New Findings Expand Options in Early HER2-Positive Breast Cancer

Joyce A. O’Shaughnessy, MD

Although HER2-positive breast cancer is an aggressive disease historically associated with high relapse and mortality rates, HER2-targeted therapies have revolutionized treatment and led to significantly improved outcomes for many patients.¹ Findings from recently reported studies have helped refine established therapeutic regimens and identify subsets of patients with early-stage disease who would benefit from new approaches, according to a panel of breast cancer experts.

Neoadjuvant Therapy

During a recent OncLive Peer Exchange^®, panel members discussed the use of HER2-targeted therapies in patients with early-stage HER2-positive breast cancer in the neoadjuvant and adjuvant settings. They provided their insights on study results reported during the 2018 San Antonio Breast Cancer Symposium (SABCS) and on developments in the field that have enabled even more women to achieve improved outcomes.AC-THP Versus TCHP

The current standard of care for patients with earlystage HER2-positive breast cancer is neoadjuvant therapy followed by surgery and 1 year of adjuvant therapy, panel members said. Neoadjuvant therapy typically combines a taxane-based chemotherapy with or without an anthracycline with the HER2targeted therapy trastuzumab (Herceptin). In women with tumors >2 cm or with node-positive disease, the cytotoxic agent pertuzumab (Perjeta), which also targets HER2, can be added. Two such commonly used neoadjuvant regimens include AC-THP and TCHP. AC-THP consists of doxorubicin (Adriamycin) and cyclophosphamide followed by paclitaxel (Taxol), trastuzumab, and pertuzumab. The drugs incorporated in the TCHP regimen are docetaxel (Taxotere), carboplatin, trastuzumab, and pertuzumab. The panelists indicated that TCHP tends to be preferred but that the decision should be made after weighing factors such as the adverse-effect profile and the risk of relapse or progression.

“If I have someone I’m worried about regarding the [adverse] effects of anthracyclines, such as cardiotoxicity, my preference would be to use TCHP,” said Aditya Bardia, MD, MPH, noting that a retrospective review at his institution found these regimens to have a similar pathological complete response (pCR) in the neoadjuvant setting. These findings, which were published in December 2018, showed a pCR of 60% with AC-THP and 63% with TCHP.²

Adam M. Brufsky, MD, PhD, said that although he tends to use TCHP almost exclusively in stage II or III breast cancers, he finds AC-THP less toxic overall because the regimen includes paclitaxel, rather than docetaxel. “That’s actually a much milder regimen when you think about it. You don’t really need growth factors,” he said. However, he noted TCHP has become his go-to neoadjuvant therapy because of its high pCR rate, which in his institution’s experience has been “in excess of 75% to 80%” in patients who are estrogen receptor (ER)-negative and HER2-positive.

Tiffany A. Traina, MD, said she favors an anthracycline-based regimen for patients with a higher-risk early-stage disease, such as node-positive disease. “But you have to acknowledge, as Aditya said, a lot of the data look very comparable in terms of benefit and using TCHP,” she said.

Moderator Joyce A. O’Shaughnessy, MD, suggested there may be regional differences in the United States when it comes to use of these treatments. “In the Northeast, there’s a little bit more anthracycline used, perhaps in general, than on the West Coast,” she said.

Achieving Pathological Complete Response

The results of several studies show that patients who achieve a pCR after neoadjuvant treatment have better outcomes. In the CTNeoBC pooled analysis, which reviewed 12 studies and included investigators from the FDA, patients who attained a pCR had improved event-free survival (EFS) and overall survival (OS), with pCR showing the greatest prognostic value in aggressive tumor subtypes such as HER2-positive, hormone receptor (HR)-negative breast cancer and triple-negative breast cancer (TNBC).³ Investigators defined pCR as the absence of invasive and in-situ cancer in the breast and axillary nodes (ypT0 ypN0) or the absence of invasive cancer in the breast irrespective of ductal carcinoma in situ or nodal involvement (ypT0/is ypN0).

During the Peer Exchange, Bardia discussed a follow-up meta-analysis to CTNeoBC, which included 52 neoadjuvant studies and further evaluated the association between pCR and outcomes.⁴ The study included >27,000 patients and provided even more evidence that those who attain a pCR, compared with those who do not, have significantly reduced disease recurrence and a reduced mortality rate. As in the CTNeoBC pooled analysis, the association between pCR and disease-free survival (DFS) was strongest among patients with HER2-positive and TNBCs. “For patients who had a pCR, the [event-free] survival was 88%, and for those who didn’t have a pCR, the [event-free] survival was 67%,” Bardia said. However, he explained that obtaining a pCR is not a guarantee of an improved survival outcome. “The question is, in those who have a pCR, can you add something to move that 88% to 95% or 98%?” he asked.

Adjuvant Therapy

O’Shaughnessy said the addition of endocrine therapy helps improve the DFS rate for patients who are also ER-positive. She proceeded to discuss the multicenter, adaptively randomized I-SPY 2 study, which is using pCR as its primary endpoint to identify neoadjuvant treatment regimens that can improve outcomes across different stage II/III breast cancer subtypes that pose a high risk of early recurrence.⁵ Although the pCR rates varied substantially by breast cancer subtype (Table), those who achieved a pCR had a 94% 3-year EFS rate.⁶ “It was really interesting that [event-free survival] was uniform across subsets [that achieved a pCR],” O’Shaughnessy said. “It certainly is encouraging now that pCR is a very reasonable thing to aim for,” she said, noting her institution uses trastuzumab preoperatively in high-risk patients to help improve pCR rates.KATHERINE Trial

Table. Pathological Complete Response Rates in I-SPY⁶

The standard of care for patients who do not achieve a pCR after neoadjuvant therapy has been identical to that for those who achieve a pCR, which is to continue the same HER2-targeted therapy used in the neoadjuvant setting for 1 year. However, these patients are now known to have worse outcomes than their pCR-achieving counterparts, indicating they might need a different therapeutic approach in the adjuvant setting to optimize their outcomes. Trastuzumab emtansine (T-DM1; Kadcyla) is an antibody—drug conjugate of trastuzumab and the cytotoxic agent emtansine (DM1), a maytansine derivative and microtubule inhibitor. The compound has shown benefit in patients with metastatic breast cancer that was previously treated with chemotherapy plus HER2-targeted therapy. The KATHERINE trial sought to assess whether T-DM1 could also improve outcomes in the adjuvant setting for patients with early-stage HER2-positive breast cancer who do not obtain a pCR following neoadjuvant therapy.^7,8 The trial findings were presented at the 2018 SABCS meeting and generated considerable excitement among the panelists.⁸ “I think this is really some of the hot news that came out of the meeting,” Traina said. In the KATHERINE trial, patients who were found to have residual disease in the breast or axilla following neoadjuvant therapy containing a taxane, with or without an anthracycline, and trastuzumab were randomly assigned to receive 14 cycles of adjuvant therapy with T-DM1 (n = 743) or trastuzumab (n = 743). At 3 years, 88.3% of patients receiving T-DM1 were free of invasive disease compared with 77.0% of those receiving trastuzumab. Distant recurrence as the first invasive-disease event occurred in 10.5% and 15.9% of these patients, respectively.

“I think what was really exciting to see is the group of women who received T-DM1 had a significant improvement in basic disease-free survival—a hazard ratio of 0.5 and an absolute difference of about 11%—favoring switching over to T-DM1 if you fail to achieve a pCR,” Traina said. “What was so interesting was that it was consistent regardless of hormone receptor status,” Heather L. McArthur, MD, MPH, added, noting this is different from what has been historically observed.

“I think you need to keep in mind that these were trastuzumab-resistant cancers and you gave them trastuzumab. So I think it’s not surprising T-DM1 was better. But I think the magnitude was quite remarkable,” Ruth O’Regan, MD, said. However, the OS data are still immature, so it remains to be seen whether T-DM1 will translate to improved survival.

The KATHERINE investigators reported increases in adverse events associated with T-DM1 compared with trastuzumab monotherapy, but these events were consistent with its known safety profile. Brufsky, who participated in another trial that used a T-DM1 regimen, noted some challenges with this regimen. “That was a tough regimen to do. It’s hard to get T-DM1 into somebody every 3 weeks for a year,” he said.

Traina agreed but pointed out that 71% of patients in the KATHERINE trial were nevertheless able to complete the full 14 cycles of T-DM1. Furthermore, most of the patients who stopped T-DM1 early did not stop adjuvant treatment altogether but switched to the historical standard of trastuzumab monotherapy for the remainder of their treatment. “This reminds me of the triple-negative space where you are enriching for a population that’s at higher risk or failed to achieve a pCR and switching therapy shows a benefit,” she said.

Weekly Paclitaxel Plus Trastuzumab

Patients with small (≤3 cm), node-negative HER2-positive breast cancers were excluded from the pivotal trials of adjuvant trastuzumab, yet have been shown to have more than just a minimal risk of disease recurrence, leading to questions on how to improve their outcomes. The single-arm, multicenter, nonrandomized APT study sought to provide some answers by treating 406 patients with such tumors with weekly paclitaxel and trastuzumab for 12 weeks, followed by 9 months of trastuzumab monotherapy.^9,10 At 7 years, 93.3% of patients who were HER2-positive were alive and free from invasive disease, leading the investigators to conclude that paclitaxel plus trastuzumab as adjuvant therapy for node-negative HER2-positive breast cancer reduces the risk of recurrence. In December 2017, the FDA approved pertuzumab in combination with trastuzumab for the adjuvant treatment of HER2-positive early breast cancer at high risk of recurrence based on the APHINITY study.¹¹

Most of the panelists said they consider adjuvant paclitaxel plus trastuzumab for patients with T1b or T1c disease, but not for those with T1a disease, which is consistent with recommendations in the National Comprehensive Cancer Network guidelines.¹² Bardia said he uses endocrine therapy alone for individuals with T1a disease, especially if they are ER-positive. “Taxol—Herceptin is a very good regimen, but there are also potential [adverse] effects with neuropathy…so I think you just have to weigh the potential risk of recurrence with the potential absolute benefit you’ll get for the addition of Taxol plus Herceptin,” he said.

McArthur agreed and emphasized the importance of tailoring recommendations to each individual patient. “I don’t have an absolute cutoff in terms of 5 mm is yes to paclitaxel/trastuzumab and then 4.5 mm is not,” she said. In contrast, O’Shaughnessy said she uses weekly paclitaxel—trastuzumab for 5 years, iDFS was 90.2% and 87.7%, respectively.¹⁴ Based on these findings, in July 2017, the FDA approved neratinib for the extended adjuvant treatment of adult patients with earlystage HER2-overexpressed/amplified breast cancer after they have completed adjuvant trastuzumab-based therapy.¹³ patients with T1a or T1b disease, unless their tumor has more high-risk features due to its size or other characteristics. In such cases, she said she adds in a platinum, usually TCH (docetaxel, carboplatin, and trastuzumab). Additionally, she said she considers administering 4 cycles of TCHP as preoperative therapy for patients with disease. Those who reach a pCR would be finished with therapy, she said, while, “If they’re clinically node-negative, I probably would de-escalate down to the trastuzumab by itself.”

The panelists noted that an ongoing challenge to treatment has been the evolving definition of HER2 positivity. “There are some patients who have HER2 positivity by copy number, perhaps with a little bit of a larger tumor. I don’t know if that’s truly going to be such a HER2-driven disease, and I might be more comfortable using polychemotherapy, rather than relying only on the weekly paclitaxel,” Traina said. O’Regan agreed that treatment decision-making is particularly challenging in such patients. “You don’t want to undertreat a triple-negative disease. I don’t tend to use anthracyclines very much, but that would be the patient where I would consider it,” she said.

Adding Targeted Therapy After Adjuvant Trastuzumab

Brufsky took a slightly different position and expressed concern that too many patients are being overtreated. “For T1c and below, I will give paclitaxel—trastuzumab. I think that’s a reasonable therapy,” he said. He pointed out that the APT trial included patients with tumors up to 3 cm, which is considered T2. “If they have node positivity once we do their lymph node dissection or sentinel dissection, they’ll get TCHP…for anything above T2, I would think about neoadjuvant therapy,” he said.Because some patients relapse after adjuvant therapy, investigators have examined a variety of treatment approaches to further reduce this risk. One such approach was assessed in the phase III, placebo-controlled ExteNET study, which randomly assigned 2840 patients with stage I to III HER2-positive breast cancer to 1 year of the pan-HER tyrosine kinase inhibitor neratinib (n = 1420) or placebo (n = 1420) after they completed their year of adjuvant trastuzumab.¹³

The primary outcome measure was invasive disease-free survival (iDFS). After 2 years, iDFS was 94.2% in the neratinib-treated group versus 91.9% in the placebo-treated group. After 5 years, iDFS was 90.2% and 87.7%, respectively.¹⁴ Based on these findings, in July 2017, the FDA approved neratinib for the extended adjuvant treatment of adult patients with early-stage HER2-overexpressed/amplified breast cancer after they have completed adjuvant trastuzumab-based therapy.¹³

The panelists discussed an ExteNET exploratory subset analysis presented at SABCS of patients with HR-positive tumors who started neratinib within 1 year of completing trastuzumab and obtained no pCR after neoadjuvant therapy.¹⁵ The analysis showed an absolute iDFS benefit of 4.6% with neratinib at 2 years and 7.4% at 5 years.

“If I have a young patient with ER-positive, HER2-positive disease, that is a patient I would consider [treating with] neratinib, even after T-DM1,” Bardia said.

O’Regan concurred, saying she was a big believer in cross-talk between the HER2 and ER pathways. However, she emphasized that there is a subset of ER-positive, HER2-positive cancers that are actually luminal A, a point Brufsky emphasized earlier in the Peer Exchange. Because luminal A tumors are actually HER2-negative, neratinib is unlikely to be beneficial in this setting. Another point the panelists made is that the standard of care had changed by the time neratinib was approved and it is yet unclear whether there will be cross-resistance between neratinib and pertuzumab and T-DM1.

McArthur said time will tell what approach she will take. “We need the experience under our belt, too, to see what patients can actually tolerate, because we are talking about maybe an AC-THP neoadjuvant therapy, and then T-DM1 after that for 14 cycles, and then a year or neratinib. That’s a lot of treatment,” she said.

References

1. Wilson FR, Coombes ME, Brezden-Masley C, et al. Herceptin (trastuzumab) in HER2-positive early breast cancer: a systematic review and cumulative network meta-analysis. Syst Rev. 2018;7(1):191. doi: 10.1186/s13643-018-0854-y.
2. Spring L, Niemierko A, Haddad S, et al. Effectiveness and tolerability of neoadjuvant pertuzumab-containing regimens for HER2-positive localized breast cancer. Breast Cancer Res Treat. 2018;172(3):733-740. doi: 10.1007/s10549-018-4959-8.
3. Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014;384(9938):164-172. doi: 10.1016/S0140-6736(13)62422-8.
4. Spring LM, Fell G, Are A, et al. Pathological complete response after neoadjuvant chemotherapy and impact on breast cancer recurrence and mortality, stratified by breast cancer subtypes and adjuvant chemotherapy usage: individual patient-level meta-analyses of over 27,000 patients. In: Proceedings From the 2018 San Antonio Breast Cancer Symposium (SABCS); December 4-8, 2018; San Antonio, TX. abstracts2view.com/sabcs18/view.php?nu=SABCS18L_1698&terms=.
5. The I-SPY 2 Trial. The I-SPY Trials website. ispytrials.org/i-spy-platform/i-spy2. Accessed January 16, 2018.
6. Yee D, DeMichele A, Isaacs C, et al. Pathological complete response predicts event-free and distant disease-free survival in the I-SPY 2 trial. Presented at: 2017 San Antonio Breast Cancer Symposium (SABCS); December 5-9, 2017; San Antonio, TX. Abstract GS3-08. uploads-ssl.webflow.com/5acff833a26e51b82579a916/5b802a250566a101868ce773_0930_8_Yee_PC.pdf.
7. von Minckwitz G, Huang C-S, Mano MS, et al; KATHERINE Investigators. Trastuzumab emtansine for residual invasive HER2-positive breast cancer [published online December 5, 2018]. New Engl J Med. doi: 10.1056/NEJMoa1814017.
8. Geyer Jr CE, Huang C-S, Mano MS, et al. Phase III study of trastuzumab emtansine(T-DM1) vs trastuzumab as adjuvant therapy in patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant chemotherapy and HER2-targeted therapy including trastuzumab: primary results from KATHERINE. Presented at: 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, TX. Abstract GS1-10. abstracts2view.com/sabcs18/view.php?nu=SABCS18L_1226&terms=.
9. Tolaney SM, Barry WT, Dang CT, et al. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med. 2015;372(2):134-141. doi: 10.1056/NEJMoa1406281.
10. Tolaney SM, Barry WT, Guo H, et al. Seven-year (yr) follow-up of adjuvant paclitaxel (T) and trastuzumab (H) (APT trial) for node-negative, HER2-positive breast cancer (BC). J Clin Oncol. 2017:35(suppl; abstr 511). meetinglibrary.asco.org/record/145548/abstract.
11. US Food & Drug Administration. FDA grants regular approval to pertuzumab for adjuvant treatment of HER2-positive breast cancer. FDA website. www.fda.gov/drugs/informationondrugs/approveddrugs/ucm590005.htm. Published December 20, 2017. Accessed January 16, 2019.
12. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Breast Cancer. Version 3.2018. NCCN website. nccn.org/professionals/physician_gls/pdf/breast.pdf. Updated October 25, 2018. Accessed January 16, 2018.
13. US Food & Drug Administration. FDA approves neratinib for extended adjuvant treatment of early stage HER2-positive breast cancer. FDA website. fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm567259.htm. Published July 17, 2017. Accessed January 16, 2018..
14. Martin M, Holmes FA, Ejlertsen B, et al; ExteNET Study Group. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(12):1688-1700. doi: 10.1016/S1470-2045(17)30717-9.
15. Gnant M, Martin M, Holmes FA, et al. Efficacy of neratinib in hormone receptor-positive patients who initiated treatment within 1 year of completing trastuzumab-based adjuvant therapy in HER2+ early stage breast cancer: subgroup analyses from the phase III ExteNET trial. Poster presented at: 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, TX. P2-13-01. abstracts2view.com/sabcs18/view.php?nu=SABCS18L_1477&terms=.