The New England journal of medicine 2019-02-14
Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer.
Abstract
Background
Patients who have residual invasive breast cancer after receiving neoadjuvant chemotherapy plus human epidermal growth factor receptor 2 (HER2)-targeted therapy have a worse prognosis than those who have no residual cancer. Trastuzumab emtansine (T-DM1), an antibody-drug conjugate of trastuzumab and the cytotoxic agent emtansine (DM1), a maytansine derivative and microtubule inhibitor, provides benefit in patients with metastatic breast cancer that was previously treated with chemotherapy plus HER2-targeted therapy.
Methods
We conducted a phase 3, open-label trial involving patients with HER2-positive early breast cancer who were found to have residual invasive disease in the breast or axilla at surgery after receiving neoadjuvant therapy containing a taxane (with or without anthracycline) and trastuzumab. Patients were randomly assigned to receive adjuvant T-DM1 or trastuzumab for 14 cycles. The primary end point was invasive disease-free survival (defined as freedom from ipsilateral invasive breast tumor recurrence, ipsilateral locoregional invasive breast cancer recurrence, contralateral invasive breast cancer, distant recurrence, or death from any cause).
Results
At the interim analysis, among 1486 randomly assigned patients (743 in the T-DM1 group and 743 in the trastuzumab group), invasive disease or death had occurred in 91 patients in the T-DM1 group (12.2%) and 165 patients in the trastuzumab group (22.2%). The estimated percentage of patients who were free of invasive disease at 3 years was 88.3% in the T-DM1 group and 77.0% in the trastuzumab group. Invasive disease-free survival was significantly higher in the T-DM1 group than in the trastuzumab group (hazard ratio for invasive disease or death, 0.50; 95% confidence interval, 0.39 to 0.64; P<0.001). Distant recurrence as the first invasive-disease event occurred in 10.5% of patients in the T-DM1 group and 15.9% of those in the trastuzumab group. The safety data were consistent with the known safety profile of T-DM1, with more adverse events associated with T-DM1 than with trastuzumab alone.
Conclusions
Among patients with HER2-positive early breast cancer who had residual invasive disease after completion of neoadjuvant therapy, the risk of recurrence of invasive breast cancer or death was 50% lower with adjuvant T-DM1 than with trastuzumab alone. (Funded by F. Hoffmann-La Roche/Genentech; KATHERINE ClinicalTrials.gov number, NCT01772472 .).
Related Questions
What adjuvant therapy would you recommend for a woman in her 90s with ER-positive, HER2-positive breast cancer who received neoadjuvant trastuzumab, pertuzumab, and anastrozole, but did not achieve a pathologic complete response?
I agree with Dr. @Dr. First Last that the available information is extremely limited. Was the decision to avoid neoadjuvant chemotherapy based solely on age, or were other comorbidities or functional status considerations involved? If she were not a candidate for standard chemotherapy, it is likely ...
What adjuvant systemic therapy would you recommend for a premenopausal woman with a germline BRCA mutation who initially presented with locally advanced, HR+, HER2-negative (FISH) IDC, but was later found on surgical pathology to have HR+, HER2+ disease (IHC 3+) after neoadjuvant chemotherapy?
In a situation like this, I would consider 1 year of adjuvant trastuzumab and pertuzumab. The HERA study showed the benefit of adding trastuzumab after a full course of adjuvant chemotherapy for HER2+ breast cancer, which would provide some (although imperfect) evidence to support such an approach. ...
Would you offer anti-HER2 therapy to a patient found to have heterogenous HER2+ residual disease after original treatment for TNBC using the KEYNOTE-522 regimen?
This is complicated and there isn't a data driven right/wrong answer for this type of situation that I am aware of. Neoadjuvant treatment can cause shifts in biomarker results in residual tumor tissue compared to the pre-treatment specimen. KY-522 didn't do re-testing of residual tumor. I am not rou...
What adjuvant therapy would you offer a post-menopausal CHEK2+ patient with HR+ HER2+ T1bN1 breast cancer and concurrent HR+ HER2- T1N0 disease?
These are hard cases. In general, the HER2 positive disease will take priority. Although it would be ideal to have treated the patient neoadjuvantly to assess response and potentially offer adjuvant TDM-1 per the KATHERINE trial, for now, I would optimize her therapy with adjuvant TCHP for 6 cycles ...
For patients with triple negative breast cancer who are planned to receive adjuvant pembrolizumab, would you recommend pembrolizumab be held until radiation is complete?
This will become a practical issue for radiation oncologists as four drugs are now approved for adjuvant treatment after neoadjuvant chemotherapy including pembro, xeloda, T-DM1, and olaparib. Out of these, olaparib and xeloda were done sequential after radiation as concern about increased side effe...
Would you provide TDM1 or capecitabine for residual disease in HR negative patients with HER2 positivity based on copy number alone?
It is not clear from the question what is meant by "copy number alone." To be HER2 positive by copy number alone is a copy number equal or greater than 6.0 (unless IHC 0 or 1 + with a ratio also < 2.0, in which case the tumor is HER2 negative). If the copy number is between 4 and 6, but the ratio is...
How do you manage trastuzumab emtansine peri-operarively?
T-DM1 hasn't been shown to impair wound healing, etc. The biggest concern would be simple thrombocytopenia, so I just check CBC prior to the surgery and try to have that scheduled and the week 2 or 3 point after treatment where plts are less likely to be affected. I am assuming this question refers ...
What treatment options would you provide a HER2+/HR+ patient with significant residual disease s/p TCHP if they go on to develop severe neuropathy following adjuvant T-DM1 therapy?
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Would you treat an ER/PR+ inflammatory breast cancer that is HER2 2+ by IHC but 5% positive by FISH as HER2 positive?
Yes, because it is inflammatory breast cancer and the standard of care is to include neoadjuvant chemotherapy anyway. In this case, I'd use neoadjuvant TCHP and then retest breast biomarkers at surgery (MRM, with ALND, is standard surgery for inflammatory breast cancer at this time) to see if there ...
Would you offer adjuvant TDM-1 to a patient with residual disease after neoadjuvant treatment for biopsy proven HER2 positive breast cancer, although residual tumor biopsy shows discordance with HER2 negative status?
Yes, I would offer T-DM1 in this case since such patients would have been included in the KATHERINE trial that showed a clear benefit in patients with residual invasive disease, unselected for repeat staining (which is not the standard of care) (1). It is plausible that the HER2 status of residual d...
How would you manage adjuvant treatment of a patient with ER+/PR+/HER2+ breast cancer and a small amount of residual disease (e.g. T1mi) following neoadjuvant TCHP?
The benefit for TDM1 was seen in the subset analysis of KATHERINE patients with residual tumors under 1cm (including T1mic) HR .66 and about a 5% absolute risk reduction. So I agree with @Dr. First Last that switching to TDM1 should be discussed with the patient.
Would you consider adjuvant TDM-1 for a patient with HR+,HER2+ breast cancer with pCR in the breast but N1mic disease post neoaduvant chemotherapy?
The Katherine Trial (NEJM 2019:380;617-280) was a randomized trial of trastuzumab emtansine (TDM-1) versus trastuzumab for patients with residual disease after HER2-directed neoadjuvant treatment. The trial was positive for TDM-1. The randomized patients included those with residual invasive disease...
Would you offer trastuzumab + pertuzumab alone for patients with early stage, HER2+ breast cancer for whom TCHP is clearly indicated but who adamantly refuse any cytotoxic therapy?
Yes, I would use this regimen pre-operatively, since our general process is to use TCHP (or THP) and de-escalate as needed for toxicity for patients with clinical stage T2 or N1 or higher. Here, the "de-escalation" is immediate due to strong patient preference (which of course should be documented)....
What pathologic response criteria do you use to determine the need for further adjuvant therapy in patients with breast cancer?
The question about which response criteria might guide further adjuvant therapy in HR+ disease after neo-adjuvant chemo is of unclear clinical significance currently. Until CDK4/6 inhibitors receive an FDA indication in the adjuvant setting, the only "systemic therapy" decision to be made after neo-...
In a patient with HR+HER2+ early breast cancer who is receiving adjuvant T-DM1 for residual disease, do you overlap endocrine therapy with T-DM1?
Yes, in the KATHERINE trial, endocrine therapy was started concurrent with the T-DM1, same with radiation as indicated. This is included I believe in the published supplement in KATHERINE. So...yes, both endocrine therapy and radiation are fine to start while on T-DM1.
Should neoadjuvant chemotherapy be recommended for HER2+, clinically LN- breast cancer measuring 2-3cm?
For cT2N0 2-3 cm HER2+ tumors I am still doing neoadjuvant dual blockade chemotherapy for eligible patients in order to assess their pCR status. This guides adjuvant therapy per the KATHERINE study. I usually reserve the APT approach for cT1N0 patients who go to surgery first and are still a stage 1...
Do you offer neoadjuvant therapy to a postmenopausal cT1cN0 , HER2+, ER/PR+ breast IDC or recommend surgery first?
This is currently a very controversial topic, with likely no single straight answer - arguments can be made for both a neoadjuvant approach in light of the KATHERINE trial and for a surgery first approach with treatment de-escalation in light of the APT trial. As others have pointed out, the recentl...
How do you approach a stage IIIC triple positive IDC, s/p neoadjuvant TCH and P, lumpectomy, and ALND with significant residual disease at the time of surgery?
I would use adjuvant T-DM1 for residual disease after standard neoadjuvant therapy for HER2+ breast cancer as described in this case. We have strong evidence from the KATHERINE randomized trial that adjuvant T-DM1 compared to trastuzumab that cuts recurrence risk by about 50% in this situation. Whil...
In patients with stage II-III HER2+ breast cancer who were not treated with neoadjuvant therapy, without having knowledge of response to neoadjuvant therapy (i.e. pCR or not) after chemotherapy, what is your preferred adjuvant HER2 directed therapy?
I largely agree with @Dr. First Last. I am also underwhelmed by the APHINITY data and limit TDM-1 to patients with residual disease after neoadjuvant therapy that includes trastuzumab +/- pertuzumab. And, while I am sure that they exist, I have yet to see the patient to whom I would recommend nerati...
Would you recommend adjuvant radiotherapy with concurrent Ado-trastuzumab emtansine (T-DM1) in your breast cancer patients?
In the Katherine trial (von Minckwitz et al. NEJM 2018) 1486 patients with non-metastatic invasive residual HER2+ breast cancer after preoperative chemotherapy were randomized to 14 cycles of trastuzumab or trastuzumab emtasine (T-DM1), an antibody-drug conjugate of trastuzumab and the cytotoxic age...