Circulating Tumor DNA and Late Recurrence

– Personalized assays identified high-risk patients

by Jeff Minerd , Contributing Writer, MedPage Today August 16, 2022

Personalized circulating tumor DNA (ctDNA) assays identified women with HR-positive, HER2-negative breast cancer who had late recurrences, suggesting that these high-risk patients can be identified for potential interventions, researchers said.

"To our knowledge, these are the first data on plasma ctDNA analysis for MRD [minimal residual disease] detection in late adjuvant HR+ breast cancer, a major and understudied cause of more than 40,000 annual breast cancer-related deaths in the United States," Heather Parsons, MD, MPH, of Dana-Farber Cancer Institute in Boston, and colleagues wrote in a "Rapid Communication" article in the Journal of Clinical Oncology.

Parson's group performed whole-exome sequencing on primary tumor samples from 103 patients with high-risk stage II-III HR+ breast cancer who were diagnosed more than 5 years prior and had no clinical evidence of recurrence. The somatic mutations detected were used to design, for each patient, a personalized ctDNA RaDaR [residual disease and recurrence] assay.

Over the next 2 years, the team collected plasma and performed the personalized ctDNA tests at routine visits every 6-12 months. Eight patients (10%) had positive MRD testing. Of these, six (7.2%) developed distant metastatic recurrence. The median ctDNA lead time was 12.4 months. One patient had a local recurrence not identified by the test.

"Here, 10% of patients were MRD-positive more than 5 years from diagnosis despite no clinical evidence of metastatic recurrence at the time of first plasma sample," Parsons and colleagues said. "Importantly, ctDNA analysis identified MRD in all cases of distant recurrence. ctDNA analysis did not identify MRD in the case of local recurrence in this study, consistent with previous reports. Additionally, ctDNA was detected in two patients who had not experienced clinical recurrence at the time of last follow-up, although imaging had not been obtained in these cases."

In addition, "these data suggest that there may be a period in which MRD is detectable via ctDNA before overt, late breast cancer recurrences. This will inform future studies of liquid biopsy to personalize treatment and prevent or delay late recurrence of early-stage breast cancer," the researchers concluded.

In the following interview, Parsons discussed additional details of the study and other relevant ongoing research.

Can you give us more details on how the individualized RaDaR assay is created for each patient?

Parsons: RaDaR is a tumor-informed, patient-specific assay. First, each patient's archival primary tumor sample underwent whole exome sequencing (WES). Then, from mutations identified in the WES, up to 51 variants were selected for assay design.

Next, each patient-specific assay was applied to cell-free DNA isolated from a patient's plasma, to the leukocyte DNA and to the tumor DNA. Samples underwent high-depth sequencing, variants were confirmed, and ChIP [clonal hematopoiesis of indeterminate potential] was filtered. Each test was then reported as either MRD+ or MRD-. For positive MRD tests, eVAF (estimated variant allele fraction) was reported.

Do you plan to continue this study with longer follow-up or additional patients?

Parsons: Yes, we are continuing to follow these patients clinically and to draw research blood samples. We believe this is an important, understudied group of patients – those with a history of HR+ breast cancer diagnosed more than 5 years prior.

Have the two patients who were MRD positive but without recurrence during the study period experienced recurrence subsequently?

Parsons: We have not yet gone back to assess follow-up for the overall cohort but plan to do this in the coming months.

You mentioned that several clinical trials are underway to investigate the efficacy of interventions based on MRD detection. Are there any results yet from these trials, or any information about when can we expect them?

Parsons: In HR+ breast cancer, there are a few trials underway evaluating intervention based on MRD detection. The DARE and LEADER studies are both enrolling patients with history of HR+ breast cancer with an MRD positive test. Patients are screened and then undergo staging scans if the MRD test is positive. If metastatic disease is not detected, they enter the study.

In both trials, investigators are evaluating the efficacy of a CDK4/6 inhibitor together with hormonal therapy.

You mentioned that researchers at the Dana Farber Cancer Institute are investigating patient understanding of and attitudes toward late recurrence in a survey study. Can you tell us more about this study and what it hopes to find?

Parsons: This is the POWER study, led by Shoshana Rosenberg. In investigating patients with HR+ breast cancer with risk of late recurrence, we found very little data available evaluating patient understanding of and attitudes toward this risk. The POWER study, which is complete and undergoing data analysis currently, enrolled participants at least 5 years from diagnosis with HR+ breast cancer.

We look forward to the results of this study to help us design patient-centered interventions and approaches to the problem of late recurrence in HR+ breast cancer.

Read the study here and expert commentary about the clinical implications here.

The study was funded by AstraZeneca, the National Cancer Institute, and Susan G. Komen.

Parsons reported research funding from Puma Biotechnology (Inst).

Primary Source

Journal of Clinical Oncology

Source Reference: Lipsyc-Sharf M, et al "Circulating tumor DNA and late recurrence in high-risk hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer" J Clin Oncol 2022; 40: 2408-2419.

Journal: DOI: 10.1200/JCO.22.00908 Journal of Clinical Oncology 40, no. 22 (August 01, 2022) 2408-2419.

Reporting: https://www.medpagetoday.com/reading-room/asco/bre...

{Both full text and reporting are available w/o charge.}

lenaaz,

I am not happy with your oncologist's office for shaming you when you pressed for more information and help! Not acceptable! This was a very reasonable request.

A few thoughts: I think that NCCS (National Coalition for Cancer Survivorship) is a non-profit doing the best advocacy around the survivorship issue. Their web page is http://canceradvocacy.org/ and their unique focus is that *every* cancer patient should leave treatment with a written survivorship plan which clearly explains the treatments they have had and on-going monitoring that is the current standard of care. This way, it can be made a part of their chart and it is easy to share with a Primary Care doc who can help you stay on track with monitoring.

Another resource that may be of help to you: https://www.cancer.net/survivorship This is the ASCO (American Society of Clinical Oncology) website targeted to patients and dealing specifically with questions related to survivorship. The resources here may be helpful.

NCCN (National Cancer Care Network) publishes the definitive standards on cancer care. They have versions for both patients and professionals. Needless to say, the professional version is much more technical and detailed. I quickly looked through the materials to see what it might have to say about survivorship care. Disappointingly, it did not say much. I did not dig into the professional version. You may want to go here and take a look https://www.nccn.org/guidelines/guidelines-detail?...

Clearly, a great deal more advocacy is needed around this issue. Sometimes, the farther you get into the breast cancer world, the more you find there is to do to make care better. Some, of course, is medical or scientific, but *we* are the experts on the patient experience and sometimes, we have to be the voice advocating for improved care. If and/or when you feel up to it, consider being a voice for improvement. We - and our loved ones - will all be healthier if we can improve cancer care. Thanks for raising this important issue.

Not research news, but some may be interested in this:

Watch "Hidden Scars" with the directors

Join directors and cancer survivors Kathleen "Casey" Clabby and Noel Storm to view their documentary, "Hidden Scars: Emotional Impact of Mastectomy and Cancer-Related Experiences," on Tuesday, September 20, 2022, at 6 p.m. (ET). The film explores the emotional impact of breast surgery both before and after the procedure. There will be time for discussion and an opportunity to learn about resources for support. This program is brought to you in partnership with Jefferson Health Sidney Kimmel Cancer Center, Unite for HER, and Living Beyond Breast Cancer. There are limited spots available, so please register as soon as possible.

Register here:

https://jefferson.zoom.us/meeting/register/tJAsf-i...

{Event appears to be free of charge.}

Estimation of the numbers of individuals living with metastatic cancer in the United States

According to researchers at the National Cancer Institute (NCI), as of 2018, more than 620,000 people in the US were living with metastatic breast, colorectal, prostate, lung, or bladder cancer or metastatic melanoma. Further, researchers expect that number to increase to nearly 700,000 by 2025.

What they're saying: "Cancer survivorship often focuses on those who have completed treatment," said Emily Tonorezos, MD, MPH, director of NCI's Office of Cancer Survivorship. "But with over 620,000 metastatic cancer survivors in this country alone, these findings highlight the growing importance of identifying and addressing the needs of these survivors, who remain on treatment or who go on and off treatment."

https://doi.org/10.1093/jnci/djac158

{Write-up courtesy of NCCS. Free access to journal article.}

Paid sick leave associated with lower mortality rates among US workers

The US is one of the only developed countries in the world that does not have a national paid sick leave policy. Yet, new research shows the benefits these policies can have for Americans. The study revealed that areas where employers were required to provide paid sick leave had lower mortality rates among working age adults. Mandatory paid sick leave policies are associated with lower rates of suicide and homicide among men and lower homicide and alcohol-related mortality among women. Yet, the recent rise of preemption laws restricting lower governments' ability to enact mandatory paid sick leave policies poses a serious risk. From 2010 to 2017, preemption laws likely contributed to a 6% increase in mortality among working adults.

The bottom line: "Lack of [paid sick leave] increases the odds of economic hardship and involuntary job loss for those who take time off to recover, which in turn can elevate the odds of suicide, drug use, and other risky behaviors. [Paid sick leave] can also produce positive spillover impacts on healthy workers by reducing exposure to sick colleagues," the study's authors wrote.

https://www.ajpmonline.org/article/S0749-3797(22)00330-0/fulltext?utm_source=NCCS+Constituent+Database&utm_campaign=d18fc425d3-HCR_MC_Sept_9_22&utm_medium=email&utm_term=0_e96359f924-d18fc425d3-54826649&mc_cid=d18fc425d3&mc_eid=12d673e585

DOI:https://doi.org/10.1016/j.amepre.2022.06.005

{Write-up courtesy of NCCS and The Hill. Access to full journal article is free.}

Coping With a Deadly Prognosis

It's not a research article and it's not even breast cancer, but this podcast (with a transcript option) may be of interest to those coping with a metastatic diagnosis.

"The Doctor's Art" is a weekly podcast that explores what makes medicine meaningful, featuring profiles and stories from clinicians, patients, educators, leaders, and others working in healthcare.

Hosts are Henry Bair and Tyler Johnson, MD. Guest is Katie Coleman who was diagnosed with metastatic oncocytoma, a rare type of kidney cancer when she was 29 years old. She talks about living with prognostic and therapeutic uncertainty.

It is a rather long (@ 48 minutes) but IMO interesting and insightful interview about the uncertainty of living with a metastatic diagnosis, especially for those diagnosed at a young-ish age - but many aspects of the uncertainty apply to anyone living with a metastatic diagnosis.

Listen at this link or Listen and subscribe on Apple, Spotify, Amazon, Google, Stitcher, and Podchaser.

https://www.medpagetoday.com/podcasts/thedoctorsar...

{No charge to access or listen but medpage and podcast sites may require registration.}