Biomarker testing will fuel the next wave of therapeutic innovation in breast cancer


Significant advances have changed the treatment paradigm in various areas of breast cancer, including treatment options for patients with HER2-positive metastatic breast cancer, HER2-negative breast cancer, and breast cancer. triple negative breast (RHN) positive for hormone receptors. . However, further advances in treatment will come from increased knowledge of breast cancer biomarkers, according to Christos Vaklavas, MD.

“We are increasingly recognizing that we need to understand the biology [of breast cancer] better. Our approaches must be adapted to the biology of cancer. Right now we’re using crude biomarkers, like PD-L1, or even before that, [estrogen receptor (ER) and] HER2,” Vaklavas said in an interview with Live® following an Institutional Perspectives in Cancer (IPC) webinar on breast cancer, which he chaired.

In the interview, Vaklavas discussed highlights from the meeting, including the increased focus on studying tumor biology in breast cancer, as well as the changing treatment landscapes for HER2 breast cancer. -positive, HR-positive breast cancer, HER2-negative breast cancer and TNBC. He is the physician in charge of breast cancer at the Huntsman Cancer Institute and an associate professor of internal medicine in the Division of Oncology at the University of Utah.

Live®: Your presentation was about HR-positive, HER2-negative breast cancer. What are the relevant updates in this space?

Vaklavas: Adding CDK4/6 inhibitors to the backbone of hormone therapy, whether letrozole, anastrozole, or potentially exemestane, was associated with equal survival benefit without progress. We have started to see benefits in overall survival [OS]specifically with ribociclib [Kisqali]. We do not know what is the pharmacological basis for this benefit specifically with ribociclib. Whether this changes practice or whether we should start prescribing ribociclib, we don’t know yet. [These developments] give us confidence that CDK4/6 inhibitors are associated with benefits in OS, but perhaps not all to the same extent.

The second takeaway [involves] oral selective ER degraders [SERDs], a new class of drugs that is emerging. The EMERALD Phase 3 trial [NCT03778931] was positive with elacestrant, but we found that a second study, the phase 2 trial AMEERA-3 [NCT04059484] with amcenestrant was negative. This new generation of SERDs may be effective in patients who have CSR1 mutations, whether they occur [at diagnosis] or they arise as a result [of treatment]and [the latter] is significantly more common. These mutations [tend] occur due to therapeutic pressure with first-line treatment.

The third point [relates] to what comes [down the pipeline]: a series of agents for patients [who] progress on 1, 2 or even 3 lines of hormone therapy. There are new antibody-drug conjugates [that are being studied in] HER2-positive and HER2-low breast cancer. In the coming months with the announcement of these results, [treatment options] will work out.

Mei Wei, MD, of the University of Utah, spoke about HER2-positive early-stage and metastatic breast cancer. What are some of the updates we’ve seen there?

[New] HER2[-targeted agents] move [into the] second line [setting]. Recently in the New England Journal of Medicinewe saw [updated data the phase 3 DESTINY-Breast03 trial [NCT03529110] with fam-trastuzumab deruxtecan-nxki [Enhertu] vs ado-trastuzumab emtansine [Kadcyla; T-DM1] in patients with HER2-positive breast cancer. [Trastuzumab deruxtecan] has been incorporated into the National Comprehensive Cancer Network guidelines, and, [potentially] soon, the FDA will approve trastuzumab deruxtecan as a second-line treatment in the metastatic setting.

Third-line treatments and beyond are still evolving at this time. We know that tucatinib [Tukysa] probably got a head start in [patients] with brain metastases, but there is new evidence that [trastuzumab deruxtecan] may also be effective in patients with active brain metastases. This hasn’t been looked at specifically, but there are studies looking into it right now. [This could be] practice changing.

Currently, a taxane, trastuzumab [Herceptin]and pertuzumab [Perjeta] is the preferred first-line treatment in the metastatic setting. [There have been] no change in adjuvant or neoadjuvant setting at this time. In the first-line metastatic setting, a taxane, pertuzumab and trastuzumab have been associated with OS benefits. However, many studies are in progress in [the first-line] space to challenge the dogma of a taxane, trastuzumab and pertuzumab.

In DESTINY-Breast03, the rate of interstitial lung disease (ILD) was lower than in the phase 2 trial DESTINY-Breast01 (NCT03248492). What are some of the intervention and management strategies that have led to this reduction?

Early recognition [was key]. An algorithm for management [of ILD] and the aggressive stopping of [trastuzumab deruxtecan] with grade 2 or greater ILD reduced the rate to approximately 10%, which is not significantly different from [the rate in DESTINY-Breast01 of] about 13%. There is still a lot to learn about the ILD and [our management] algorithm. There is still much to learn about natural history. [Does increased exposure to the drug] increase the risk of ILD? Is there something idiosyncratic, something special about these patients who develop ILD?

We have to understand that, and I have patients who have PID or lymphocytic lung carcinomatosis. At least until recently, we were appalled at the idea of ​​giving these patients HER2[-targeted therapy]. Now I’m a little bolder and giving these patients HER2[-targeted therapy] with the idea that the disease will go into remission, and [we can] worry about ILD later.

Namita Chittoria, MBBS, of the University of Utah, focused on TNBC. What is important for practicing oncologists to know about advances in this area?

The biggest breakthrough in recent years is the approval of sacituzumab govitecan-hziy [Trodelvy] as third-line treatment [for patients with unresectable locally advanced or metastatic TNBC who received 2 or more prior systemic therapies, with at least 1 of prior therapy for metastatic disease]. The data is compelling to use this drug in patients with metastatic breast cancer.

The second biggest advancement or evolution in the practice was the approval of pembrolizumab [Keytruda] in the adjuvant setting alongside carboplatin plus paclitaxel, followed by epirubicin and cyclophosphamide in patients with early stage, non-metastatic, stage II or III TNBC. There are some developments in terms of the adjuvant setting, such as the OlympiaA phase 3 trial [NCT02032823]who rated [adjuvant] olaparib [Lynparza] in patients with a germline BRCA1/2 mutation.

Moving on to Cristina DeCesaris, MD, University of Utah’s presentation on new radiotherapy regimens for de-escalation in breast cancer, what would you say has emerged in this space?

Techniques are improving and they are becoming safer. The biggest advancement is that there are many clinical trials whose results will change practice, as they incorporate biological characteristics of the disease captured with [the Oncotype DX test]mainly to increase or decrease radiation therapy. [The field is] move away from one size [treatment approach] and studies the biology of the disease and adapts accordingly [a patient’s] radiotherapeutic approach.

Do you have any anecdotal experiences with defused therapy?

Our facility is participating in the I-SPY Phase 2 trial [NCT01042379]. Until recently, the dogma was to complete a set of agents in the preoperative setting. I-SPY has pushed the boundaries a bit further, and with the use of MRIs and biopsies, we get what is called a pre-residual cancer burden [RCB]. Pre-RCB [gives] the likelihood of having obtained a complete pathological response [pCR] based on MRI and tumor biopsy.

If the pre-RCB is high, the patient has a high probability of having achieved a pCR. Then they do not need to receive epirubicin and cyclophosphamide, the second half of treatment. So far, with all of the patients we have submitted to pre-RCB, their pre-RCB [result] was consistent with [their achieving] a full answer. [In those cases,] we omitted epirubicin and cyclophosphamide, and the patients were operated on.

Is there any ongoing or planned research at the Huntsman Cancer Institute that you wanted to highlight?

The FORESEE trial [NCT04450706] what we are doing incorporates the development of patient-derived xenografts and patient-derived organoids in patients with HR-negative breast cancer. [The study is examining] newly diagnosed patients with metastatic breast cancer––either TNBC [in the] first-line or HR-positive, HER2-negative breast cancer having exhausted endocrine options. We take a biopsy and we generate organoids derived from the patient. These organoids are miniature reflections of the patient’s cancer, and we leverage these organoids to perform mid-throughput drug screens.

We integrate the information we collect from these mid-rate medication screens, [along] with circulating tumor DNA and tumor tissue DNA testing and compile a report that we share with the patient, with the most likely medications the patient will respond to [to] as a second-line treatment.

We would like to predict what is the optimal treatment for second-line patients with metastatic TNBC or metastatic HR-positive, HER2-negative breast cancer who has exhausted all endocrine options, because at present the choice of Second-line treatment comes down to a bit of guesswork. We [usually] give patients chemotherapy that cancer has never seen before, assuming these chemotherapies will have the greatest benefit. However, we call it Functional Precision Oncology because essentially we are taking it one step further. We’re not looking at DNA and RNA right now. We take snapshots of the genomic composition of cancer. But we leverage these organoids to perform mid-throughput drug screens.

What other questions are trying to find answers in clinical research on breast cancer?

Some of the questions are about what the future holds and how all these new therapies are going to be integrated. The KEYNOTE-355 Phase 3 trial [NCT02819518] led to the current standard of care chemotherapy with pembrolizumab. The key question I ask myself is whether we should treat everyone with this intensive regimen rather than spreading a few agents, spreading a few cycles or spreading certain toxicities. [over time] in patients who are going to do well anyway. As a scientific community, we conduct clinical trials to understand [that and] defuse therapy. We are not there yet, but I hope we will get there.

How would you sum up all the advances we’ve seen recently in breast cancer, where the field is now and potentially where it’s headed?

Now we are [relying more on] MammaPrint, OncotypeDX, next generation sequencing, PIK3CA [mutation status], mutational load, and mismatch repair competence or deficit. All these biomarkers have more and more therapeutic implications. Advances in understanding breast cancer biology bring more biomarkers and more biomarker-focused therapeutic interventions [to patients].


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