When to De-Escalate TNBC Treatment?

When Erin Reardon, MD, started the doxorubicin phase of her neoadjuvant chemotherapy, she was already convinced she had crossed the threshold into overtreatment for her stage II, node-negative triple-negative breast cancer (TNBC).

The harsh chemotherapy known as the “Red Devil” is part of the standard 1-year protocol for patients with stage II or III TNBC. The regimen, evaluated in the Keynote-522 trial, calls for 24 weeks of the immune checkpoint inhibitor pembrolizumab in the neoadjuvant setting alongside neoadjuvant carboplatin/paclitaxel chemotherapy for the first 12 weeks, followed by doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide chemotherapy for the next 12 weeks. Patients then undergo surgery, followed by another 27 weeks of pembrolizumab.

It is a long and grueling protocol. Even before the red drip started, Reardon, then 48 years old, could no longer feel the lump in her breast. Her pathology also suggested her treatment was working.

“One of my pathologists mentioned that I had a high percentage (almost 85%) of tumor infiltrating lymphocytes (TILs) in the stroma of my tumor,” Reardon told Medscape Medical News. She also found a private pathology lab that identified high programmed death ligand 1 expression in the tumor. “These two findings portended an extremely good prognosis for me,” she wrote in a personal account of her experience.

But Reardon was an emergency physician, not a cancer expert. And when she told her specialists about these promising findings, she felt dismissed. “Four different oncologists — told me it meant nothing,” she said. But “if it meant nothing, why would the pathologist have even mentioned it?”

That’s what prompted Reardon to start digging. Her research all led to one conclusion: She was not a standard patient with TNBC.

“They were throwing this massive treatment at me, and I actually had a much better prognosis from the start,” she said.

Despite wondering if she really needed to continue her lengthy neoadjuvant regimen, Reardon could not muster the courage to go rogue. She went ahead with the Red Devil, sinking into a nightmare of thyroid dysfunction, “tremendous fatigue, nausea, explosive diarrhea, hair loss, joint and muscle discomfort, loss of salary due to inability to work, inability to drive due to brain fog, and loss of mobility,” she wrote.

“I really wanted to be that person that just quit when I knew that I was better — I really did think about it hard,” she recalled. “But I was too scared because of all the people that were staring at me saying, ‘This isn’t what we do.’”

Making a Big Move

After completing her neoadjuvant treatment and undergoing surgery, Reardon learned that her surgical specimen showed a pathologic complete response. There was no visible sign of cancer remaining.

At that point, Reardon took the plunge.

Against her team’s advice, she abandoned the rest of the protocol, declining a further 27 weeks of adjuvant pembrolizumab.

“I already knew the cancer was gone,” she said. “And then when I got the all-clear after the surgery, I said, ‘I am not putting any more of that in my body; I’m done.’”

Almost 2.5 years later, she remains cancer-free.

But Reardon knows she’s an outlier. She had the advantage of a medical degree, the ability to understand research studies, and the finances to seek out expert advice.

And while most patients should not abandon treatment without strong evidence and guidance from an oncologist or care team, Reardon was able to make informed decisions, in large part, because of research from Marleen Kok, MD, PhD, a specialist in breast cancer immunotherapy from the Netherlands Cancer Institute in Amsterdam, the Netherlands. Kok is well-known for her work in TNBC de-escalation, in particular the identification of TILs and other biomarkers that may indicate which patients have a good prognosis and might safely shorten the KEYNOTE-522 protocol.

In December 2022, soon after Reardon’s diagnosis, she and her husband reached out to Kok, who had recently given a TNBC de-escalation presentation at the San Antonio Breast Cancer Symposium. Kok and her team were already preparing a paper on the topic, but when they heard Reardon’s story, they decided to include it in their piece.

In the article, Kok, Reardon, and colleagues described Reardon’s experience as “the disconnect between how patients experience treatment and the impression of the treating oncologist. It also illustrates physician’s hesitation to deviate from standard guideline–consistent therapies,” which is driven by limited clinical trial evidence on reducing adjuvant therapy as well as a lack of biomarkers to help clinicians tailor treatment decisions to individual patients.

This hesitance permeates oncology practice in the United States, and to a lesser extent in Europe, said Kok. One concern is “if you de-escalate, which is against the guidelines, there is the risk that, if something goes wrong, a patient could sue you,” she said.

But rigidly following guidelines can also do harm, said Kathy Miller, MD, a breast cancer specialist and professor of oncology and medicine at Indiana University School of Medicine in Indianapolis. “It doesn’t make sense to keep lumping all patients together,” Miller told Medscape Medical News. “We need to start subdividing and trying to identify the people for whom we can eliminate or pull back treatment to reduce toxicity and cost while still maintaining excellent outcomes.”

Kok also urges clinicians to think outside the current TNBC treatment guidelines toward a future of more personalized therapy, one where patients might not need the full KEYNOTE-522 regimen.

But to be able to tailor treatment effectively, oncologists need biomarker data to identify patients with a promising prognosis. Guidelines are usually based on evidence from large phase 3 studies, and such studies are almost exclusively funded and conducted by the pharmaceutical industry. “Because biomarkers are going to help clinicians use fewer drugs, it goes against the business model from pharma’s perspective,” said Kok.

“Many of those industry trials didn’t even collect tissue to do biomarker analysis, or if they did, they’re keeping those results very close to the chest,” said Miller.

However, academic-run trials are now trying to fill that knowledge gap.

Some small studies suggest that most patients with stages II-III TNBC who achieve a pathologic complete response and have TILs over 30% after anthracycline-free neoadjuvant chemotherapy live at least 5 years. This survival finding indicates that these patients could be eligible for de-escalation strategies.

Two ongoing larger phase 3 trials, OptimICE-pCR and SCARLET, are going a step further by collecting tissue, evaluating biomarkers, and comparing lighter protocols with the standard early TNBC regimen. Kok’s phase 2 BELLINI trial is examining the link between TILs and tumor response to neoadjuvant immunotherapy alone, without chemotherapy. The phase 2 NeoTRACT trial will assess whether TILs in and around the tumor affect tumor shrinkage in patients with TNBC and whether treatment can be personalized on the basis of this response. And one new trial, if approved, will use TILs to identify TNBC patients with such low risk that they can forgo all systemic therapy and receive only surgery, Miller added.

Working With Patients

But results from these trials are several years away, so how can clinicians avoid overtreating patients in the interim?

Most Dutch clinicians would likely agree that patients with a pathologic complete response, like Reardon, can safely stray from guidelines and forgo adjuvant pembrolizumab, said Kok.

For Miller, it’s a matter of informed consent. “I am very careful in explaining to patients who want to go ‘off road,’ shall we say, that we are now in an area where I don’t have the data to guide us,” Miller said. But there are enough data to suggest that de-escalation might be a reasonable approach, perhaps even superior, in the right patients, she said.

One caveat to implementing de-escalation strategies in the United States is whether insurance companies will approve an abridged protocol. Health insurers in the United States base their coverage decisions on guidelines, and “I have had difficulty with some US insurance companies getting approval if I am not planning to give that patient the full KEYNOTE-522 regimen,” Miller said.

Despite the evidence gaps, working with patients remains critical, Reardon said. Looking back on her cancer journey, Reardon considers herself a survivor, not only of her cancer but also of the KEYNOTE-522 regimen and her battle with her care team.

The lack of support from her specialists was “nearly as devastating to me as my cancer itself,” she said.

Going forward, Miller hopes more doctors will be willing to work with their patients who are struggling with their treatment.

“Some physicians are more willing than others to negotiate with patients about their care,” Miller said. But “I worry about those ladies who feel like their treatment team, or the medical establishment, if you will, is so inflexible and unwilling to negotiate with them that the only way they can follow that strategy is to just stop coming,” she added.

Kate Johnson is a Montreal-based freelance medical journalist who has been writing for > 30 years about all areas of medicine.