ctDNA Helps Identify Targets in HR+, HER2- Metastatic Breast Cancer

In In The News by Barbara Jacoby

From: targetedonc.com


A 56-year-old, postmenopausal woman presents with a palpable right breast mass with no clinically abnormal axillary lymph nodes. Core biopsy showed the patient had grade II invasive ductal carcinoma (IDC), was estrogen receptor-positive (ER+)/progesterone receptor-positive (PR+), and had HER2 immunohistochemistry (IHC) of 0; Ki-67 was at 33%. Lumpectomy and sentinel lymph node (SLN) biopsy showed a 3.0 c grade 2 IDC, but 2 SLNs were negative for malignant cells. The patient had a 21-gene recurrence score of 27 then received docetaxel and cyclophosphamide for 4 cycles followed by radiation therapy and completed 5 years of adjuvant aromatase inhibitor (AI).

Three years later after completion, she reported right-sided abdominal pain and mild nausea. A CT scan showed 3 suspicious liver lesions (right lobe, largest 2 cm) and a liver biopsy showed adenocarcinoma consistent with breast primary ER+/PR+, HER2 IHC 0. Her liver enzymes were normal and comprehensive molecular testing from the tissue biopsy showed no actionable alterations. AI plus palbociclib (Ibrance) was initiated. The therapy was tolerated well, with grade 2 neutropenia that did not require dose modification of palbociclib. Twenty months later, follow-up imaging showed increased size of both liver nodules and 2 new lung nodules, the largest measuring 0.9 cm. Her ECOG performance status is now 0, and liver enzymes are still normal.


  • Do you repeat biomarker testing at this point?
  • If you saw this patient today, what would be your next step?​

HOPE S. RUGO, MD​, FASCO: In this situation, we’re better off getting next generation sequencing [NGS], because it’s going to take at most 2 weeks to get results, and these patients have 2 weeks. So, it’s better for you to find out whether a patient has a mutation before you go on to the next step in treatment, because that may both change what you’re going to do as a standard therapy, and also provide clinical trial options in the local area that may be of interest for your patient. But even within standard therapy this is important [to do].

Now, the question about doing tissue testing from liver or blood is an important one, and an interesting one. Generally, in somebody who I biopsy their liver 20 months before, I’d probably send circulating tumor DNA [ctDNA] rather than re-biopsy their liver [when considering the patient’s] safety and pain. When I’m worrying that their tumor isn’t ER+ anymore, then I’m going to biopsy the liver. Or, for example, one of my patients had progression with a large gastric mass invading her pancreas that I biopsied, because that looked [out of the ordinary]. So, it depends on what you’re looking for. If the patient has no ctDNA, which…a patient with a very bone-only low tumor burden might not have a lot of ctDNA, you might want to biopsy the liver as well.

So, what would be your next step is now the question. What platform or methodology do you use? Do you send out your NGS?

ALBERT DEKKER, MD: I would chose not to biopsy the patient [in this case], and not to do a liquid biopsy. I would typically do that after the second line of therapy, but I do send [all the tests] out. I do not have the ability to do any testing in house.

RUGO: It’s interesting, because now that we have a drug for patients who have an ESR1 mutation that works better than fulvestrant. [With elacestrant (Oserdu)], I think it’s a new era where we might be thinking [to test the patient] right away.1 Plus, we might be combining some of our drugs like targeting PI3K in the second-line setting. It has become more important for us to get NGS before we go to second-line [therapy] to understand [our options] better. So then, do you get genomic testing at each progression? Or only at certain periods of time?


RUGO: I think that a lot of people are doing that now. It’s sometimes frustrating, because there are specific genomic changes that we can target, but there are not very many of them [in this disease]. So, if we run out [of targets]—I keep waiting for somebody to have a mutation that I can target and then they don’t, but they still have bad cancer, so this is a work in progress.

CHAUDHARY: With ESR1 mutations, they seem to be more common with second progression. So, would you still do another NGS to look for the ESR1 mutation [at that point]?

RUGO: You could, and I think it goes up to about 40% [of patients have an ESR1 mutation on second progression] when they have untreated disease in the first-line metastatic setting….2 So, it seems like now when we’re doing ctDNA [tests], we find [the ESR1 mutation] more frequently…and you may see multiple mutations as well. So, I do test [for mutations] both in the second- and third-line setting but I see quite a number that pop up after, or during, the first line of therapy.

MELODY BENJAMIN, MD: When do you do the ctDNA [collection]? Do you do that when you are not able to biopsy someone or put them through a biopsy? What I don’t understand what the advantage or disadvantage of that would be, other than putting someone through a biopsy.

RUGO: That’s the most obvious one, but I think the other problem is that sometimes you can do a liver biopsy and you just get fragments of tumor; you just don’t get that much tumor and you can’t even do the test. You can’t get a core from the lung safely, and bone marrow has decalcification so it’s not informative. So, the advent of having ctDNA has been incredible because not only can you check when you don’t want to do a biopsy or can’t, but you also can do serial testing that allows you to see mutations that are acquired over time. It has tremendous value for those reasons, but it’s also easy to collect.


1. Varella L, Cristofanilli M. Evaluating Elacestrant in the management of ER-positive, HER2-negative advanced breast cancer: evidence to date. Onco Targets Ther. 2023;16:189-196. doi:10.2147/OTT.S400563

2. Brett J, Spring L, Bardia A, et al. ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer. Breast Cancer Res. 2021;23(85). doi:10.1186/s13058-021-01462-3