NGS and ctDNA Considered in Advanced Breast Cancer After Progression

Ruth M. O'Regan, MD (Moderator)

Professor

Chair

Charles Ayrault Dewey Professorship of Medicine

Department of Medicine (SMD)

University of Rochester Medical Center

Rochester, NY

CASE SUMMARY

• A 52-year-old, postmenopausal woman had a history of grade II, node-negative invasive ductal carcinoma (IDC).
• Estrogen receptor positive (ER+) and progesterone receptor positive (PR+); HER2 immunohistochemistry (IHC) 0; Ki-67 20%​ of the right breast; 21-gene recurrence score, 27
• Initial therapy included chemotherapy, radiation therapy, and 5 years of adjuvant anastrozole.
• Three years after completing anastrozole​, metastatic progression was discovered, including symptomatic bone involvement (multiple vertebrae and bilateral iliac crests).
  • Bone marrow aspiration confirmed ER+/PR+, HER2 IHC 0, stage IV IDC.
  • ECOG performance status: 1
  • Mild anemia
• The patient started letrozole and ribociclib (Kisqali) with denosumab (Xgeva), with good clinical response and marked improvement in her pain​.
  • Required 1 dose reduction to 400 mg ribociclib due to neutropenia.
• Twenty months after starting therapy, routine staging scans showed new FDG-avid sclerotic and lytic bone lesions​.
  • She noted mild increase in lower back pain​.
  • Laboratory studies were normal.

RUTH M. O’REGAN, MD: It looks like most people in the first-line setting would do tissue-based next-generation sequencing [NGS], on its own.... Any thoughts on this?

KASHIF ALI, MD: You can use a company that does both and it doesn't cost the patient anything extra. If [you] do both concurrently, even if you're one of the pilot sites like we are, you can use them concurrently. Certainly, why not just do both if it's not going to cost the patient anything extra? You may possibly get some information out of [either test] if their tissue doesn't come out inadequate.

TIFFANY A. TRAINA, MD: I like the speed with which we get an answer from ctDNA. With a newly diagnosed patient with metastatic breast cancer, I still want that tissue biopsy done to confirm their ER/PR/IHC [status]. But the molecular profiling I find takes a bit longer, so I tend to send off the ctDNA to get a quick answer, so I can start with my planning, but go ahead and send off the tissue-based NGS also.

O’REGAN: I think that's very reasonable as well.

JOSÉ MÉNDOZA, MD: I also like blood-based assays as they may actually capture more molecular abnormalities that may be missed [otherwise] given sometimes heterogeneity or different levels of expression.

DISCUSSION QUESTIONS

• Do you routinely re-biopsy or order ctDNA testing at each progression?
  • Through how many lines of therapy?
  • Which test is preferable?
• Is there a situation in which you would not obtain NGS with disease progression on endocrine therapy [ET] plus a CDK4/6 inhibitor?

TRAINA: My practice is generally at progression I would do ctDNA testing. We know that development of an ESR1 mutation is often a mechanism of resistance to therapy, and it's driven by prolonged aromatase inhibitor exposure. We're more likely to see those [mutations] develop under the selective pressure of aromatase inhibitor use. I do send ctDNA as a rapid turnaround test at progression looking for new actionable mutations, [as well].... There's a lot that we can learn from that testing. I tend to do that at each progression where I am considering an ET and targeted therapy. And often in the journey for our patients with hormone receptor–positive disease, we reach a point where an ET approach isn't necessarily in their best interest anymore, and we're moving on to systemic chemotherapies instead. At that point, I'm less likely to be sending off ctDNA to help guide therapy.

O’REGAN: I agree. I think that's the decision making. I think ctDNA, as you say, is easy to do; you don't have to put patients through a biopsy and the results come back very quickly. I don't think there's, now that we've got ctDNA, a situation where I wouldn't do that on progression of ET and a CDK4/6 inhibitor. I have seen a few patients like this who had very rapid progression on first-line treatment. You don't see that very often—I still think I would send it—but that would be the only instance where I might think twice about it.

MÉNDOZA: The only exception may be, if after many lines of ET, we have exhausted that.... We're looking for the possibility that a tissue biopsy may yield something more than that, something like HER2 low. But that's closer to once you have exhausted all the possibilities in terms of endocrine management.

O’REGAN: That's a good point as well. To go back to what Dr Traina was talking about, with the acquired mutations, so along with ESR1, AKT1, which is a target for capivasertib [Truqap], is acquired. Then HER2 as well, HER2 mutations are rare, but they do occur in ER-positive metastatic disease and there are data with niraparib [Zejula] and trastuzumab and ET in that setting.