Editor’s Note: With the success of landmark clinical studies such as KEYNOTE-522, neoadjuvant treatment for early-stage triple-negative breast cancer (TNBC) has fully entered the era of immunotherapy combined with chemotherapy. While this strategy has significantly improved pathological complete response (pCR) rates and delivered substantial survival benefits, it has also raised one of the most debated questions in current clinical practice:For patients who achieve pCR following neoadjuvant immunotherapy, should postoperative immunotherapy be continued in the adjuvant setting to consolidate benefit, or should treatment be de-escalated by discontinuing immunotherapy?
In this edition of Oncology Frontier, Professor Nanlin Li from Xijing Hospital of the Air Force Medical University and Professor Guohui Han from Shanxi Cancer Hospital engage in an in-depth discussion of this critical and evolving clinical dilemma.
Professor Nanlin Li: Adjuvant Immunotherapy Should Be Continued After pCR
Regarding the ongoing debate over whether immunotherapy should be continued during the adjuvant phase after patients with TNBC achieve pathological complete response (pCR) following neoadjuvant immunotherapy, my position is very clear: postoperative immunotherapy should absolutely be continued.
The core basis for this conclusion comes from the pivotal Phase III KEYNOTE-522 study. We are all very familiar with this trial, which enrolled more than 1,000 patients and evaluated eight cycles of neoadjuvant chemotherapy combined with pembrolizumab.
The study not only demonstrated excellent overall efficacy in patients who failed to achieve pCR, but also successfully met its dual primary endpoints of improved pCR rate and event-free survival (EFS).
Based on earlier follow-up analyses, the survival advantage in patients achieving pCR initially appeared less pronounced. However, by the fifth year of follow-up—during the sixth interim analysis—the pCR population still demonstrated an absolute 4% improvement in EFS.
This 4% EFS gain carries major clinical significance.
For comparison, one may consider the landmark KATHERINE study in HER2-positive breast cancer, in which intensified adjuvant therapy with T-DM1 versus trastuzumab in patients with residual disease improved overall survival (OS) by 4.7% only after seven years of follow-up.
Therefore, achieving a 4% EFS improvement at five years in TNBC patients who have already achieved pCR is absolutely meaningful and worth pursuing.
We all recognize that TNBC is an extremely aggressive and difficult-to-treat disease subtype. Our ultimate treatment goal is to prevent recurrence and metastasis over a 10-year horizon and achieve true clinical cure.
To accomplish this, I believe it is essential to fully capitalize on the postoperative treatment window and deliver sufficiently intensive systemic therapy during the adjuvant phase.
From the perspective of current clinical standards, this has already become the prevailing consensus.
Major domestic and international guidelines—including NCCN, CSCO, CBCS, and ESMO—all recommend following the KEYNOTE-522 treatment design. Regardless of whether patients achieve pCR or non-pCR status after neoadjuvant therapy, adjuvant immunotherapy should be continued to complete one full year of treatment. This is also consistent with the indications approved by both the U.S. FDA and China’s NMPA, providing a unified framework for clinical decision-making.
Of course, it remains uncertain whether relatively low-risk patients derive equal benefit from adjuvant immunotherapy. However, this situation is somewhat analogous to the college entrance examination system: until we identify a superior method for selecting talent, adhering to the current system remains the most practical approach.
Similarly, before more precise risk stratification tools become available, following the highest-level existing evidence remains the most scientifically sound and safest strategy.
At the same time, I strongly look forward to future large-scale randomized controlled trials specifically stratifying pCR patients, which could ultimately provide the data needed to support more individualized and precise de-escalation strategies.
Professor Guohui Han: We Must Carefully Consider the Risks of Overtreatment
I would like to approach this issue from the perspective of avoiding overtreatment and advancing individualized care.
There is no doubt that the KEYNOTE-522 study demonstrated improved pCR rates and long-term survival outcomes through the use of pembrolizumab across both the neoadjuvant and adjuvant settings in early-stage TNBC.
However, an important question remains: once patients achieve pCR after neoadjuvant therapy and transition into a relatively low-risk population, does continuing pembrolizumab during the adjuvant phase necessarily provide additional survival benefit?
I remain somewhat cautious regarding the current strategy and believe we should await the results of further prospective studies.
Although immunotherapy has substantially improved outcomes in early-stage TNBC, we cannot overlook the risk of immune-related adverse events (irAEs). In addition, under current healthcare reimbursement conditions, immunotherapy for early-stage breast cancer has not yet been fully covered by medical insurance, and completing an entire course of treatment can impose a considerable economic burden on patients.
Under these circumstances, we must remain vigilant about the possibility of overtreatment.
At present, we still cannot definitively conclude whether patients who achieve pCR could maintain similarly excellent long-term outcomes even if adjuvant immunotherapy were discontinued.
From an evidence-based medicine perspective, current guideline recommendations are indeed derived from studies evaluating the overall benefit of full-course immunotherapy. However, it is important to recognize that KEYNOTE-522 did not specifically randomize pCR patients to either “continue immunotherapy” or “stop immunotherapy” in the adjuvant setting.
Because we lack direct evidence from such dedicated randomized controlled trials, I remain cautious regarding the absolute benefit of continued treatment in this lower-risk subgroup.
Therefore, I believe it is appropriate to postpone definitive conclusions until additional evidence becomes available.
Several randomized studies specifically evaluating pCR patients are currently ongoing, and these trials will provide crucial data. Only after clearly determining whether meaningful survival differences exist between continuation and discontinuation strategies can we make more confident clinical judgments.
That said, in current real-world practice—and before new evidence emerges—I fully agree that we should continue adhering to existing evidence-based standards and strictly follow the KEYNOTE-522 treatment design.
In practical terms, this means that even patients who achieve pCR should continue pembrolizumab during the adjuvant phase according to current standards of care.
However, I strongly believe that once future large-scale randomized studies focused on lower-risk populations are reported, current guidelines may very well be refined and optimized.
At that point, more precise risk stratification systems may allow us to clearly identify which patients truly require full-course immunotherapy and which patients may safely undergo treatment de-escalation after achieving pCR, including discontinuation of adjuvant immunotherapy.
Professor Nanlin Li
Professor Guohui Han
