Doctors Debate: Is Neoadjuvant Chemotherapy Appropriate for T1c HR-, HER2+ Breast Cancer?

Kevin Kalinsky MD, MS

Neoadjuvant chemotherapy is currently a consideration for patients with estrogen receptor (ER)–positive breast cancer whose tumors are more than 2 cm. This treatment consideration is based on findings from the phase 3 KRISTINE trial (NCT02131064), which showed that significantly more patients achieved a pathologic complete response (pCR) after receiving neoadjuvant systemic chemotherapy plus dual HER2-targeted blockade compared with ado-trastuzumab emtansine (T-DM1; Kadcyla) plus pertuzumab (Perjeta).¹

A standing question for oncologists is what to do for patients with tumors smaller than 2 cm. The question led to a debate on whether to administer neoadjuvant chemotherapy to patients with T1c hormone receptor–negative, HER2-positive breast cancer during the Physicians’ Education Resource®, LLC (PER®) 38th Annual Miami Breast Cancer Conference®.

During the debate, Kevin Kalinsky MD, MS, argued for the use of neoadjuvant chemotherapy to treat this patient population, and Kelly K. Hunt, MD, took the opposing position.²

Kalinsky is the acting associate professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine and director of the Glenn Family Breast Center as well as Breast Medical Oncology at Winship Cancer Institute of Emory University in Atlanta, Georgia.

Kelly K. Hunt, MD

Hunt is a professor and chair in the Department of Breast Surgical Oncology in the Division of Surgery and holds the Hamill Foundation Distinguished Professorship in Honor of Dr Richard G. Martin Sr at The University of Texas MD Anderson Cancer Center (MD Anderson) in Houston, Texas.

Argument in Favor of Neoadjuvant Chemotherapy

Kalinsky argued that biology should be the basis for a physician’s decision on whether to administer neoadjuvant chemotherapy. In practice today, many oncologists base their decision on tumor size, which, according to Kalinsky, does not provide enough information to decide whether to give neoadjuvant chemotherapy.

“This argument is based upon the fact that we’ve seen a change in how we treat patients with HER2-positive breast cancer,” Kalinsky explained in an interview with Targeted Therapies in Oncology. “We know that pathologic response can be high in HER2-positive disease and even higher for those patients who have hormone receptor–negative tumors compared with those who have hormone receptor–positive tumors. And we’ve seen [that] the pathologic complete response could be a very important indicator for how patients do. If patients have residual disease, then they should be getting T-DM1, as per the KRISTINE trial.”

Kalinsky noted studies conducted by MD Anderson and one conducted by the National Comprehensive Cancer Network (NCCN) to support this viewpoint.³ The MD Anderson study, which included 98 patients with HER2-positive, node-negative (N0) T1c breast cancer, revealed a 5-year disease-free survival (DFS) rate of 77.1%; in the NCCN study of 4113 patients with HER2-positive and hormone receptor–negative T1a/b breast cancers, the 5-year DFS was 83.3%.⁴ These studies showed the risk of recurrence in patients with HER2-positive breast cancer was high despite the fact that the tumors were less than 2 cm.

Regarding the data from both studies, Kalinsky stated, “I was making the point that we should be treating these patients with systemic therapy. Ultimately, these patients, even if they have a T1c breast tumor, need a new therapeutic regimen. The benefit of giving [treatment] before surgery, as opposed to after surgery, is that if you give it before surgery, you get to see in real time how they’re responding to the treatment.”

Further, a pooled analysis of reports from PubMed, Embase, and Medline databases of clinical trials administering neoadjuvant treatment to patients with breast cancer assessed pCR rate by various tumor subtypes. The study investigated data from 13,856 patients enrolled in 12 different neoadjuvant trials. Of those patients, 11,955 were included in the responder analysis. The study ultimately illustrated how pCR correlates with outcomes in patients treated with or without trastuzumab (Herceptin). An increase in the pCR rate was observed in the population of patients with HER2-positive, hormone receptor–positive tumors treated with trastuzumab, but in the HER2-positive, hormone receptor–negative subgroup that received trastuzumab, the pCR rate was even higher. A deeper look into the various subgroups of the study revealed that in the patients with HER2-positive, hormone receptor–negative breast cancer who were treated with trastuzumab, the achievement of a pCR or nonachievement of a pCR was found to be a prognostic indicator for event-free survival improvement (FIGURE).⁵

Kalinsky’s argument was rounded out with supporting data from the KATHERINE trial (NCT01772472) of adjuvant T-DM1 versus trastuzumab as treatment for patients with HER2-positive, early breast cancer who had residual invasive disease after completion of neoadjuvant therapy.⁶ A total of 1486 patients were enrolled to the study and randomized evenly to receive either trastuzumab emtansine or trastuzumab for 14 cycles. Invasive DFS (IDFS) was explored as the primary end point of the study.⁷

“This was a practice-changing study....[T]he data from that were subsequently published in the New England Journal of Medicine, which showed even an improvement in invasive disease-free survival at 3 years. Looking at the data in the forest plots, even those patients who had clinically small tumors or lymph N0 tumors, if they had residual disease, benefited from getting T-DM1. That was the crux of the argument that these patients should be receiving neoadjuvant therapy because if they have residual disease, then T-DM1 would be clinically relevant.”

Overall, 88.3% of patients were free of invasive disease at 3 years in the T-DM1 arm compared with 77.0% in the trastuzumab arm. IDFS was significantly higher with T-DM1 compared with trastuzumab (HR, 0.50; 95% CI, 0.39-0.64; P<.001). In addition, assessment of the freedom from distant recurrence showed an 89.7% rate among patients treated with T-DM1 compared with 83.0% of patients treated with trastuzumab (unstratified HR, 0.60; 95% CI, 0.45-0.7).

The study population included patients with clinical characteristics such as inoperable/operable disease, ER-positive/ER-negative status, prior use of anthracycline therapy, and neoadjuvant treatment with either trastuzumab alone, trastuzumab plus pertuzumab, and trastuzumab plus another HER2-targeted therapy. Notably, across all subgroups, treatment with T-DM1was beneficial for patients with residual HER2-positive breast cancer. Furthermore, patients with small tumors and lymph N0 tumors also derived benefit from T-DM1.

Kalinsky closed his argument by highlighting the APT clinical trial (NCT00542451) of adjuvant paclitaxel and trastuzumab for N0 HER2-positive breast cancer, which suggests that chemotherapy can be deescalated in the neoadjuvant setting and escalated in the adjuvant setting.

“My argument for giving neoadjuvant therapy is that one could consider giving a less aggressive neoadjuvant regimen if patients have residual disease and have not achieved a pathologic complete response. Then we can escalate in the adjuvant setting because we have data that doing so can improve outcomes,” Kalinsky said.

Findings from the APT trial were later highlighted to support Hunt’s argument against neoadjuvant chemotherapy for the treatment of patients with T1c hormone receptor–negative, HER2-positive breast cancer.

Argument Against Neoadjuvant Chemotherapy

Hunt began her presentation with an explanation of how chemotherapy and HER2-targeted therapies can impact patients’ outcomes and quality of life (QOL). Specifically, these therapies can sometimes lead to significant toxicity and chronic conditions, and therefore, any decision on treatment should be based on the patient’s biology and stage.²

“In terms of patients with early-stage breast cancer, we now understand that not everyone needs all the therapies and [that] there are appropriate patients [for whom] we can scale back our systemic therapies, especially those that have more toxicity and are very expensive and require patients to go to treatment centers more often,” Hunt explained in an interview with Targeted Therapies in Oncology. “We know that patients who have early-stage breast cancer and those who have HER2-positive and ER-positive breast cancer probably do not need the same amount of systemic therapy as those with more advanced disease and those with ER-negative disease. So there are several reasons that not everyone needs to receive neoadjuvant therapy. Stage [of tumor] is still important and so [is] getting that information up front for these patients who present with more early-stage disease.”

APT was an uncontrolled, single-group, multicenter, investigator-initiated study of 406 patients whose tumors measured up to 3 cm. Hormone-positive status was found in 67% of the study population; 41.6% of patients had tumors more than than 1 cm but less than 2 cm, and 98.5% had N0 tumors.⁸

Of those enrolled and evaluated on treatment, 87.7% completed all 52 weeks of therapy. Treatment discontinuation occurred in 24 patients due to protocol-specified toxicity, and another 6 patients discontinued therapy due to unspecified toxicities. Twenty-nine patients remained in the study at final analysis: 2 patients died, 17 withdrew, and 10 were lost to follow-up.

At a median follow-up of 4 years and maximum follow-up period of 6.2 years, the 3-year IDFS rate was 98.7% (95% CI, 97.6%-99.8%). Local recurrence or death was observed in 6 patients, showing a 3-year rate of recurrence-free survival of 99.2% (95% CI, 98.4%-100%).

Hunt noted during the presentation that when IDFS was observed according to hormone receptor status or tumor size, there was no difference.2,8 There were also 4 cases of distant recurrence with a time to event of 53 months (range, 27-63 months), according to the 7-year follow-up results.⁷

“The trial results suggest that there are patients who…if staged with up-front surgery, they’re node negative and they have a small tumor, then they can benefit from less therapy. Just receiving the one HER2-targeted agent and paclitaxel, as opposed to using a more extensive dual HER2-targeted therapy regimen like we do with the neoadjuvant setting, is feasible,” Hunt said.

Hunt further supported her position with an explanation of the heterogeneity of HER2-positive breast cancer and the cost and consequences of selecting certain treatment options.

Disease biology

The biology of HER2-positive breast cancer includes 4 intrinsic subtypes, Hunt explained. Approximately 65.5% given long-term follow-up on adjuvant paclitaxel and trastuzumab in the Prediction Analysis of Microarray (PAM) 50 analysis of the APT trial had HER2-enriched tumors, whereas 13.7% had luminal B tumors, 12.6% had luminal A, and 7.9% had basal-like tumors. Risk-of-recurrence score for those 264 patients was 3.4% among the 9 patients with low-risk disease, 21.2% in the 56 patients with intermediate-risk disease, and 75.4% in the 199 patients with high-risk disease.

“Similar to what the previous speaker showed, we do see that...ER-negative disease has a slightly higher recurrence rate, but remember that some of these patients in the APT trial had larger tumors and node-positive disease,” Hunt explained.

Cost and consequences

Hunt noted the significant cost and toxicity associated with using HER2-targeted therapy. The cost of treatment is amplified when patients have to spend more time away from work to undergo more intensive treatment regimens, she explained. More toxicities can result in additional treatments to the regimen to manage these adverse effects. Early treatment discontinuation can be another adverse result of the toxic effect of therapy. On treatment with T-DM1 in the ATEMPT trial (NCT01853748), 17% discontinued treatment early compared with only 6% of patients who received paclitaxel plus trastuzumab.⁹

Hunt concluded the debate by noting that when deciding on whether or not to administer neoadjuvant chemotherapy, oncologists should consider the heterogeneity of HER2-positive breast cancers, the positive long-term outcomes of paclitaxel in combination with trastuzumab for small N0-positive tumors, and that therapy can be de-escalated to improve QOL in patients.²

Weighing the Strategies

Both physicians had certain points that they agreed upon.

“I think we both agreed on the importance of giving systemic therapy,” Kalinsky said. “Dr Hunt raised the point...that we because these HER2 drugs can be quite effective, we’ve been able to decrease the intensity of the chemotherapy [from what] we’ve needed previously. So [Hunt] and I both presented data on regimens such as paclitaxel plus [trastuzumab] for which the long-term data have been reported from Sara Tolaney, MD, MPH, and her colleagues. Hunt made the point that maybe we don’t need to be as aggressive with the chemotherapy that we’re giving, and I completely agree with that. Where our argument differs was whether we needed to give that before or after surgery. Ultimately, I think we agree that yes, we can maybe be less intense with the chemotherapy that we select but that there could be a benefit for giving new adjuvant therapy, given the implications if patients have residual disease.”

Hunt hinted that outside the debate arena, she may have taken a different approach to treatment for a patient with T1c hormone receptor–negative, HER2-positive breast cancer.

“This is an argument that I frequently favor in terms of using neoadjuvant therapy for patients because my institution has had a long history of using the neoadjuvant approach to downsize the primary tumor to decrease the nodal burden and to assess response,” she said. “So pathologic complete response after neoadjuvant therapy is a very powerful predictor of outcome. Also, we now have data from more recent trials suggesting that those patients who have residual disease after neoadjuvant chemotherapy do benefit from additional systemic therapy in the adjuvant setting. So I think that [Kalinsky] has some strong arguments.”

_References:

_{1. Hurvitz SA, Martin M, Symman WF, et al. Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2018;19(1):115-126. doi:10.1016/ S1470-2045(17)30716-7}

_{2. Kalinsky K, and Hunt K. Medical Crossfire®: neoadjuvant chemotherapy for t1c HR-negative/HER2-positive breast cancer? yes or no. Presented at: Miami Breast Cancer Conference®; March 4-7, 2021; virtual. Accessed May 12, 2021.}

_{3. Gonzalez-Angulo AM, Litten JK, Broglio KR, et al. High risk of recurrence for patients with breast cancer who have human epidermal growth factor receptor 2-positive, node-negative tumors 1 cm or smaller. J Clin Oncol. 2009;27(34):5700-5706. doi:10.1200/JCO.2009.23.2025}

_{4. Luis I, Ottesen RA, Hughes ME, et al. Time trends in the use of adjuvant chemotherapy (CTX) and outcomes in women with T1N0 breast cancer (BC) in the National Comprehensive Cancer Network (NCCN). J Clin Oncol. 2013;31(suppl 15):1006. doi:10.1200/jco.2013.31.15_suppl.1006}

_{5. 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}

_{6. von Minchwitz G, Huang CS, Mano MS, et al; KATHERINE Investigators. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2019;380(7):617-628. doi:10.1056/NEJMoa1814017}

_{7. Tolaney SM, Guo H, Pernas S, et al. Seven-year follow-up analysis of adjuvant paclitaxel and trastuzumab trial for node-negative, human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol. 2019;37(22):1868-1875. doi:10.1200/JCO.19.00066}

_{8. 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}

_{9. Tolaney SM, Trippa L, Barry W, et al. TBCRC 033: a randomized phase II study of adjuvant trastuzumab emtansine (T-DM1) vs paclitaxel (T) in combination with trastuzumab (H) for stage I HER2-positive breast cancer (BC) (ATEMPT). Can Res. 2020;80(suppl 4):GS1-05. doi:10.1158/1538-7445.SABCS19-GS1-05}