Adjuvant therapy, the chemotherapy given after surgical removal of a tumor to destroy any remaining cancer cells, has long been a blunt instrument in colon cancer. For decades, treatment intensity has been assigned largely on the basis of anatomical staging, the depth of tumor invasion through the bowel wall and the number of lymph nodes involved. Patients deemed high risk by these pathological criteria have typically received combination chemotherapy regimens, while those considered lower risk have received single-agent treatment or, in some cases, observation alone. This one-size-fits-many approach inevitably overtreats some patients, exposing them to toxicities such as peripheral neuropathy, diarrhea, fatigue and long-term nerve damage without any proven benefit, and undertreats others whose residual disease goes undetected until it reappears as metastatic recurrence.

Circulating tumor DNA offers a fundamentally different lens. Tumors continuously shed fragments of their DNA into the bloodstream, and highly sensitive assays can detect these fragments by looking for tumor-specific mutations or abnormal methylation patterns. In the context of colon cancer, the presence of detectable ctDNA after surgery is one of the most powerful predictors of eventual recurrence yet identified, outperforming conventional imaging and standard tumor markers. A positive postoperative ctDNA result indicates that microscopic disease almost certainly persists somewhere in the body, while a negative result suggests, with a high degree of confidence, that no measurable residual disease remains. The logical corollary is that patients with persistent ctDNA might benefit from more aggressive therapy, whereas those who clear their ctDNA might be spared unnecessary treatment.

Translating that logic into practice, however, has proven difficult. Most ctDNA studies to date have been observational, measuring the marker and correlating it with outcomes without letting it dictate treatment. The few interventional trials that have used ctDNA to assign therapy have generally done so in a static way, taking a single postoperative measurement and using it once. PEGASUS was designed to go further by making ctDNA a dynamic, longitudinal guide. In the trial, patients with microsatellite-stable, high-risk stage II or III colon cancer underwent serial blood testing, and the results were used to direct both the initial choice of adjuvant chemotherapy and subsequent decisions about whether to continue, de-escalate, or escalate treatment after the standard adjuvant period had ended.

The population studied was deliberately chosen to be clinically challenging. Microsatellite-stable tumors, which constitute the majority of colon cancers, do not respond to immune checkpoint inhibitors and carry a worse prognosis than their microsatellite-instability-high counterparts. High-risk stage II disease, defined by features such as bowel obstruction or perforation, poorly differentiated histology, lymphovascular invasion or inadequate lymph node sampling, sits in a particularly gray zone of practice, where the benefit of adding oxaliplatin to fluoropyrimidine chemotherapy is debated and treatment decisions vary widely between centers. Stage III disease, with its proven lymph node involvement, carries a substantial recurrence risk even after apparently complete resection. For all of these patients, the trade-off between the toxicity of intensive chemotherapy and the danger of undertreating occult disease is acute and personal.

The feasibility question that PEGASUS addressed is not trivial. A ctDNA-guided strategy demands that blood samples be drawn, processed and analyzed on a tight timeline so that results arrive in time to inform treatment decisions. It requires laboratories to maintain consistent assay sensitivity across repeated measurements for the same patient, because a test that flickers between positive and negative near its detection limit creates clinical ambiguity. It requires oncologists to accept a new kind of evidence, a molecular measurement, as the basis for withholding or adding cytotoxic drugs, and it requires patients to understand that a negative blood test does not guarantee cure but may justify a lighter treatment burden. Any one of these links could break the chain, and the trial was structured to determine whether the whole chain could hold together in practice.

De-escalation is the arm of the strategy with the greatest potential to change daily practice. If serial ctDNA testing shows that a patient has no detectable residual disease after surgery, or that ctDNA clears rapidly once chemotherapy begins, the rationale for continuing full-intensity combination chemotherapy weakens considerably. Oxaliplatin, the component of standard regimens most associated with permanent peripheral neuropathy, is the natural target of such de-escalation. Avoiding even a fraction of unnecessary oxaliplatin exposure across the large population of high-risk colon cancer survivors would represent a meaningful quality-of-life gain, sparing patients years of numbness, cold sensitivity and functional impairment, while reducing healthcare costs associated with managing chemotherapy toxicities.

Escalation, conversely, addresses the patients whom standard staging fails. A patient whose ctDNA remains detectable despite completing a full course of adjuvant chemotherapy is, by the logic of the biomarker, harboring active microscopic disease that current treatment has not eradicated. In conventional practice such a patient would simply be monitored, with treatment resuming only once relapse became visible on scans, often at a point when cure is no longer possible. A ctDNA-guided postadjuvant strategy opens a window in which additional or alternative therapy can be considered while the disease burden is still molecular rather than radiographic. Whether such escalation improves survival is a question that feasibility trials like PEGASUS set the stage for but cannot fully answer; establishing that the strategy can be delivered consistently is the necessary first step.

The significance of the trial extends beyond colon cancer. The concept of minimal residual disease guidance, in which molecular testing determines treatment intensity, is being pursued in breast cancer, pancreatic cancer, gastric cancer and a range of other tumor types, and the operational lessons from PEGASUS are likely to inform all of these efforts. The trial also contributes to a broader rethinking of how adjuvant therapy decisions are made, moving the field away from population averages and toward individualized risk. As ctDNA assays become more standardized and more affordable, the barrier to adopting such strategies shifts from technology to clinical governance: which laboratories, which thresholds, which timelines, and who bears responsibility for acting on a positive result.

What PEGASUS ultimately demonstrates, within the limits of a phase 2 design, is that the vision of blood-test-guided cancer treatment can be operationalized for one of the most common malignancies worldwide. Colon cancer affects well over a million people each year globally, and a substantial fraction undergo surgery with curative intent followed by adjuvant chemotherapy whose value in any individual case is uncertain. If serial ctDNA monitoring can reliably sort these patients into those who need maximal therapy and those who do not, the result would be a rare win on both fronts of oncology: better outcomes for patients with hidden residual disease and fewer toxic treatments for those already cured by surgery. The trial’s findings now form part of the growing evidence base that will determine whether molecular residual disease testing becomes a routine companion to the surgeon’s knife and the oncologist’s infusion chair, transforming follow-up after colon cancer surgery from a period of anxious waiting into a period of active, data-driven decision-making.

Subject of Research: Circulating tumor DNA-guided adjuvant and postadjuvant treatment in resected high-risk stage II and III microsatellite-stable colon cancer

Article Title: Circulating tumor DNA-guided de-escalation or escalation of adjuvant therapy in high-risk stage II and stage III colon cancer: the phase 2 PEGASUS trial

Article References: Marsoni, S., Montagut, C., Pietrantonio, F., Sartore-Bianchi, A., Lazzari, L., Bergamo, F., Zampino, M. G., Tarazona, N., Mandalà, M., Tamberi, S., Elez, E., Santos Vivas, C., Luraghi, P., Prisciandaro, M., Tosi, F., Ciardiello, D., Vidal, J., Seguì, V., Palazzo, M., … Lonardi, S. (2026). Circulating tumor DNA-guided de-escalation or escalation of adjuvant therapy in high-risk stage II and stage III colon cancer: the phase 2 PEGASUS trial. Nature Cancer. https://doi.org/10.1038/s43018-026-01237-9

Image Credits: AI Generated

DOI: 10.1038/s43018-026-01237-9

Keywords: circulating tumor DNA, colon cancer, adjuvant chemotherapy, PEGASUS trial, de-escalation, escalation, microsatellite stability, minimal residual disease, stage III colon cancer, precision oncology, oxaliplatin, biomarker-guided therapy

The study, published in Breast Cancer Research and Treatment, retrospectively analyzed 87 women with metastatic triple-negative breast cancer who received Trop-2 antibody-drug conjugates between April 2020 and December 2025. Nearly all patients were treated with sacituzumab govitecan, an antibody-drug conjugate that links a topoisomerase I inhibitor payload to an antibody targeting Trop-2, a cell-surface protein abundantly expressed in triple-negative tumors. Two patients received sacituzumab tirumotecan, a related agent. Patients were divided into three groups: 60 received the antibody-drug conjugate alone, 13 received it together with the PD-1 inhibitor pembrolizumab, and 14 received a triple-agent regimen combining the antibody-drug conjugate, pembrolizumab, and the oral anti-angiogenic drug apatinib. All patients received at least two cycles of therapy in the second-line or later setting.

The results describe a clear stepwise gradient of activity. The objective response rate was 31.7 percent with monotherapy, 38.5 percent with the dual combination, and 57.1 percent with the triple-agent regimen. Disease control rates followed the same pattern, rising from 78.3 percent to 84.6 percent and then to 92.9 percent. More consequential still were the survival figures. Median progression-free survival was 3.8 months with monotherapy, 10.0 months with the dual combination, and 15.4 months with the triple-agent combination, over a median follow-up of 15.2 months. In pooled analysis, any combination therapy was associated with a hazard ratio of 0.387 for progression or death compared with monotherapy, and the benefit persisted after propensity-score-based overlap weighting, with an adjusted hazard ratio of 0.49.

The biological logic underlying the triplet is rooted in the interplay between tumor vasculature and antitumor immunity. Low-dose VEGF pathway inhibition is known to promote vascular normalization within tumors, reversing the hypoxic, immunosuppressive microenvironment that blunts immune checkpoint blockade. Preclinical work has shown that anti-angiogenic therapy enhances CD8-positive T cell activity, and that the OPN-TGF-beta pathway upregulates PD-1 on these T cells, increasing their sensitivity to PD-1 blockade. Clinical evidence has been accumulating in parallel: the ATRACTIB trial suggested that adding bevacizumab to atezolizumab and paclitaxel improved outcomes including in PD-L1-negative disease, and a multicenter phase II trial of camrelizumab, apatinib, and eribulin achieved a 37 percent response rate in heavily pretreated patients regardless of PD-L1 status. The new study extends this concept to an antibody-drug conjugate backbone.

Importantly, the exploratory subgroup analyses suggested that the activity of the triple-agent combination may not be confined to PD-L1-positive tumors. The interaction P-value between treatment effect and PD-L1 status was 0.098, and among the 39 patients with confirmed PD-L1-positive disease, median progression-free survival had not been reached in the triplet group compared with 5.0 months on monotherapy, a statistically significant difference. Prior treatment with a PD-1 inhibitor, documented in roughly half of the cohort, also did not appear to diminish the benefit of the triplet, with an interaction P-value of 0.828. This is clinically meaningful because primary resistance to checkpoint inhibitors occurs in approximately 60 percent of PD-L1-negative triple-negative breast cancers, and immunotherapy rechallenge after progression is often viewed with skepticism.

One of the most intriguing findings emerged from an interaction test involving prior platinum exposure. Among patients who had previously received platinum chemotherapy, the hazard ratio for the triple-agent regimen versus monotherapy was 0.19, a dramatic reduction in the risk of progression or death, whereas among platinum-naive patients the hazard ratio was 1.11, showing essentially no difference. The interaction P-value of 0.039 suggests that platinum-pretreated patients may represent a subgroup particularly likely to benefit from the triplet, possibly because platinum sensitivity reflects underlying DNA damage repair deficiencies that also influence antibody-drug conjugate efficacy. The authors caution that this observation is exploratory and requires prospective validation, but it provides a concrete hypothesis for patient selection in future trials.

Safety data were reassuring. With prophylactic measures applied across the entire cohort, grade 3 or higher treatment-related adverse events occurred in 20.0 percent of monotherapy patients, 15.4 percent of the dual-combination group, and 14.3 percent of the triple-agent group, a difference that was not statistically significant. The most common severe toxicities were leukopenia and neutropenia across all groups. No treatment-related deaths were recorded, and no grade 3 or higher febrile neutropenia, hyperbilirubinemia, rash, or oral ulceration was reported. The starting dose of the antibody-drug conjugate was individualized according to performance status, with patients scoring 2 on the Eastern Cooperative Oncology Group scale receiving reduced starting doses below 80 percent of the standard level. Notably, an antibody-drug conjugate starting dose of at least 80 percent was associated with improved progression-free survival, underscoring the importance of maintaining dose intensity where tolerable.

Beyond the clinical outcomes, the research team developed an exploratory genomic scoring system aimed at identifying which patients are most likely to respond to the triple-agent strategy. The system incorporates mutations in 17 genes connected to Trop-2 antibody-drug conjugate sensitivity, homologous recombination repair, and angiogenesis pathways. Genes promoting therapeutic response, such as ATR, which may sensitize tumors to topoisomerase I inhibition and correlate with higher mutational burden and immunotherapy benefit, received positive weighted scores, while resistance-associated genes received negative scores. Patients whose total score exceeded zero were classified as likely to benefit from the triplet, and Fisher’s exact testing showed the classification was statistically significant. Genes such as VEGFRA and VEGFRB, tied to angiogenesis signaling, may indicate sensitivity to the anti-angiogenic component. The authors emphasize that the model’s principal value at this stage is hypothesis generation rather than clinical deployment.

The study also confirmed several prognostic patterns familiar from earlier research. Patients who initiated antibody-drug conjugate therapy in the second or third line had significantly longer progression-free survival than those treated later, at 5.8 versus 3.0 months. The presence of liver metastases, brain metastases, or visceral disease more broadly each independently predicted shorter progression-free survival after multivariable adjustment, with hazard ratios of 2.38, 2.51, and elevated risk for visceral involvement overall. These findings reinforce that disease biology and metastatic pattern remain dominant determinants of outcome even in the era of antibody-drug conjugates, and they highlight the need for improved risk stratification in biologically aggressive disease.

The investigators are transparent about the limitations inherent in a retrospective, single-center, non-randomized design. Selection bias and residual confounding cannot be excluded, baseline characteristics such as treatment line and PD-L1 status differed descriptively across groups, and the small size of the combination cohorts, 13 and 14 patients respectively, limits statistical power. Sensitivity analyses restricted to second- or third-line patients yielded directionally consistent but non-significant results, likely reflecting reduced sample size. To address these constraints, the team has launched a prospective randomized controlled trial, registered as NCT06851299, designed to rigorously test the efficacy and safety of Trop-2 antibody-drug conjugate-based combination regimens and to validate the genomic risk score. If those results confirm the signals described here, a triplet regimen combining a Trop-2 antibody-drug conjugate, PD-1 blockade, and anti-angiogenic therapy could reshape the treatment algorithm for one of breast cancer’s most lethal forms, extending meaningful survival to patients who currently have few good options.

Subject of Research: Trop-2-directed antibody-drug conjugate monotherapy and combination therapy for pretreated metastatic triple-negative breast cancer

Article Title: Exploring trop-2-directed ADCs monotherapy and combination therapy in pretreated mTNBC: a real-world study

Article References: Liu, J., Ding, L., Wang, J., Chen, T., Long, T., Li, Q., Chai, J., Yao, H., Wang, Y., & Zhao, J. (2026). Exploring trop-2-directed ADCs monotherapy and combination therapy in pretreated mTNBC: a real-world study. Breast Cancer Research and Treatment, 219(2), Article 10. https://doi.org/10.1007/s10549-026-08070-9

Image Credits: AI Generated

DOI: 10.1007/s10549-026-08070-9

Keywords: Trop-2 antibody-drug conjugates, metastatic triple-negative breast cancer, sacituzumab govitecan, PD-1 inhibitors, anti-angiogenic therapy, triple-agent combination therapy, pembrolizumab, apatinib, progression-free survival, biomarker-guided therapy, real-world study, immune checkpoint inhibitors

The study, published Aug. 6 in Cell Reports Medicine, addresses one of the central challenges in oncology: two tumors that appear similar under a microscope can respond very differently to the same therapy. Breast cancer treatment decisions are increasingly guided by biomarkers, such as hormone-receptor status, HER2 amplification and DNA-repair alterations, but these measurements do not always reveal which drug will work best in a particular patient. The UCSF team investigated whether living tumor models could provide a functional test of treatment response alongside genomic and clinical information.

To create the organoids, researchers placed cells taken from patient tumors into a specialized gel engineered to support the biological conditions of the original cancer. Over several weeks, the cells organized into compact, three-dimensional structures containing hundreds or thousands of cells. Unlike conventional cancer cell lines grown as flat layers, organoids preserve aspects of tumor architecture and retain many of the molecular features found in the tissue from which they were derived. Their small size also makes it possible to expose large numbers of organoids to multiple drugs in parallel.

The team established a biobank of organoids from early-stage invasive breast cancers and compared their behavior with clinical information from patients enrolled in the I-SPY2 trial. I-SPY2 is designed to accelerate the testing of therapies for high-risk breast cancer by evaluating several treatments simultaneously in biologically defined patient groups. The trial has generated “response predictive subtypes,” molecular classifications intended to estimate how tumors will respond to therapies such as immunotherapy, platinum chemotherapy, PARP inhibitors and dual-HER2-targeted drugs.

Using these predictive subtypes and additional tumor biomarkers, the researchers built a computational framework to forecast how individual organoids would react to specific treatments. They then tested the predictions experimentally. The model was especially evaluated in organoids derived from triple-negative breast cancers, a subtype that lacks estrogen and progesterone receptors and does not show elevated levels of HER2. Because triple-negative tumors have fewer established molecular targets and can rapidly develop treatment resistance, patients are often treated with intensive chemotherapy, including platinum-based drugs.

One treatment combination examined in the study was veliparib plus platinum chemotherapy, referred to as VP. Veliparib inhibits PARP proteins, which help repair certain forms of DNA damage, while platinum drugs damage DNA directly. The combination is intended to overwhelm the tumor’s repair machinery, but not every triple-negative tumor is vulnerable to it. Among the organoids, the model identified one sample, designated TORG40, as having a particularly high likelihood of resistance. Laboratory experiments subsequently confirmed that TORG40 showed limited sensitivity to VP, providing a test of the prediction system.

The researchers then used TORG40 to conduct a high-throughput drug screen involving 386 small-molecule inhibitors. The screen highlighted ABT-263, a compound that targets proteins involved in cellular survival and can promote the removal of damaged or stressed cells. When ABT-263 was combined with cisplatin, a platinum chemotherapy drug, the treatment produced a markedly stronger effect against the resistant TORG40 organoid than either agent alone. The result suggests that functional drug screening may uncover vulnerabilities that are not obvious from standard biomarkers, although the combination remains an experimental finding rather than an established treatment.

The organoid experiments also identified HSP90 inhibitors as potential candidates for further study. HSP90 is a molecular chaperone that helps stabilize and maintain numerous proteins, including proteins involved in cancer growth and survival. Blocking HSP90 can disrupt several signaling pathways at once, which may be useful in tumors driven by complex or overlapping mechanisms. The researchers linked the organoid findings to a subset of I-SPY patients who appeared to respond more favorably to drugs in this class, offering an example of how laboratory observations can be connected back to clinical trial data.

The investigators emphasize that the organoids do not reproduce the full environment of a tumor inside the body. They lack blood vessels, immune cells, stromal tissue and the broader organ systems that influence how cancer cells receive signals and how drugs are distributed. The study also did not determine whether organoid-guided treatment decisions would improve patient outcomes over months or years. Even so, the findings support a “reverse translational” strategy in which clinical trial data are used to generate laboratory predictions, and organoid experiments are then used to discover and prioritize therapies. With further validation in prospective clinical studies, patient-derived organoids could eventually become a practical bridge between molecular biomarkers and more individualized breast cancer treatment.

Subject of Research: Lab-produced tissue samples

Article Title: Biomarker-guided responses in patient-derived organoids predict effective therapies in breast cancer

News Publication Date: 6-Aug-2026

Web References: https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(26)00390-3

References: DOI: 10.1016/j.xcrm.2026.102973

Keywords: Breast cancer, triple-negative breast cancer, patient-derived organoids, tumor organoids, personalized medicine, biomarkers, drug resistance, combination therapy, cisplatin, veliparib, PARP inhibitors, HSP90 inhibitors, I-SPY2 trial, precision oncology