Assessing Factors for Sequencing Therapies in ER+ Advanced Breast Cancer

In In The News by Barbara Jacoby


In the first article of a 2-part series, Aditya Bardia, MD, MPH, leads a discussion on what factors influence sequencing treatment for patients with estrogen receptor positive advanced breast cancer.


A 62-year-old woman presented with a 6 cm right breast mass, which has been slowly growing for 1 year with palpable axillary nodes​. Her liver function test was within normal limits and a CT scan showed 2 liver nodules, with the largest being 2 cm​. A bone scan showed extensive disease in thoracic spine and ribs​ and a breast biopsy showed she had grade 2 invasive ductal carcinoma. Her disease was estrogen receptor (ER) and progesterone receptor (PR) positive, her HER2 immunohistochemistry score was 0, and she was BRCA1/2 negative​. A liver biopsy confirmed metastatic disease with similar markers​, T3N1M1. She had an ECOG performance status of 0.

Treatment with letrozole (Femara) plus ribociclib (Kisqali) was initiated​, and bisphosphonate was given to address bone metastasis. A best response of partial response was achieved​ and 30 months after treatment initiation, follow-up imaging showed enlarging liver nodules and 2 new lung nodules with the largest measuring 1.2 cm. Her ECOG performance status was now 1​, her liver function tests were still normal​, and her HgbA1c was also normal.


  • If you saw this patient today, what would be your next step?

ADITYA BARDIA, MD, MPH: The patient [in this case] did start treatment with ribociclib aromatase inhibitor [AI]. It worked well, they had a partial response, but then 13 months after treatment the patient had disease progression, and now had new lung nodules. The question is what to do next.

So, what would you consider? Would you do a biopsy? Would you change therapy, or would you do genomic testing? If you do genomic testing, would you do it based on tissue or circulating tumor DNA [ctDNA]?

FRANTZ FRANCISQUE, MD: I usually do a biopsy when the patient’s disease progresses, to check their mutation status, [and if there is an actionable target]. I usually will do it on their tissue, preferably.

KETAN DOSHI, MD: We can do a liquid biopsy as an ESR1 mutation can be detected on a liquid tumor biopsy.

BARDIA: That’s a good point, especially for acquired alterations like ESR1. You might miss them if you sequence the primary tumor, so either a plasma-based biopsy or a fresh tissue biopsy of a metastatic lesion would be reasonable. That could also help with testing for ER, PR, and HER2.


  • ctDNA was sent for genomic testing. It did not show PIK3CA, ESR1 or other actionable mutations to target.

BARDIA: Now, in this case, the patient had plasma-based genotyping done. It did not show mutations in neither PIK3CA nor ESR1. Essentially, there were no actionable mutations, which is not an uncommon scenario. It is difficult to predict who would have [an actionable mutation] versus those who do not have one, therefore you have to sequence everyone…. So let’s [discuss a treatment option like] endocrine therapy plus everolimus. Would anyone choose that regimen?

OLEG GLIGICH, MD: I would choose that. It is a standard BOLERO-2 [NCT00863655] regimen that has withstood the test of time.1 It has a good response rate and duration of response. That being said, the landscape is changing a lot now, and depending [on the results of their next-generation sequencing], you can have other options to use.

BARDIA: It is a reasonable option. Have you had any issues with mucositis [using everolimus plus exemestane (Aromasin)]? How do you manage it with everolimus?

GLIGICH: If you prescribe the regimen enough, you know that if you utilize dexamethasone [alongside the combination therapy], most patients do relatively well [with mucositis].

BARDIA: It is also much less [of an issue] now with the use of the steroid mouthwash. So, as long as you use the correct mouthwash, particularly in the first 2 cycles [of treatment], that’s where you see mucositis [and can treat it]. The BOLERO-2 regimen is reasonable then, especially given that this patient did not have an ESR1 mutation. If there was an ESR1 mutation, if you were to still choose endocrine therapy with everolimus, I would lean towards [combining fulvestrant (Faslodex)] and less everolimus over exemestane plus everolimus in the setting of [patients whose disease harbors an] ESR1 mutation.

JEFFREY BUBIS, DO: So, you said within the ESR1-mutated population you would lean towards [giving those patients] fulvestrant. Would that be regardless of whether they had progressed on fulvestrant with a CDK4/6 inhibitor?

BARDIA: That is correct. Since ESR1 mutations are usually acquired alterations to an AI, because AIs lower estrogen, the tumors develop a mutation in the ER, which makes it estrogen-independent and is how patients become resistant to AIs. However, drugs that target ER directly, like fulvestrant, in principle would work in that setting. The problem is fulvestrant is not [great in this setting], and that is why there is interest in oral selective ER degraders [SERDs] in the ESR1 mutation setting. Still, I would prefer fulvestrant over an AI [for a patient with an ESR1 mutation in their disease].

POORVI DESAI, MD: Do you ever see ESR1 mutations in patients who have not been subject to anti-estrogen endocrine therapy?

BARDIA: I have not seen that, and we have looked at resistance to tamoxifen.2 In general, it doesn’t come up. I have not seen it in the setting of fulvestrant either. It is usually with an AI, which is why if you sequence for a primary breast cancer, in general, we don’t see ESR1 mutations because it is an acquired alteration.

The second option that [has been discussed is] fulvestrant plus a CDK4/6 inhibitor. Would anyone who would choose that option care to comment?

PHU N. TRAN, MD: To me, if the patient had disease progression but it doesn’t look like they are in any crisis…then this regimen would be more tolerable than the previous one. It has an indication for that, and [patients have a] pretty good experience with the combination in terms of tolerability and some efficacy as well.3

BARDIA: If you use a CDK4/6 inhibitor, would you use the same one, [which was ribociclib in this case], or would you switch the drug?

TRAN: I don’t know if there’s any difference in terms of efficacy between the 2 after the patient becomes resistant to one. So, I would probably keep the 1 I used, unless there’s new data that I don’t know about.

BARDIA: In general, we would use intravenous agents later on. We would prefer to use oral agents [in this case], although fulvestrant is an intramuscular shot before going to chemotherapy.


1. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366(6):520-9. doi:10.1056/NEJMoa1109653

2. Brett JO, Spring LM, Bardia A, Wander SA. ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer. Breast Cancer Res. 2021;23(1):85. doi:10.1186/s13058-021-01462-3

3. Mittal A, Molto Valiente C, Tamimi F, et al. Filling the gap after CDK4/6 Inhibitors: Novel endocrine and biologic treatment options for metastatic hormone receptor positive breast cancer. Cancers (Basel). 2023;15(7):2015. doi:10.3390/cancers15072015