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ACS Research Highlights

ID of Biomarkers May Improve Life for Breast Cancer Survivors

Thinking and Living With Cancer (TLC) Clinical Trial findings may help older breast cancer survivors reduce risks for cognitive decline and hastened aging.

The Challenge

Decades of scientific innovation have led to a decrease in deaths from breast cancer. Of course, surviving longer may have its own challenges. Many of the 3.9 million breast cancer survivors in the United States have long-term effects resulting from both the cancer and its treatment, which can make life more difficult.

One issue, for instance, is cancer-related cognitive decline (CRCD). For years, scientists have recognized that treatment for breast cancer, which may include surgery and possibly one or more systemic therapies (like chemotherapy, targeted therapy, and hormonal therapy), may adversely affect the mind.

Although these treatments kill cancer cells, they may also damage cells and stimulate inflammatory biomarkers to circulate and cross into the brain cells, causing harm.

That damage to the brain can potentially lead to declines in a survivor’s daily functioning, work performance, and social and emotional well-being.

But research about the role of inflammatory markers has had inconsistent findings. 

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  • Biologic age/epigenetic aging
  • C-reactive protein (CRP)
  • Epigenetics
  • Interleukin-6 (IL-6) 

The Research

The Thinking and Living With Cancer (TLC) study examines the effect of systemic treatments for breast cancer on cognitive decline and quality of life in women age 60 and older.

TLC researchers particularly focus on how cognition (attention, processing speed, learning and memory, and executive function, like filtering distractions and switching tasks) may be affected by genetics, inflammatory biomarkers, sleep, and physical measures like walking speed and grip strength.

The Thinking and Living With Cancer (TLC) Study In Brief

Three factors in the design of the TLC study set it apart from previous similar ones. It was one of the first studies to:

  • Focus specifically on breast cancer survivors who are age 60 and older (who make up the majority of breast cancer survivors).
  • Include a control group of women the same age who don’t have cancer.
  • Follow-up with participants for multiple years, rather than just immediately before and after treatment.

From its start in 2010 to its close at the end of 2023, the TLC study will follow an estimated enrollment of 1,700 participants from 6 cancer centers across the United States for up to 5 years.

Participants are divided into 2 approximately equal groups of women ages 60 to 90. One group includes those recently diagnosed with breast cancer, while women in the other group (the control group) are cancer free. Women in both groups were similar in age, education level, and race. None of the women had dementia or a psychiatric or neurological disorder at the beginning of the study.

Results from the TLC study will help improve the quality of care for the growing number of older women with breast cancer by:

  • Identifying women likely to have serious negative effects from systemic treatments
  • Developing strategies to minimize any negative treatment-related effects

Within the last 5 years, American Cancer Society research grants have helped fund three scientists who have co-authored several studies using data from TLC participants:

  • Sunita Patel, PhD, from the City of Hope, Duarte, CA, focuses her research on risk and protective factors (especially from inflammation biomarkers) for cancer-related neurocognitive conditions that affect thinking, reasoning, and memory related to cancer. She’s had 2 ACS grants, with the most recent ending in June 2022.
  • Judith Carroll, PhD, from the University of California Los Angeles (UCLA), had an ACS grant from 2016 to 2020 focused on biobehavioral vulnerability to accelerated aging in breast cancer survivors.
  • Kathleen Van Dyk, PhD, from UCLA, had an ACS grant from 2017 to 2019 focused on cognitive decline in breast cancer survivors. 


TLC Study “1:” High blood levels of an inflammation biomarker - c-reactive protein  - may signal later cognitive decline in breast cancer survivors.

A 2022 study described in the Journal of Clinical Oncology was supported by an ACS grant awarded to neuropsychologist Patel and included previous ACS grantees Carroll and Van Dyke as co-authors. Using longitudinal TLC data, this study is one of the first to examine the long-term relationship between chronic inflammation and cognition in a large group of older breast cancer survivors and to compare these effects with those observed in a control group of women in the same age range without a personal history of cancer.

“This study used data from TLC participants to evaluate a specific inflammation biomarker called c-reactive protein (CRP). We wanted to learn 3 things:

(1) If higher CRP levels in the blood predict later changes to thinking and memory caused by cancer treatments.

(2) If higher CRP has stronger effects on cognition  in the TLC group of breast cancer survivors than they are in the TLC control group of women without cancer.

(3) Whether CRP could be useful to identify older breast cancer survivors at risk for cognitive problems."

Sunita Patel, PhD City of Hope in Duarte, CA ACS Research Grantee and Co-author of Several TLC Studies

Sunita Patel, PhD
City of Hope in Duarte, CA
ACS Research Grantee and Co-author of Several TLC Studies

The researchers evaluated neuropsychological tests and questionnaires at each visit and measured C-reactive protein (CRP) – a key marker of inflammation – from participants’ blood samples.

Levels of CRP increase with inflammatory conditions like rheumatoid arthritis, some heart diseases, and infection. The levels increase rapidly with severe tissue damage from injury or progressive cancer.

Their results showed that the cancer survivors:

  • Had higher inflammation levels (as measured by circulating levels of CRP) before they began systemic cancer therapy.
  • Were significantly more likely to report cognitive problems compared with women in the control group.

TLC Study “2:” High blood levels of another inflammation biomarker ­– interleukin-6 (IL-6) – were associated with lower cognition scores.

Another study focused on inflammation and the risk of CRCD was also co-authored by previous ACS grantees Patel, Carroll, and Van Dyke. It was published in the ACS journal, Cancer, but did not receive supporting funds from ACS.

For this study, TLC researchers identified high levels of the interleukin-6 (IL-6) protein in the blood as part of the reason that breast cancer survivors age 60 and older had worse long-term neurocognitive function compared with the control group of women the same age.

Interleukins are proteins involved in controlling acute inflammatory responses in the body. They’re the body’s defense against “invaders,” like wounds, viruses, or diseases. The production of c-reactive protein is thought to be linked with the production of IL-6. Too much IL-6 has been linked with diabetes, rheumatoid arthritis, and cancer. Both physical and psychological stress can cause temporary increases in IL-6.

The researchers noted that the women with cancer had higher IL-6 levels than the control group even before receiving systemic treatment.

The authors conclude that the results “are intended to build an evidence base about the mechanistic pathways of CRCD and to suggest potential targets for intervention to reduce the risk of or mitigate cognitive problems in the aging population of cancer survivors.”

TLC Study “3:” Preliminary findings showed women age 60 and older with breast cancer, especially those receiving chemotherapy, had greater epigenetic aging than the control group of women without cancer.

A third study using TLC data, co-authored by previous ACS grantees Patel, Carroll, and Van Dyke, and published in the ACS journal Cancer, without supporting funds from ACS, investigated how chemotherapy affected biological aging in older breast cancer survivors.

Chronological age changes with each birthday. Biological aging, though, is a gradual and progressive process driven by the accumulation of damage caused by life experiences and exposures. Increased biological age increases the risk for cancer and other age-related diseases.

One way biological age is identified is with epigenetic changes. These changes to the genes/DNA don’t affect the genetic sequence or code. Epigenetic aging is associated with many factors including diet, exercise, sleep, response to stress, and disease and its treatment.

While often lifesaving, cancer treatment can also cause damage and drive further aging. This study showed that older breast cancer survivors experience accelerated aging and worse functional outcomes after cancer treatment, particularly chemotherapy. This first-of-its-kind study could help guide clinical cancer care to improve survivors’ quality of life.

Two additional TLC co-authors received previous ACS research grants—more than 10 years ago. Jeanne Mandelblatt, MD, MPH, of Lombardi Comprehensive Cancer Center, Georgetown University, in Washington, DC, was either a senior or lead author for all 3 studies. Paul Jacobsen, PhD, of the Healthcare Delivery Research Program at the National Cancer Institute in Bethesda, Maryland was a co-author on both of the inflammation studies.

Why Does It Matter? 

Results from the TLC study provide stronger evidence that chronic inflammation is connected to cognitive problems in older breast cancer survivors. This information may be useful for healthcare providers to identify survivors who may have an increased risk of cognitive decline and require additional surveillance or interventions designed to reduce inflammation.

Measuring biological age throughout survivorship care may also help guide care for older breast cancer survivors to minimize poor outcomes and improve quality of life.

This work lays the groundwork for future studies of other cancer treatments at various time points throughout care, in more diverse populations, and with additional inflammatory markers.