Exploring the potential of immunotherapy in early-stage triple-negative breast cancer

Triple-negative breast cancers, which are more frequently diagnosed in younger women, are a subtype of breast tumor characterized by the absence of hormone receptors and HER2 overexpression. As a result, they do not respond to hormone therapy or HER2-targeted treatments. Their prognosis is generally less favorable than that of other breast cancer subtypes.

Immunotherapy, particularly immune checkpoint inhibitors, has transformed the treatment of several cancers. In stage II and III triple-negative breast cancer, the addition of immunotherapy to chemotherapy before surgery increases the likelihood of achieving a pathological complete response and improves event-free survival, thereby reducing the risk of disease recurrence. However, for patients with small stage I tumors, chemotherapy administered before or after surgery remains the standard of care when indicated.

“Today, some patients with localized stage I triple-negative breast cancer receive chemotherapy even though some of them may not actually need it. It is essential to explore strategies that preserve treatment efficacy while reducing short- and long-term side effects. The POP-DURVA study aims to assess whether very early administration of immunotherapy can induce a sufficient antitumor response and pave the way for treatment de-escalation in selected patients,” explains Dr. Joana Ribeiro.

A study designed to detect an initial signal of activity

POP-DURVA is a prospective, multicenter, single-arm phase 2 study sponsored by Gustave Roussy. It evaluated a short course of durvalumab, an anti-PD-L1 immunotherapy, administered before standard treatment, which consisted either of surgery or preoperative chemotherapy, in patients with stage I triple-negative breast cancer and tumors measuring less than two centimeters.

The primary objective of the study was to determine whether these two immunotherapy injections were sufficient to induce a pathological complete response, defined as the absence of any detectable viable cancer cells in the breast tissue specimen and axillary lymph nodes removed during surgery. The study was primarily designed to identify an early signal of activity and to improve understanding of the biological mechanisms underlying sensitivity or resistance to immunotherapy. It was not intended to demonstrate that durvalumab could replace chemotherapy in routine clinical practice.

The 78 patients enrolled received two injections of durvalumab administered 15 days apart. To be eligible, patients had to have a tumor measuring no more than 2 cm, no clinically detectable lymph node involvement, and at least 5% tumor-infiltrating lymphocytes (TILs), indicating preexisting immune activity within the tumor microenvironment.

Following this short treatment sequence, patients were reassessed to determine whether they could proceed directly to surgery or required additional chemotherapy.

Clinical responses observed within the first weeks

Results presented at ESMO show that after only two injections of durvalumab, administered over a short period and without concomitant chemotherapy, evidence of clinical activity was observed in a subset of patients.

A major pathological response was achieved in approximately 11% of patients, indicating a substantial reduction in tumor burden. POP-DURVA also reports the case of a 31-year-old patient in whom no residual tumor cells were found in the surgical specimen following only two administrations of durvalumab.

“Observing a pathological response after only two injections of immunotherapy is particularly encouraging. Although our study was not designed to change treatment standards, it shows that a small number of patients display remarkable sensitivity to immunotherapy alone,” says Ribeiro.

Beyond tumor shrinkage: Remodeling the immune microenvironment

One of the most important findings of POP-DURVA concerns the changes observed within the tumor microenvironment. Analyses performed before and after treatment show that durvalumab induced increased mobilization of immune cells within the tumors of several patients.

Among the changes observed were an increase in tumor-infiltrating lymphocytes and a higher frequency of tertiary lymphoid structures (TLS), organized aggregates of immune cells involved in activating antitumor immune responses.

“We found that immunotherapy can induce profound biological changes within just a few weeks. Even when it does not immediately lead to complete tumor disappearance, immunotherapy appears capable of reshaping the immune environment in a way that promotes antitumor immunity,” explains Ribeiro.

Among 62 patients with paired pre- and post-treatment samples, RNA sequencing also revealed increased expression of genes associated with immune activation and target-cell killing mechanisms. These molecular findings complement the microscopic observations and provide further insight into changes occurring within the immune infiltrate. An exploratory analysis of 41 patients who proceeded directly to surgery after durvalumab also showed that greater increases in tumor-infiltrating lymphocytes were associated with lower proportions of residual viable tumor.

“We are observing consistent changes at multiple levels: more lymphocytes within tumors, changes in their organization, and stronger molecular signals associated with immune activity. These findings allow us to explore the relationship between immune remodeling and tumor regression, although their long-term clinical significance remains to be established,” says Ribeiro.

Better identifying patients who may benefit from immunotherapy alone

POP-DURVA is part of UNLOCK, a program of the PRISM Institute. This translational research initiative was developed at Gustave Roussy to better understand how innovative therapies, including immunotherapies, exert their effects.

Tumor, blood and stool samples were collected at multiple time points throughout the patient journey. These samples will undergo extensive analyses combining immunohistochemistry, RNA sequencing and emerging single-cell biology approaches. Preliminary exploratory analyses at the individual-cell level have already provided insights into T-cell populations that may contribute to the immune signals observed.

The objective is to identify the biological characteristics that distinguish patients who are particularly sensitive to immunotherapy from those who still require chemotherapy.

“One of the ambitions of the UNLOCK program is to develop true precision immunology. Ultimately, we hope to better identify patients who could benefit from treatment de-escalation, thereby limiting exposure to more intensive therapies without compromising their chances of cure,” concludes Ribeiro.

Provided by
Comprehensive Cancer Centre Gustave Roussy

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