Women older than age 70 diagnosed with triple-negative breast cancer had significantly improved overall survival if they received adjuvant and/or neoadjuvant chemotherapy, according to an analysis of data from more than 16,000 women enrolled in the National Cancer Database. The estimated 5-year overall survival was 68.5% for the women receiving chemotherapy vs 61.1% for those not receiving chemotherapy although it was recommended, and 53.7% for patients for whom chemotherapy was not recommended nor given. The results were reported by Crozier et al in The Lancet Oncology.¹

The study arose directly from a “real-life clinical question,” lead author Jennifer A. Crozier, MD, told The ASCO Post. Dr. Crozier is Assistant Professor, Breast Medical Oncology, and Director of Breast Cancer Research at Baptist MD Anderson Cancer Center, Jacksonville, Florida.

“[W]hen I saw the results showing a significant survival benefit for the [older] women who received chemotherapy, I said, ‘We have got to find a way to support these women during this treatment.’”

— Jennifer A. Crozier, MD

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“In Florida, we see many patients older than 70 with aggressive triple-negative breast cancer,” she noted, “but due to the scarcity of data on the benefits of chemotherapy in older patients with this disease, clinicians have had to rely on extrapolated estimates of efficacy from studies with mostly younger patients.”

Study Design

The study was designed to look at triple-negative breast cancer in older women on a larger scale to give guidance on how to balance more aggressive treatment with its concomitant potential toxicities and the functional status, comorbidities, and life expectancy of older adults. If the results had shown there was no difference in survival among the older women who received chemotherapy, Dr. Crozier said that she would then know to de-escalate chemotherapy for these patients. “But when I saw the results showing a significant survival benefit for the women who received chemotherapy, I said, ‘We have got to find a way to support these women during this treatment.’”

The study included 16,062 women aged 70 years and older with stage I to III nonmetastatic invasive ductal or lobular carcinoma of the breast who had documented estrogen receptor–negative, progesterone receptor–negative, and HER2-negative disease and who received surgical intervention at the primary site. Eligibility was limited to women with a primary tumor measuring 6 mm or greater at its largest dimension or at least one positive lymph node. Median follow-up was 38.3 months.

“Women with larger tumors and node-positive disease are more likely to be recommended chemotherapy, but even with smaller node-negative tumors, we still frequently recommend chemotherapy.”

— Jennifer A. Crozier, MD

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“To reduce bias in this retrospective analysis, data were also specifically extracted to divide patients into three subgroups: patients who were documented as being recommended to receive chemotherapy but ultimately did not receive it, either due to patient choice or other (undocumented) reasons; patients who received chemotherapy, preoperatively or postoperatively; and patients for whom chemotherapy was not recommended and not given,” the authors explained.

Almost half of the study participants (7,485 patients, or 46.6%) did receive chemotherapy. That rate is much lower than for younger patients, Dr. Crozier noted. “In younger patients, probably more than 80% of those who have triple-negative breast cancer are going to receive chemotherapy.”

Chemotherapy was recommended but not received by 16.6% of patients (2,659). The most common reasons for declining chemotherapy were concerns about potential side effects and quality of life, Dr. Crozier reported. “The unfortunate part is that this is treatment trying to prevent metastatic disease, and we know that giving chemotherapy outside of an 8-week window after surgery lowers the efficacy of that treatment to help prevent metastatic disease. We still follow those patients closely, but in the back of our minds, we know they are at higher risk than their counterparts who took chemotherapy earlier.”

“If a patient does not have a complete response to neoadjuvant chemotherapy … we know that patient is at higher risk going forward.”

— Jennifer A. Crozier, MD

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Chemotherapy was not recommended for 35.7% of patients (5,732). The chemotherapy status was missing for 186 patients.

Median tumor size was larger in the group that did receive chemotherapy, and those patients were also more likely to have later-stage disease. “We were able to take that into account though, and it did not affect the results,” Dr. Crozier noted. “Women with larger tumors and node-positive disease are more likely to be recommended chemotherapy,” she added, “but even with smaller node-negative tumors, we still frequently recommend chemotherapy.”

‘Chemotherapy Does Make a Difference’

“Multivariate Cox regression analysis of a propensity score–matched sample comparing those who received chemotherapy with those who were recommended but not given chemotherapy (n = 1,884 matched pairs) identified improved overall survival with chemotherapy (hazard ratio [HR] = 0.69, 95% confidence interval [CI] = 0.60–0.80]; P < .0001),” the authors reported. After stratifying the propensity score–matched sample, they found this benefit persisted for node-negative women (HR = 0.80, 95% CI = 0.66–0.97]; P = .007), node-positive women (0.6 [0.64–0.91]; P = .006), and those with a comorbidity score greater than 0 (HR = 0.74, 95% CI = 0.59–0.94; P = .013).

The finding that patients recommended for but not receiving, chemotherapy had an overall survival benefit “confirms the hypothesis that patients who are considered by their surgical oncologist to be eligible to receive chemotherapy and able to tolerate that therapy represent a subgroup of patients who would live longer with or without chemotherapy,” the authors noted. Yet the study results also indicate a survival advantage for those actually receiving chemotherapy.

“Women who are deemed healthy enough by their physicians and feel comfortable with the potential risks and benefits do have a survival benefit,” Dr. Crozier affirmed. “They are being recommended chemotherapy usually because they are overall healthier than women who were not recommended chemotherapy, and that is why it is nice to have that comparison between those two groups of patients—those who were recommended to receive chemotherapy and followed through with it vs the women who were recommended (so deemed healthy enough), but for whatever reason chose to decline—and to see that survival difference of more than 7%. So, chemotherapy does make a difference, even though these women are older than 70.”

A Swedish registry study by Janeva et al in The Lancet Healthy Longevity² found significant survival benefits for surgically treated patients aged 70 years and older with triple-negative breast cancer without distant metastases who also received chemotherapy. The 5-year breast cancer–specific survival rate was 85% with adjuvant chemotherapy and 68% without. And the 5-year overall survival rate was 79% with chemotherapy and 49% without. “The Swedish study had a smaller population and less diversity, but it was really interesting to see the same findings across the world,” Dr. Crozier commented.

Timing of Chemotherapy

An editorial in The Lancet Oncology³ pointed out that although current practice guidelines advise neoadjuvant therapy, the percentage of patients who received neoadjuvant therapy was only 17.9% in the U.S. study and only 4% in the Swedish study. Dr. Crozier said that the small percentage of patients receiving neoadjuvant therapy would not impact the survival data. “We are definitely seeing a trend toward more neoadjuvant chemotherapy in general, but neoadjuvant vs adjuvant chemotherapy doesn’t change overall survival,” she said.

“Neoadjuvant chemotherapy does help us prognostically. If a patient does not have a complete response to neoadjuvant chemotherapy—if we still see a lot of cancer cells in the breast—we know that patient is at higher risk going forward,” Dr. Crozier said. Patients who do not respond to chemotherapy could then be encouraged to enroll in clinical trials to prevent metastatic disease in the future.

Whether patients with triple-negative breast cancer who opt for chemotherapy receive neoadjuvant or adjuvant chemotherapy depends on the tumor stage and size, she said. “For stage I breast cancers, we often move forward with upfront surgery, especially if we can’t feel the tumor on exam, because otherwise it would be more difficult to monitor chemotherapy without repeated imaging.”

Predicting Toxicities

“Treatment of older patients with breast cancer is complicated by questions about assessment of functional status, comorbidities, life expectancy, and expected tolerance,” the study authors wrote.

“We sometimes do the ‘Get up and go test.’ Can you get up from a chair, not using your arms, and walk without difficulty? That is something very simple that has actually translated—at least in the neurology world—to being effective in demonstrating somebody’s functional status,” Dr. Crozier said. Nevertheless, she acknowledged that functional status alone does not necessarily predict tolerance to therapy. Asked if there are other more accurate ways to predict who might experience toxicity, Dr. Crozier replied, “not yet.”

The editorialists wrote that clearer guidance is needed for medical oncologists about the appropriate use of chemotherapy in older patients (“beyond the concept of frailty”). They called for frailty stratification to identify patients at higher risk of complications and noted that “the transition from fitness to frailty is a continuum.” They also recommended “collaboration between the cancer specialist and geriatrician and interpretation of the geriatric assessment.”

Finally, Dr. Crozier emphasized the importance of social support. “If patients have that support, where we know someone is encouraging them to drink the 64 oz of water a day we recommend during chemotherapy, if they are getting three meals a day and proper nutrition, that is all contributing to them feeling better on treatment overall. Patients need rides to and from the infusion center, help if they have a problem at night, and someone making sure they have all their medications and are able to take them accurately.” 

DISCLOSURE: Dr. Crozier has served as a consultant or advisor to Novartis and Puma Biotechnology, has participated in a speakers bureau for Agendia, and has received institutional research funding from Agendia and Seattle Genetics.

REFERENCES

1. Crozier JA, Pezzi TA, Hodge C, et al: Addition of chemotherapy to local therapy in women aged 70 years or older with triple-negative breast cancer: A propensity-matched analysis. Lancet Oncol 21:1611-1619, 2020.

2. Janeva S, Zhang C, Kovacs A, et al: Adjuvant chemotherapy and survival in women aged 70 years and older with triple-negative breast cancer: A Swedish population-based propensity score-matched analysis. Lancet Healthy Longevity, November 30, 2020 (early release online). 

3. Curigliano G, Pravettoni G: Use of chemotherapy in elderly patients with early-stage triple-negative breast cancer. Lancet Oncol 21:1543-1545, 2020.