Liquid Biopsy Shown to Be Effective in Assessing Response to Breast Cancer Drugs

Hand in surgical glove holding up small beaker of blood.

Analyzing a patient blood sample can reveal mutations present in free-floating tumor DNA and guide clinicians in tailoring treatments.

Two new studies led by Memorial Sloan Kettering researchers demonstrate the potential of the liquid biopsy, which uses blood samples drawn from cancer patients to analyze trace amounts of free-floating tumor DNA.

Research shows that this minimally invasive approach can reveal essential information about which genetic mutations may be driving the cancer — especially when it is advanced — and can help predict how specific patients will respond to certain therapies.

The studies were led by MSK physician-scientist Sarat Chandarlapaty and Physician-in-Chief José Baselga and reported this week at the San Antonio Breast Cancer Symposium.

A liquid biopsy offers advantages over a conventional tumor biopsy. Since surgery is not needed, patients can be tested more frequently. In addition, a liquid biopsy may provide a more global — and therefore more accurate — picture of the patient’s cancer. Sequencing free-floating tumor DNA may better capture the diversity of genetic alterations found in cancer cells in different parts of the body, including the primary tumor and metastases.

“Testing for mutations in the blood can help identify the population of patients who might benefit most from certain drugs or drug combinations,” Dr. Baselga says. “The liquid biopsy analyses in these two studies gave us incredibly important information. Going forward, liquid biopsy will become standard practice for testing new drugs monitoring response to current therapies.”

Both studies involved women whose breast cancers were hormone receptor–positive, meaning that their cancer cells bear receptors — proteins — that pick up signals from hormones telling the cells to grow. These patients often receive drugs called aromatase inhibitors that slow or stop the growth of hormone-sensitive tumors (a treatment called hormone therapy). Although aromatase inhibitors are usually effective, some patients develop resistance, so researchers are studying therapies that combine new drugs with the standard treatment.

Mutations Are Common and Lead to Worse Outcomes

Dr. Chandarlapaty and colleagues analyzed liquid biopsies from 541 patients enrolled in the phase III BOLERO-2 clinical trial, which previously found that adding the drug everolimus to the aromatase inhibitor exemestane improved outcomes for most advanced estrogen receptor (ER)–positive breast cancer patients. (ER-positive patients have cancer cells with an estrogen receptor on their surface, allowing the hormone to fuel their growth.)

Their analysis of the blood samples revealed that women had significantly worse overall survival if their cancer cells carried one or both of two specific mutations that occur in the gene that makes the estrogen receptor: D538G and Y537S. The researchers detected the D538G mutation in 83 patients, the Y537S mutation in 42 patients, and both mutations in 30 patients.

“There is a real diversity in how tumors respond to drugs targeting the estrogen receptor, and therefore a real diversity in patient outcomes,” Dr. Chandarlapaty explains. “We wanted to find out whether mutations in this receptor are common in patients with advanced breast cancer — and if so, whether this affects how well the patients respond to treatment. This study shows us that people with the mutations don’t respond to the currently used therapies as well and die from their disease sooner.”

His team was surprised by how common the D538G and Y537S mutations were in this patient group — and especially by how often the mutations were detected in the blood samples compared with samples from the primary tumors.

He says there are likely two reasons for this: “Tumors are often heterogeneous, so a sample from the tumor may miss cancer cells containing a specific mutation. In addition, some mutations develop as a result of resistance to treatment, so a liquid biopsy may detect mutations not found in the primary tumor sample, which often is taken earlier.”

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Presence of Mutation Predicts Success of Treatment

A team led by Dr. Baselga found that detecting a mutated PIK3CA gene in a blood sample can predict how well some advanced breast cancer patients may respond to the experimental drug buparlisib. A mutated PIK3CA gene can activate the PI3K disease pathway, which promotes resistance to hormone therapies. Buparlisib blocks the PI3K pathway, and thus may increase a woman’s sensitivity to hormone therapy.

The team analyzed blood samples from 587 patients entering the phase III BELLE-2 trial, which is testing the safety and effectiveness of adding buparlisib to the standard hormone drug fulvestrant to treat women with ER-positive breast cancer who have grown resistant to aromatase inhibitors.

A simple blood test proves to be quite sensitive in detecting very important alterations.
Sarat Chandarlapaty Physician-Scientist

While the entire study population benefited from the combination therapy, the presence of a PIK3CA mutation in a patient’s liquid biopsy had the most striking effect. Among patients who carried the PIK3CA mutation, those that received buparlisib plus fulvestrant had seven months of progression-free survival (PFS) — the length of time after the treatment during which the patient lived with the cancer and it did not get worse — compared with only 3.2 months for those receiving fulvestrant plus a placebo.

“These effects are quite dramatic in patients with the PIK3CA mutation — an increase from three months to seven months is huge,” Dr. Baselga said. “For the first time, we show that inhibiting the PI3K pathway may be a viable option for patients with hormone therapy–resistant breast cancer.”

Among those who did not have the PIK3CA mutation, there was no difference in PFS, suggesting that adding buparlisib did not provide any advantage. Being able to identify patients who will not benefit from the new drug combination is also important, as the side effects proved to be significant, with 25 percent of patients having serious adverse events such as high blood sugar and potential early signs of liver damage.

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A New Way of Monitoring Tumors

Both of these highlighted studies provide a glimpse into how the liquid biopsy has emerged as a powerful diagnostic and treatment tool for people with cancer. Dr. Chandarlapaty emphasized the essential role this technique will play in guiding the development of new therapies.

“This is a vital point for the medical community — a simple blood test proves to be quite sensitive in detecting very important alterations,” he says. “Finding out which cancers respond best to which treatments is key to helping make breast cancer care more precise and effective.”

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The study led by Dr. Chandarlapaty was supported by Novartis and MSK’s Center for Metastasis Research. The study led by Dr. Baselga was funded by Novartis.


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Interesting article...I'm curious as to how this new technology might be used in my case. I was diagnosed w/ stage 2A estrogen-positive breast cancer. After a bilateral mastectomy, testing showed my tumor to be extremely responsive to hormone therapy, so I'm currently taking tamoxifen, with the idea that I'll be switched to the aromatase inhibitors w/in the next year or two. Other than manual exams by my surgeon and oncologist, I feel I'm not being watched too closely for recurrence. How does a patient know (in a timely fashion) if she's developed resistance to the hormone therapy, and when this new blood screening would prove to be crucial?

Dear Lisa, we are sorry to hear about your diagnosis. It’s best to follow up with your oncologist to discuss whether any additional tests (whether they be imaging exams or blood tests) are needed in your particular situation to determine when and if you develop disease recurrence. Thank you for reaching out to us.

I read with great interest the information about the use of liquid biopsy. Here are my questions:
1. How does an early stage hormone positive patient know whether her aromatase inhibitor is actually working?
2. How does the oncologist or patient discover that the AI has stopped working?

3. Is the liquid biopsy used only in advanced breast cancer patients with metastasized tumors, or can it be used in early stage patients also?
4. For an early stage lymph negative breast cancer who has had bilateral mastectomy does MSKCC recommend any treatment other than AI or in conjunction with AI?

Thank you for your help.

Thank you for reaching out. Unfortunately, we cannot answer personal medical questions as every case is affected by a large number of factors (including whether an aromatase inhibitor is working as well as the best treatment for a patient).

In addition, although it holds great promise, liquid biopsy is still in an investigative stage. The use of this test at MSKCC for breast cancer patients is being done only as part of a research protocol which is not usable for clinical management.

If you would like to make an appointment with a Memorial Sloan Kettering physician for a consultation, please call our Physician Referral Service at

800-525-2225 or go to

Thanks for your comment.

Can a liquid biopsy be used at this time instead of a regular pelvic biopsy in a clinical trial of estrogen-positive breast cancer?

Dear Mary, liquid biopsies are still experimental at this time and are not part of standard clinical care. It’s too early to know in which circumstances they will be most useful. Thank you for your comment.

In the two years since the publication of this article, has liquid biopsies proven their worth? Are they now included in standard or even non-standard clinical care? It looks as if the liquid biopsy could be used to track the efficacy of the patient's treatment. Has it been used in this domain?

Dear Alan, liquid biopsies continue to be a growing area of research, including for use in tracking the efficacy of treatments, but they are not yet considered standard care for any type of cancer. Thank you for your comment.

Are liquid biopsies now included in standard or even non-standard clinical care? Are they a routine at the MSK? Any information on other centers outside the States? Is the liquid biopsy used by now to track the efficacy of the patient’s treatment including neoadjuvant treatment? Is it sensitive enough and specific enough to monitor AI neoadjuvant treatment for over a year meant to achieve lumpectomy rather than mastectomy? Would it replace MRI especially in the case of lobular carcinoma or if done frequently enough, would it catch resistance to therapy before the MRI is performed?

Dear Daniela, liquid biopsies are currently done at MSK only as a part of certain clinical trials. They have not yet become the standard of care for any types of cancer. Thank you for your comment.

Are liquid biopsies only used to assess mutations or can they be used to assess disease progression in patients that have no measurable tumor. Also can you help me find liquid biopsy related clinical trials that are completed or ongoing so I can keep track of this fascinating development and how it might help me. Thanks, LG