoxifen
Tamoxifen + LHRH
None
|
50 (34.9)
31 (21.6)
30 (20.9)
4 (2.7)
28 (19.5)
|
33 (40.7)
20 (24.7)
13 (16.1)
1 (1.2)
14 (17.3)
|
Bone modulating agents - n (%)
Zoledronic acid
Denosumab
None
|
9 (6.3)
2 (1.4)
132 (92.3)
|
5 (6.1)
2 (2.5)
74 (91.4)
|
Abbreviations: Adjuvant (adj), Aromatase inhibitors (AI); Human epidermal growth factor receptor 2 (HER2); Luteinizing hormone releasing hormone (LHRH); Neoadjuvant systemic therapy (NAST); Not applicable (NA); Number (n); Residual disease (RD); Trastuzumab (H); Trastuzumab emtansine (T-DM1); Trastuzumab/Pertuzumab (HP). Percentages may not total 100 because of rounding.
Table 3 – Description of patients who developed brain metastases
Age at BM development (years)
|
Clinical stage
|
Pathological stage
|
Metastatic biopsy HR status
|
Metastatic biopsy HER2 status
|
Time to BM development from breast surgery (months)
|
Initial metastatic sites
|
Number of BM
|
1st local therapy
|
1st systemic therapy
|
60
|
IIIC
cT1N3
|
pCR, ypT0N0
|
+
|
IHC 3+
|
2
|
Brain only
|
4
|
Surgery and SRS
|
Tucatinib/ Capecitabine/ Trastuzumab
|
52
|
IIIB cT4N1
|
pCR, ypT0N0
|
NA
|
NA
|
14
|
Brain only
|
4
|
SRS
|
Tucatinib/ Capecitabine/ Trastuzumab
|
56
|
IIIB cT4N0
|
pCR, ypT0N0
|
NA
|
NA
|
21
|
Brain only
|
>10
|
WBRT
|
Tucatinib/ Capecitabine/ Trastuzumab
|
44
|
IIB cT2N1
|
pCR, ypT0N0
|
+
|
IHC 3+
|
22
|
Brain only
|
7
|
Surgery and SRS
|
Tucatinib/ Capecitabine
|
66
|
IIIB cT4N1
|
IIA ypT1miN1a
|
+
|
IHC 2+, FISH amplified
|
10
|
Brain, lymph nodes, soft tissue
|
2
|
SRS
|
T-DXd
|
37
|
IIIA cT2N2
|
IIB
ypT2N1a
|
+
|
IHC 3+
|
12
|
Brain only
|
1
|
Surgery and SRS
|
AI + OS
|
61
|
IIB cT2N1
|
IA
ypT1aN0
|
-
|
IHC 3+
|
14
|
Brain, Lung
|
1
|
Surgery and SRS
|
T-DXd
|
60
|
IIIA cT3N1
|
IIA
ypT2N0
|
NA
|
NA
|
23
|
Brain only
|
1
|
SRS
|
AI + OS
|
Abbreviations: Aromatase inhibitors (AI); Brain metastases (BM); Human epidermal growth factor receptor 2 (HER2); Immunohistochemistry (IHC); Not applicable (NA); Ovarian suppression (OS); Pathological complete response (pCR); Stereotactic radiosurgery (SRS); Trastuzumab deruxtecan (T-DXd); Whole brain radiotherapy (WBRT)
With a median follow up of 24 months, 8 patients developed BM at initial recurrence, 4/325 (1.2%) with pCR and 4/143 (2.8%) with HER2(+) RD (p = 0.7). None of the patients who developed BM had HER2(-) RD. In the 8 patients who developed BM, all 4 patients with pCR presented with intracranial only disease, while in HER2(+) RD group 2 had both intracranial and extracranial metastases and 2 had intracranial disease alone. First line BM local therapy received included surgery (3 patients), stereotactic radiosurgery (4 patients), and whole brain radiotherapy (1 patient).
IDFS events occurred in 22/594 (3%) patients. In these 22 patients, distant recurrence, locoregional recurrence, contralateral invasive breast cancer and death from other causes occurred in 16 (72%), 1 (5%), 1 (5%) and 4 (18%) patients respectively. Patients with RD had a higher likelihood of having an IDFS event, 14/269 (5.2%) in those with RD and 8/325 (2.5%) in patients with pCR (p = 0.016) [Figure 2]. In the evaluable 224 patients with RD, there was no difference in IDFS between 9/143 (6%) patients with HER2(+) RD or 5/81 (6%) with HER2(-) RD (p = 0.10).
In the 16 patients who developed metastatic disease, 7 had pCR, 7 had HER2(+) RD and 2 had HER2(-) RD. 4/16 patients did not have metastatic biopsy HER2 status assessment due to brain only disease or insufficient tissue for analysis. Of those who had metastatic biopsy HER2 testing, 4 pCR patients all had HER2(+) metastatic disease, 6 HER2(+) RD patients had 4 HER2(+) and 2 HER2(-) metastatic disease and both of the 2 HER2(-) RD patients developed HER2(-) metastatic disease.