Genomic Testing Is Critical for Improved Personalized Medicine and Treatment Sequencing in Breast Cancer

The expansion of available therapeutics for patients with breast cancer within the past decade has significantly changed treatment approaches in this space, according to Lida A. Mina, MD. Novel antibody-drug conjugates (ADCs) such as fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) and sacituzumab govitecan-hziy (Trodelvy) continue to be explored outside of HER2-positive breast cancer, especially with the inception of HER2-low classification. Moreover, the optimal sequencing of these therapies, particularly CDK4/6 inhibitors in hormone receptor (HR)–positive, HER2-negative disease, is still under debate.

Mina, who is a senior associate consultant at the Women’s Cancer Program, and chair of the Mayo Arizona Breast Cancer and GYN disease working groups in the Division of Hematology and Medical Oncology at the Mayo Clinic Comprehensive Cancer Center in Phoenix, Arizona, stated that sequencing efforts are necessary for navigating the number of options in the breast cancer armamentarium. The identification of novel targets through next-generation sequencing (NGS) also allows for a more individualized approach to treatment.

“[For] any new diagnosis of breast cancer, especially [in] the metastatic setting, we need to figure out the [patient’s] HER2 status,” ​​Mina said following an OncLive^® State of the Science Summit™ on breast cancer, which she cochaired. “This not only [includes] positive or negative [status but] HER2-low [disease]. Second, this is the new era for NGS and genomic testing, [which will help us] learn more about these tumors.”

In an interview with OncLive, Mina expanded on key topics discussed by herself and her colleagues at the meeting, including the evolving role of ADCs across breast cancer subtypes, current data on the use of CDK4/6 inhibitors in the metastatic and adjuvant settings in HR-positive, HER2-negative breast cancer, and the increased use of genomic testing and NGS to improve the sequencing of agents in triple-negative breast cancer (TNBC).

OncLive: How has the use of ADCs evolved within breast cancer?

Mina: ADCs have been in the making for a while and initially [were] introduced in blood cancers and in leukemias. The first ADC was approved back in 2000. However, they didn’t make their way [into breast cancer until] 2013 with the first approval of ado-trastuzumab emtansine [Kadcyla; T-DM1], and then in 2019 with T-DXd. More recently, sacituzumab govitecan was approved in 2020. [ADCs] have really revolutionized breast cancer treatment. We now have over 100 ADCs being investigated in different types of clinical research across not only breast cancer but other malignancies.

Could you briefly describe the mechanism of action for these ADCs?

In our presentation, we focused mainly on HER2-positive tumors. The main thing about those ADCs, which are also called magic bullets, is to know that it’s not only the antibody itself that makes it effective, [but] the chemotherapy that’s linked to this antibody. The actual mechanism [of ADCs] is working on a selective delivery of a toxic payload, and it starts with the ADC targeting a certain antigen. [Both] T-DM1 and T-DXd target HER2. However, the payload is different. With T-DM1, we use emtansine, which is the anti-microtubule payload, whereas T-DXd [has] the topoisomerase I inhibitor. The idea is to target the HER2-positive cells, and ultimately cause degradation of the ADCs and release the payload. The benefit of those drugs, specifically T-DXd, was seen across many trials.

What data have supported the approval of T-DXd in both HER2-positive and HER2-low breast cancers?

T-DXd [was] first approved [for HER2-positive breast cancer based on] the [phase 3] DESTINY Breast-01 trial [NCT03248492]. It wasn’t until like the [phase 3] DESTINY Breast-03 trial [NCT03529110] that T-DXd was compared with T-DM1 and was found to markedly improve progression-free survival [PFS] as well as overall survival [OS]. The median PFS with T-DXd when compared to T-DM1 in the second-line setting was 4 times longer. The median OS was significantly longer, and not yet reached. [These findings] transformed the treatment approach [for patients with] metastatic HER2-positive [disease].

The interesting thing [about] those drugs is they [don’t just work] in HER2-positive [disease]. During my talk, I highlighted a subgroup which we now call HER2-low [breast cancer]. The impressive phase 3 DESTINY Breast-04 study [NCT03734029] for T-DXd was presented initially at the 2022 ASCO Annual Meeting. This study highlighted a group of patients with HER2-low disease. This [classification] is completely new to us breast medical oncologists and is described as having an immunohistochemistry [IHC] of 1+ or 2+, but a negative FISH [fluorescence in situ hybridization]. In that patient population, T-DXd was compared with treatment of physician’s choice. It did show significant improvement in PFS [for] all patients, and specifically in the HR-positive, HER2-low patient population. This study makes us realize that T-DXd is a new standard of care for the HER2-low population, [and we now have] a duty to identify the HER2-low patient population, which makes up more than 50% of the patients we see in clinic.

Regarding the presentation given by Shakeela Bahadur, MD, of Banner MD Anderson Cancer Center, which key trials have informed the use of CDK4/6 inhibitors in the metastatic setting for HR-positive breast cancer? What challenges still exist when attempting to determine the optimal sequencing of these agents?

Dr Bahadur did a great job presenting the data on CDK4/6 inhibitors both in the metastatic setting, as well as in the early-stage setting. She initially highlighted the [phase 3] PALOMA-3 study [NCT01942135] looking at patients that progressed on prior endocrine therapy in the metastatic setting. [The trial] compared fulvestrant [Faslodex] with fulvestrant [plus] palbociclib [Ibrance]. In that patient population, PFS was significantly improved. Unfortunately, the OS did not pan out to be statistically meaningful.

[The phase 3] MONARCH-2 study [NCT02107703], on the other hand, [evaluated] the addition of abemaciclib [Verzenio] to fulvestrant, compared with fulvestrant [alone]. That patient population [also] progressed on first-line endocrine therapy. In that setting, PFS was significantly improved, and the OS was shown to have a statistically significant signal. We are still awaiting the updated results [from the phase 3] MONARCH-3 trial [NCT02246621] at this time.

In the [phase 3] MONALEESA-2 study [NCT01958021], ribociclib [Kisqali] was added to letrozole and was compared with letrozole alone in postmenopausal women who had not received prior endocrine therapy. In that study, we saw that PFS was significantly improved, and OS was significantly improved after a median follow-up of 18 months in all patient subgroups. This led most of the community, with a lot of controversy, to favor first-line ribociclib when choosing a CDK4/6 inhibitor. In the metastatic setting, however, it is important to know that those medications are very different as far as toxicity. It’s always very important to individualize [these agents] when [considering] one vs the other.

Looking at how to sequence those CDK4/6 inhibitors, especially in the metastatic and estrogen-sensitive patient population, is an area that we don’t know too much about. We do have a little bit of data on sequencing one CDK4/6 inhibitor and then switching to ribociclib, [which] is a possibility based on [those data]. I don’t know how this is going to pan out if most of the community is starting with ribociclib. We don’t have the data for other switches yet. It is [a practice] that’s still debatable, and we do a lot of the switching based on toxicity. At least in [the metastatic] setting, this is something that’s being done.

What is the potential role for CDK4/6 inhibitors in the adjuvant setting for patients with early-stage HR-positive, HER2-negative breast cancer?

We [also] have those 3 CDK4/6 inhibitors being introduced in an earlier setting. The phase 3 PALLAS study [NCT02513394] was the first to look at palbociclib for 2 years in the adjuvant setting in patients who were HR-positive after completion of their adjuvant therapy within 12 months. The addition of palbociclib in the adjuvant setting did not [show] any significant difference in either 3-year disease free survival [DFS] or distant recurrence [vs endocrine therapy alone], so that [study] was negative.

On the other hand, the [phase 3] monarchE study [NCT03155997] looked at a high-risk patient population. [Cohort 1 included] those with more than 4 axillary lymph nodes that were positive or 1 to 3 positive lymph nodes with grade 3 disease, or a tumor size more than 5 cm. Cohort 2 was a little bit more finicky and was based on [the presence of] Ki67. The addition of abemaciclib in the adjuvant setting led to a significant improvement ininvasive DFS. [This study] led to the approval of abemaciclib in the adjuvant setting. Requirement of a Ki67 [score greater than 20%] was removed from the FDA label [for abemaciclib] on March 3, 2023. The expanded FDA approval [for abemaciclib] removed the Ki67 testing requirements, which makes it easier for patients to access the drug. We’re still waiting for the NATALEE trial [NCT03701334] results, which is a phase 3 study of ribociclib in the adjuvant setting. We had a press release saying that the study met its pre-planned interim analysis. However, we don’t have the full data yet.

How could novel targets in breast cancer address unmet needs in the breast cancer space, per the presentation given by Felipe Batalini, MD, of Mayo Clinic Comprehensive Cancer Center?

That’s where the whole field is moving. For example, ESR1 mutations are something that we are starting to investigate in the ER-positive [space]. We have the approval of elacestrant [Orserdu], based on the [phase 3] EMERALD study [NCT03778931] in patients with ESR1-mutated metastatic breast cancer after a CDK4/6 inhibitor. [The agent] improved PFS in that patient population. Other important targets include the BRCA mutation. This is something that we are looking [for] not only in the germline, but also [through] somatic [testing]. It has opened up a whole new [set of] approvals for medications like PARP inhibitors across all subtypes of breast cancer, not only TNBC. In this era, we are moving [towards increased] NGS of those tumors so that we can identify more and more of those targets that will make the treatment of [patients with] breast cancer much more individualized and targeted.

Your co-chair Karen S. Anderson, Md, PhD, of the Mayo Clinic Comprehensive Cancer Center, discussed TNBC management, which now includes the use of immunotherapy in PD-L1-positive patients, ADCs, and chemotherapy. What is your experience with sequencing these agents in practice?

This is an exciting time for [patients with] TNBC because finally we have approvals for several new drugs. Immunotherapy has been a big change in the TNBC field. In the metastatic setting, it has become very important for us to do NGS and a complete IHC on those cancer cells. We usually first approach it by looking at PD-L1 testing. PD-L1 has been a very evasive marker because it didn’t show predictive value in the early-stage setting, but it has more of a predictive value in the metastatic setting. [There’s] still a lot to know about [this marker], but in patients who do have PD-L1–positive tumors, our first [approach to] treatment is to proceed with chemotherapy in combination with immunotherapy.

After that, there are a lot of other drugs approved. One of them that comes to mind is the ADC sacituzumab govitecan, [which has] been recently approved in that specific patient population. Even though this is an ADC, it is known to have significant chemotherapy-[like] adverse effects [AEs]. Beyond this, we have T-DXd, [which is] approved in the HER2-low [population]. In DESTINY Breast-04, close to 60% of patients had TNBC, so this drug could potentially be used [for this population]. Again, the problem [is that] we don’t know too much about sequencing, and [using an] ADC after an ADC is always very challenging. However, that’s how we try to approach it. As mentioned earlier, BRCA testing is going to be very important, and PARP inhibitors [are preferred over] many of those ADCs in the metastatic setting. That’s something that we would favor after immunotherapy if a patient has BRCA positivity.

Please discuss one or two trials in the breast cancer space that are being conducted at your institution.

There is a lot of research going on [at Mayo Clinic]. One area that we’re now working on is evolutionary adaptive therapy. [We are] looking into adjusting chemotherapy or drug doses to move from what we used to call the maximum tolerated dose to a dosage that’s either intermittent or lower dosage. [We aim] to not only avoid toxicity, but hopefully improve the efficacy [of these agents].