Optimizing Treatment Strategies in the Evolving HR+/HER2- Breast Cancer Paradigm

Over the past 10 years, data from studies including the TAILORx (NCT00310180) and RxPONDER (NCT01272037) studies have reshaped treatment standards for patients with hormone receptor–positive, HER2-negative breast cancer, according to Timothy J. Pluard, MD. The use of recurrence scores determined by 21-gene assays in these studies have begun to optimize the use of adjuvant chemotherapy, sparing those who would not derive benefit from its use.^1,2

“We’re using far less chemotherapy and relying more heavily on endocrine therapy [and] that’s been a huge benefit,” Pluard said in a recent OncLive Peer Exchange. “We’re entering an era where we’re trying to optimize endocrine therapy, identify patients who may benefit from a more intensive endocrine regimen, and identify those who may have a good prognosis and may be able to de-escalate their endocrine therapy.”

Pluard was joined by an expert panel of breast oncologists who discussed how personalization efforts have begun in early-stage disease, updates in the neoadjuvant and adjuvant settings, and the evolving role of CDK4/6 inhibitors are reshaping the treatment landscape.

“We can always benefit from drug development, safer drugs, etc,” VK Gadi, MD, PhD, said. “More drugs are good, but we are increasingly moving into a space where the art of precision medicine is driven by the biomarkers. We need to know [this information about] the patients, not just based on stage and other criteria to optimize.” Gadi noted that the gap in obtaining and analyzing this information is one of the unmet needs in treating patients with hormone receptor–positive, HER2-negative disease. “It’d be great to have tools that say this patient’s truly at much higher risk than this other one, based on a molecular feature, maybe ctDNA [circulating tumor DNA], or something like that. We need to flush out the development of those markers to be precise, because when these tools are approved, initially, it’s for everybody, so to speak. Yet we know most of the patients don’t need it [and] don’t benefit [from it]. This is the heart of the matter. That’s the biggest unmet need I personally see moving forward.”

Aditya Bardia, MD, MPH, took this point further to add that the field is missing dynamic biomarkers. “We have Oncotype DX, MammaPrint, but [those assays are] looking at the genomic profile at baseline,” he said. “But [with] endocrine therapy, we continue for 5 years, sometimes 10 years, and we need better ways of monitoring that and guiding who needs 5 years, who needs 10 years, not looking at the original specimen, but at the end of 5 years, assessing biology, such as by ctDNA to decide who needs longer therapy vs who do not.”

Having this information represents the first step in a long road for implementation into standard practice and moderator Komal Jhaveri, MD, FACP, noted that there have been recent big leaps in progress. Some of those in the immunotherapy space with data presented during the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, such as updates from the phase 2 I-SPY 2 trial (NCT01042379).³

“For [patients with] HER2-positive or TNBC [triple-negative breast cancer], we use a lot more neoadjuvant therapy because we see that there is an improvement in pathologic complete response [pCR] that can translate into event-free survival,” Jhaveri said, adding that that has not translated to patients with hormone receptor–positive disease.

Gregory Vidal, MD, PhD, noted that data from I-SPY 2 have signaled some efficacy that mandates further study. “[In I-SPY 2] investigators used oral paclitaxel vs IV [intravenous] paclitaxel with some familiar drugs, such as carboplatin, and then immunotherapy. And that combination showed a slightly increased [pCR] rate, which was interesting and needs further studies. I-SPY 2 is an adaptive response trial and overall, [the regimen] appears safe and there appear to be some signals.”

At the 2023 ASCO meeting, findings were presented from patients treated with the anti–PD-1 monoclonal antibody dostarlimab-gxly (Jemperli) which was added to oral paclitaxel and encequidar, a p-glycoprotein pump inhibitor, plus carboplatin followed by doxorubicin/cyclophosphamide. In the subgroup of patients with hormone receptor– positive, HER2-negative breast cancer who were given the regimen (n = 44), the estimated pCR was 22% compared with 14% among historic control data (n = 201). The probability of the regimen being successful in a phase 3 trial was 53%.³

“That is exciting because when we think about immunotherapy, we’re not thinking about hormone receptor–positive breast cancer, we’re thinking about TNBC. This is an important [and] interesting initiative to try to see if there is a role [for immunotherapy],” Jhaveri said. “The I-SPY trial has set the stage [as a way] to identify promising therapies in the neoadjuvant setting that then have a leg that could lead to an approval. The best example that we have is pembrolizumab [Keytruda] and the I-SPY evaluation of neoadjuvant pembrolizumab in KEYNOTE-522 [NCT03036488],⁴ which is a randomized phase 3 [trial] that changed our standard of care for patients with high-risk TNBC.”

Vidal added that tactics used in the neoadjuvant setting may also serve to inform treatment in the adjuvant setting. “For example, the coopERA BC study [NCT04436744] looked at giredestrant, which is an oral SERD [selective estrogen receptor degrader] vs aromatase inhibitor, [to determine] whether a decrease in Ki-67 [expression], or cell cycle arrest, could predict benefit [in the] long term,” he said. Giredstrant was evaluated in untreated patients with early ER-positive, HER2- negative breast cancer with a baseline Ki-67 score of at least 5%. Patients were given neoadjuvant giredestrant with palbociclib (Ibrance) vs anastrozole (Arimidex) plus palbociclib.⁵

In the final analysis, findings showed that greater Ki-67 suppression was observed with giredestrant at week 2 and was maintained after surgery. The relative reduction from baseline was –75% (95% CI, –80% to –70%) in the experimental arm vs –67% (95% CI, –73% to –59%) in the control arm at 2 weeks. After surgery these rates were –81% (95% CI, –86% to 75%) vs –74% (95% CI, –80% to –67%), respectively.⁵

At week 2 complete cell cycle arrest was observed in 20% of patients in the giredestrant/palbociclib arm (n = 107) compared with 13% in the anastrozole/palbociclib arm (n = 94). After surgery this was observed in 24% of evaluable patients in the SERD arm (n = 93) vs 16% of patients in the control arm (16%).⁵

“It appears to be that when you give giredestrant, we have a decrease in Ki-67 [expression],” Vidal said. “We see an increase in cell cycle arrest at surgery. And that led to an adjuvant study using this oral SERD vs aromatase inhibitor, which is what we do standard in that population.”

Bardia commented on the decreased use of chemotherapy overall and added that his preference is to keep chemotherapy in the neoadjuvant setting when it is called for. “The use of chemotherapy either in the neoadjuvant or adjuvant setting, is decreasing now with the RxPONDER and TAILORx data. If there is a patient who does need adjuvant chemotherapy, for example they have multiple positive lymph nodes and the physician sent [them for] Oncotype DX [testing] and it’s high, I would rather use chemotherapy in the neoadjuvant setting than in the adjuvant setting…. The challenge there is, what’s a good biomarker to assess in ER-positive disease? Because the pCR rate is so low, you cannot look at pCR. Ki-67 with chemotherapy is not a good marker. We don’t have a good marker to look at to judge the success of a therapy in the neoadjuvant setting, and I think that’s been the challenge. Moving forward, we need to see studies comparing chemotherapy with CDK4/6 inhibitors. We’ve already decreased the use of chemotherapy. Can we decrease it even further with the use of CDK4/6 inhibitor? There are trials ongoing in Europe looking at this strategy of how we can further use CDK4/6 inhibitors in this setting.”

Determining Adjuvant Therapy

At the 2023 ASCO Annual Meeting, updated data on the use of ctDNA detection to determine the adjuvant therapy provided insights to guide postsurgical treatments. The phase 3 PENELOPE-B trial (NCT01864746) evaluated endocrine therapy plus 1 year of palbociclib in patients with hormone receptor–positive, HER2-negative breast cancer with residual invasive disease vs placebo. Patients had received prior neoadjuvant chemotherapy.⁶

The results of the trial failed to meet the primary end point with an HR of 0.93 (95% CI, 0.74-1.17; P = .525) for invasive disease-free survival (iDFS) with palbociclib vs placebo. Investigators noted there were no differences observed in the subgroup analysis.⁷ The ctDNA analysis, however, showed that among those who has ctDNA present after neoadjuvant chemotherapy and surgery were at a very high risk for early relapse. Investigators noted that this may signal an limited efficacy of adjuvant endocrine therapy.⁶

“These are early data, but very provocative,” said Bardia, who was an investigator on the study.⁶ “The PENELOPE-B trial looked at patients who had residual disease despite neoadjuvant therapy, [randomly assigned] to endocrine [therapy] plus endocrine [therapy] with a CDK4/6 inhibitor. The overall sample size was more than 1000, but in the ctDNA analyses, it was approximately 10% of that population. They wanted to look at patients who had baseline samples before a patient started endocrine therapy, which is critical, and then cycle 7, day 1, and at the time of progression if a patient had progression. They had approximately 70 patients who had ctDNA data available. Seven of them had detectable ctDNA, and these were the patients who were really at high risk of recurrence. So ctDNA appears to be a very strong prognostic marker, even more than grade and other clinical pathological features that we use, and in future studies it will [likely] be something that we consider either as a stratification factor or as a high-risk factor. I think the bigger question then is that if it’s a prognostic factor, but how can we convert that to a predictive factor in terms of something that’s actionable?”

In the clinic, oncologists face the challenge of keeping their patients informed with the most accurate and up-to-date information regarding the utility of markers such as ctDNA. Gadi noted, “People are very curious about this. They’re reading about it on Dr Google and I’m sure ChatGPT will be informing them very soon about it as well. The challenge really is operationalizing that in general practice in the general population. As you know, the data around biomarker testing, even in the metastatic setting where we have indications, things such as getting ESR1 testing and PIK3- mutation testing, is hard. We just need a lot more education for the payers, our colleagues, etc, on how we would order these tests in a regular fashion, track them, and then make decisions once data come in, on what we do when we see persistence of ctDNA. So that’s where my anxieties are about being able to get the test. This is another instance where innovation can inadvertently worsen disparity because [few individuals] will be at centers that can continue to do this type of testing. Where we’re going to see problems is in communities of color and others where [getting] access to these tests is even [harder].”

The road may be long for identifying and implementing effective prognostic markers for adjuvant therapy, but updated data from several studies have provided promising outlooks for available therapies. This included data from the monarchE trial (NCT03155997) examining abemaciclib (Verzenio) and endocrine therapy, and the phase 3 NATALEE trial (NCT03701334) of ribociclib (Kisqali) plus endocrine therapy.^8-11

For patients with high-risk disease, the CDK4/6 inhibitor abemaciclib is approved in combination with endocrine therapy. In March 2023, the FDA updated the approval to remove the Ki-67 expression requirement. At the 4-year landmark analysis, the HR for iDFS was 0.66, with an absolute improvement of 6.4%. The iDFS rates were 85.8% with abemaciclib/endocrine therapy (n = 2808) vs 79.4% with endocrine therapy alone (n = 2829; P < .0001).¹² A major concern with this regimen is toxicity, Gadi noted that counseling patients on the expected adverse effects (AEs) is paramount. “[In] thinking about how to counsel patients, [diarrhea] is the toxicity that we have to focus on. In our practice, we work on provider education so that our other providers who are working with us can keep the patient [looking at treatment] in a positive light and spin. We want to be prophylactically providing agents to help with these problems as they arise. There might be other strategies that we can explore through clinical studies, etc, and learn what might be some other ways to control this,” he said.

Jhaveri agreed, adding, “It’s going to be an individualized approach for a given patient depending on what baseline comorbidities they have, what kind of profession they’re in, what their age is, what we expect with them, and what their experience with a given drug is and what their preferences are. Ultimately, it’s going to be a shared decision-making process that we will have [with] our patients.”

A few years down the road, however, Gadi said that ribociclib may provide an alternative option for patients. He added that there are other considerations to consider with this treatment choice such as length of treatment and potential AEs such as neutropenia. “I’m starting to do this exercise and it’ll be interesting once the agents are both available, which is a great luxury to have 2 agents. But there are these subtleties that I think we’re all going to have to [talk about] with our patients,” he said.

In a presentation at 2023 ASCO meeting, among 2549 patients who received ribociclib plus a nonsteroidal aromatase inhibitor the 3-year iDFS rate was 90.4% vs 87.1% among 2552 patients who received a nonsteroidal aromatase inhibitor alone (HR, 0.748; 95% CI, 0.618-0.906; P = .0014).¹¹ The absolute benefit was 3.3% and the risk of invasive disease was reduced by 25.2% with the addition of ribociclib.

“[NATALEE] included patients with medium-risk [disease] who were not included in monarchE,” Bardia explained. “[This group] was defined as patients with stage II disease who had some other high-risk features such as grade 3 or Ki-67 or high genomic risk and patients with stage III disease. The second was the dose of ribociclib; it was 400 mgas opposed to 600 mg that is used in the metastatic setting. The rationale was that with the lower dose, you’ll have less toxicity, especially in the adjuvant setting where [adherence] and tolerability is a critical issue. Third was the duration. The duration of ribociclib was 3 years as opposed to 2 years with abemaciclib in monarchE.” Bardia noted that additional follow-up is needed to properly analyze duration of treatment and overall survival, and without the approval to support the regimen, it remains a drug to watch.

References

1. Sparano JA, Gray RJ, Makower DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018;379(2):111-121. doi:10.1056/NEJMoa1804710
2. Kalinsky K, Barlow WE, Gralow JR, et al. 21-gene assay to inform chemotherapy benefit in node-positive breast cancer. N Engl J Med. 2021;385(25):2336-2347. doi:10.1056/NEJMoa2108873
3. Yeung KY, Kalinsky K, Yau C, et al; I-SPY Investigators. Oral paclitaxel, carboplatin, and dostarlimab (OPE/Cb/D) without and with trastuzumab in early-stage, high-risk breast cancer: Results from the neoadjuvant I-SPY 2 TRIAL. J Clin Oncol. 2023;41(suppl 17):LBA520. doi:10.1200/JCO.2023.41.17_suppl.LBA520
4. FDA approves pembrolizumab for high-risk early-stage triple-negative breast cancer. FDA. July 26, 2021. Accessed August 28, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-high-risk-early-stage-triple-negative-breast-cancer
5. Fasching PA, Bardia A, Quiroga V, et al. Neoadjuvant giredestrant (GDC-9545) plus palbociclib (P) versis anastrozole (A) plus P in postmenopausal women with estrogen receptor-positive, HER2-negative, untreated early breast cancer (ER+/HER2– eBC): final analysis of the randomized, open-label, international phase 2 coopERA BC study. J Clin Oncol. 2022;42(suppl 16):589. doi:10.1200/JCO.2022.40.16_suppl.589
6. Turner NC, Marm. F, Kim SB, et al. Detection of circulating tumor DNA following neoadjuvant chemotherapy and surgery to anticipate early relapse in ER positive and HER2 negative breast cancer: analysis from the PENELOPE-B trial. J Clin Oncol. 2023;41(suppl 16):502. doi:10.1200/JCO.2023.41.16_suppl.502
7. Loibl S, Marm. F, Martin M, et al. Palbociclib for residual high-risk invasive HR-positive and HER2-negative early breast cancer—the Penelope-B trial. J Clin Oncol. 2021;39(14):1518-1530. doi:10.1200/JCO.20.03639
8. FDA approves abemaciclib with endocrine therapy for early breast cancer. FDA. October 12, 2021. Accessed August 28, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-abemaciclib-endocrine-therapy-early-breast-cancer
9. FDA expands early breast cancer indication for abemaciclib with endocrine therapy. FDA. March 3, 2023. Accessed August 28, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-expands-early-breast-cancer-indication-abemaciclib-endocrine-therapy
10. Hamilton EP, Hyun Kim J, Eigeliene N, et al. Efficacy and safety results by age in monarchE: adjuvant abemaciclib combined with endocrine therapy (ET) in patients with HR+, HER2-, node-positive, high-risk early breast cancer (EBC). J Clin Oncol. 2023;41(suppl 16):501. doi:10.1200/JCO.2023.41.16_suppl.501
11. Slamon DJ, Stroyakovskiy D, Yardley DA, et al. Ribociclib and endocrine therapy as adjuvant treatment in patients with HR+/HER2− early breast cancer: primary results from the phase III NATALEE trial. J Clin Oncol. 2023;41(suppl 17):LBA500. doi:10.1200/JCO.2023.41.17_suppl.LBA500
12. Johnston SRD, Toi M, O’Shaughnessy J, et al. Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): results from a preplanned interim analysis of a randomised, open-label, phase 3 trial. Lancet Oncol. 2023; 24(1):77-90. doi:10.1016/S1470-2045(22)00694-5