Capturing Tumor Evolution With Serial Biopsies May Guide Treatment Changes to Benefit Patients With Breast Cancer

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Molecular testing and genomic testing are now considered standard of care in breast cancer, guiding treatment decisions in early breast cancer and targeted therapies in the metastatic setting. “But tumors evolve,” Virginia Kaklamani, MD, DSc, reminded participants at the 2022 Lynn Sage Breast Cancer Symposium,1 “and the only way for us to capture this evolution is by doing serial biopsies, preferably liquid biopsies, so we can see how we might change our treatment to benefit patients.”

Dr. Kaklamani is Professor of Medicine and Leader, Breast Oncology Program, Mays Cancer Center, UT Health, San Antonio, MD Anderson Cancer Center. The symposium was hosted by the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago.

Capturing Modifications

Dr. Kaklamani cited the PADA-1 trial2 as a “fascinating trial” that demonstrated the value of capturing tumor modifications. The study recruited more than 1,000 women with hormone receptor–positive, HER2-negative metastatic breast cancer and no prior systemic treatment for metastatic disease.

“Tumors evolve, and the only way for us to capture this evolution is by doing serial biopsies, preferably liquid biopsies, so we can see how we might change our treatment to benefit patients.”
— Virginia Kaklamani, MD, DSc

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In the first line, patients “received an aromatase inhibitor plus palbociclib,” Dr. Kaklamani noted. “But then they received serial blood tests checking for blood ESR1 mutations. If patients had increasing blood ESR1 mutations, they were randomly assigned either to continue therapy with an aromatase inhibitor plus palbociclib or to switch to fulvestrant plus palbociclib.”

The patients who switched to fulvestrant, a selective estrogen receptor degrader (SERD), had a median progression-free survival of 11.9 months vs 5.7 months for those continuing standard care. Patients who crossed over after clinical disease progression “did not do as well as those who started fulvestrant where there was rising blood ESR1,” Dr. Kaklamani reported, and they had a median progression-free survival of 3.5 months. “We should be capturing these blood ESR1 modifications,” Dr. Kaklamani stated.

Enter Elacestrant

Another SERD, elacestrant, was tested in “a pivotal trial, which will likely lead to the approval of this drug in breast cancer,” Dr. Kaklamani predicted. The EMERALD trial3 included patients with metastatic estrogen receptor–positive, HER2-negative breast cancer who experienced disease progression or relapse on or after one or two lines of endocrine therapy for advanced disease, one of which was given in combination with a CDK4/6 inhibitor. Patients were randomly assigned to receive either elacestrant or investigators’ choice of fulvestrant or an aromatase inhibitor.

“Patients who had an ESR1 mutation and received elacestrant did better,” with clinically meaningful improvements in progression-free survival, “showing that these oral SERDs can overcome endocrine resistance in patients with an ESR1 mutation,” Dr. Kaklamani stated.

Early-Stage Breast Cancer

ASCO guidelines list several biomarker assays for adjuvant endocrine therapy and chemotherapy in patients with early-stage breast cancer, with “Oncotype DX having the highest level of evidence, followed by MammaPrint,” Dr. Kaklamani said. The assays are useful for patients who are estrogen receptor–positive and node-negative or have one to three positive nodes.

The TAILORx trial randomly assigned patients with breast cancer into low, intermediate, and high risk based on Oncotype DX scores, with the low-risk group receiving endocrine therapy alone, the high-risk group receiving chemotherapy and endocrine therapy, and the intermediate-risk group randomly assigned to hormone therapy with or without chemotherapy.


  • The Breast Cancer Index (BCI) is the only test recognized by the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology and ASCO to predict which patients are likely to benefit from the extension of adjuvant antiestrogen therapy beyond 5 years.
  • The BCI is indicated for use in women diagnosed with hormone receptor–positive, lymph node–negative or lymph node–positive, early-stage, invasive breast cancer who are distant recurrence–free.

“The prognostic results in the low-risk group were exceptionally good, with an invasive disease–free survival of 93.8%, showing this group is doing so well that it is extremely unlikely chemotherapy would benefit those patients,” Dr. -Kaklamani reported. In the intermediate-risk group, some patients younger than age 50 “had a small, but potentially clinically meaningful improvement in their outcomes with the addition of chemotherapy.”

Dr. Kaklamani continued: “Another large trial, RxPONDER, looked at patients with one to three positive lymph nodes. Overall, there was no benefit from chemotherapy in postmenopausal patients, but premenopausal patients had clinically meaningful benefits from chemotherapy,” a 4.9% improvement in invasive disease–free survival. “I think most oncologists would agree about recommending chemotherapy for the majority of these patients,” Dr. Kaklamani said.

Discordant Results

The MINDACT trial used the 70-gene profiler MammaPrint to evaluate patients with early-stage breast cancer. If clinicopathologic and genomic risks were both low, patients received endocrine therapy (if they were estrogen receptor–positive) or no therapy. If clinicopathologic and genomic risks were both high, patients received chemotherapy. In the discordant cases, where one risk category was high and the other was low, the patient was randomly assigned to treatment.

These most recent data showed “the group with the best prognosis was the group that was concordantly low—low clinical and low genomic risks. The group with the worst prognosis was the one where both clinical and genomic risks were high. The discordant groups were somewhere in between,” Dr. -Kaklamani reported. “The differences were not huge. These patients overall did pretty well, with between 90% and 97% distant metastasis–free survival. So, this trial was more of a prognostic trial and not a chemotherapy predictive trial.”

Extended Endocrine Therapy

Molecular profiles may also help to determine who may benefit from extended endocrine therapy. A trial with letrozole found that patients with a low Breast Cancer Index (BCI) did not benefit from extended endocrine therapy, but patients with a high BCI had an absolute benefit of 16.5%.4 “Based on this, we can talk to a patient about whether she should continue endocrine therapy for another 5 years,” Dr. Kaklamani said.

A substudy of the aTTOm trial showed that node-positive patients “had a small improvement in outcomes by taking tamoxifen for 10 years instead of 5,” Dr. Kaklamani noted, but patients with a high BCI had the greatest benefit. The BCI may enable clinicians “to discuss with patients whether they will receive a benefit from extended endocrine therapy,” she commented.

The new HER2DX assay incorporates 17 genomic, clinical factors, and other factors to predict prognosis and guide treatment in HER2-positive patients, “which we don’t really have an assay for now,” Dr. Kaklamani noted. It is “unclear how we are going to use this in the future or whether we are going to use this clinically.” 

DISCLOSURE: Dr. Kaklamani has served as a consultant or speaker for Menarini, Exact Sciences, and Pfizer.


1. Kaklamani V: Molecular biomarkers and genomic assays in breast cancer. 2022 Lynn Sage Breast Cancer Symposium. Presented September 22, 2022.

2. Bidard FC, Hardy-Bessard AC, Bachelot T, et al: Fulvestrant-palbociclib vs continuing AI-palbociclib upon detection of circulating ESR1 mutation in HR+ HER2– metastatic breast cancer patients: Results of PADA-1, a UCBG-GINECO randomized phase 3 trial. 2021 San Antonio Breast Cancer Symposium. Abstract GS3-05. Presented December 9, 2021.

3. Bardia A, Neven P, Streich G, et al: Elacestrant, an oral selective estrogen receptor degrader vs investigator’s choice of endocrine monotherapy for ER+/HER2– advanced/metastatic breast cancer following progression on prior endocrine and CDK4/6 inhibitor therapy: Results of EMERALD phase 3 trial. 2021 San Antonio Breast Cancer Symposium. Abstract GS2-02. Presented December 8, 2021.

4. Sgroi DC, Sestak I, Cuzick J, et al: Prediction of late distant recurrence in patients with oestrogen-receptor-positive breast cancer. Lancet Oncol 11:1067-1076, 2013.