The patient’s story began in September 2019, when she first noticed a small, mobile mass in her left breast measuring roughly 2 by 1 by 1 centimeters. The lump caused no tenderness, no skin changes, and no nipple discharge, so she initially ignored it. Two months later, at another hospital, mammography and breast color Doppler ultrasound both classified the lesion as Breast Imaging Reporting and Data System category III—a designation implying a probably benign finding with less than a 2 percent risk of malignancy—and recommended routine follow-up. Over the following three months, however, the mass grew dramatically, reaching approximately 4 by 3 by 2 centimeters and occasionally becoming painful. That rapid enlargement prompted her admission to the reporting hospital in March 2020, where physical examination found a smooth, moderately firm, mobile mass without skin ulceration, nipple retraction, or enlarged lymph nodes in the armpits.

The imaging workup revealed a striking contradiction. Mammography at the outside hospital had graded the lesion BI-RADS 3, but repeat ultrasound at the new institution upgraded it to BI-RADS 4A, indicating a small but real suspicion of malignancy of roughly 2 to 10 percent. The ultrasound showed a solid, irregular, lobulated mass at the 11 o’clock position of the left breast, containing strip-like blood flow signals with low-resistance arterial waveforms—a vascular pattern that would later prove telling. Chest computed tomography confirmed a mound-shaped mass in the upper inner quadrant with an unclear boundary on plain scan. Meanwhile, laboratory results were entirely unremarkable: blood counts, liver and kidney function, and coagulation were normal, and the tumor markers CEA, CA 15-3, CA 125, and CA 19-9 all sat comfortably within reference ranges. The team noted that breast angiosarcomas frequently produce negative results on routine malignant tumor markers, rendering these tests of extremely low diagnostic value in such cases.

Reconciling the discordant imaging grades against current standards proved decisive in shaping the diagnostic pathway. According to the fifth edition of the American College of Radiology BI-RADS criteria, the 2024 National Comprehensive Cancer Network breast guidelines, and the 2021 Chinese Society of Breast Surgery fibroadenoma guideline, the combined clinical and imaging picture did not meet formal indications for contrast-enhanced breast MRI, bone scintigraphy, or percutaneous core needle biopsy. Those tools are reserved for high-risk patients, radiologically indeterminate lesions with definite malignant suspicion, or preoperative staging of confirmed cancers—not for discordant low-grade BI-RADS 4A lesions accompanied by benign mammographic findings. The clinicians therefore concluded the lesion was highly suggestive of a benign fibroadenoma and recommended elective surgical resection, a decision that conformed to guidelines but, as they later acknowledged, failed to account specifically for the lesion’s rapid growth.

Surgery took place on March 11, 2020, under general anesthesia, and it was here that the case pivoted. Intraoperative frozen section pathology suggested a spindle cell tumor tending toward a vascular origin, with definitive classification awaiting immunohistochemistry. Because the team had rarely encountered such lesions, and because committing to a radical operation on an uncertain diagnosis carried obvious risks, they consulted the patient’s family and made the unusual decision to temporarily suspend the surgery. Final pathology returned on March 17: the excised nodule, about 3.5 by 2.5 by 1.8 centimeters, was packed with anastomosing slit-like vascular channels infiltrating breast lobules and fat, lined by a single layer of endothelial cells showing mild nuclear atypia and occasional mitoses. Immunohistochemistry showed strong positivity for the endothelial markers CD34, CD31, and FLT-1, along with vimentin and smooth muscle actin, while epithelial markers EMA and broad-spectrum cytokeratins were negative. The Ki-67 proliferation index was 25 percent. The diagnosis was low-grade angiosarcoma.

To be certain, the slides were sent for outside consultation at a higher-level hospital, which returned on March 20 with a confirmatory and slightly more concerning picture: part of the tumor showed the mild, well-formed vascular pattern, but other areas were solid, densely cellular, and pleomorphic with mitotic figures, extensive hemorrhage, and necrosis. The consultants recommended optional molecular testing for c-Myc, KDR, and VEGFR2—markers mainly useful for distinguishing primary from radiation-associated secondary angiosarcoma—though the team ultimately judged these unnecessary given the clear histopathological diagnosis. After a hospital-wide multidisciplinary team discussion, the patient underwent completion resection of the remaining left breast tissue plus sentinel lymph node biopsy on March 23. Frozen section confirmed an R0 resection with clear microscopic margins and no sentinel node metastasis, and final pathology found no residual cancer in the surrounding breast, nipple, skin, or basal margin, with zero of three sentinel nodes involved.

The staging and treatment decisions reflected the peculiar biology of this tumor. Under the eighth edition of the AJCC staging system, the disease was classified as stage I (T1N0M0). Unlike conventional breast carcinoma, which spreads chiefly through lymphatic channels, primary breast angiosarcoma metastasizes predominantly through the bloodstream, seeding the liver, lungs, bone, and brain early, while regional lymph node involvement is extremely rare. Routine axillary lymph node dissection is therefore not recommended, and the team performed only a sentinel node biopsy for accurate staging, sparing the patient unnecessary surgical trauma. Beginning April 3, 2020, she received eight cycles of adjuvant chemotherapy—four of doxorubicin plus cyclophosphamide followed by four of paclitaxel—completed without significant adverse reactions by the end of July 2020.

The prognosis data assembled in the report underscore why vigilance matters. Secondary angiosarcoma of the breast, which typically arises after radiotherapy for breast cancer or in the setting of chronic lymphedema known as Stewart-Treves syndrome, carries a five-year overall survival of roughly 38 percent with a recurrence-free survival of about 43 months. Primary breast angiosarcoma fares somewhat better, with a five-year overall survival near 49 percent and recurrence-free survival of about 44 months, with outcomes tied to stage, histological grade, and tumor size. Diagnosis remains the hardest part: mammography yields false negatives in roughly a third of patients because of dense glandular tissue, ultrasound lacks specificity despite showing heterogeneous masses and increased blood flow, and MRI—considered the most useful non-invasive modality—reveals heterogeneous signals and avid contrast enhancement reflecting the tumor’s rich vascularity. Core needle biopsy, the usual route to preoperative diagnosis, frequently returns false negatives because of bleeding risk and marked tumor heterogeneity, meaning most cases are only confirmed after surgery.

Emerging evidence is beginning to reshape treatment thinking for this orphan disease. A meta-analysis by Skarentzos and colleagues found that adjuvant chemotherapy significantly improved survival in primary breast angiosarcoma, with a hazard ratio of 0.11, while radiotherapy showed no survival benefit. Anthracycline-, ifosfamide-, and paclitaxel-containing regimens are considered the most effective, though the disease’s rarity means evidence rests on small series and case reports rather than large trials. Genomic research is opening new doors: the Angiosarcoma Project, a patient-partnered genomic study, has suggested that inhibitors of the phosphatidylinositol-3-kinase catalytic alpha subunit could become targeted therapeutic options, and next-generation sequencing may eventually identify actionable alterations in tumors like this one.

Follow-up tells the story’s encouraging end. The patient was re-examined at one, three, and six months after surgery, then roughly every six months, with breast ultrasound, chest CT, abdominal and urinary tract ultrasound, blood counts, and tumor markers. As of November 5, 2025—more than five years after her diagnosis—she showed no sign of local recurrence or distant metastasis. The authors argue their case carries three broader lessons: that a rapidly growing, benign-appearing breast mass in a postmenopausal woman deserves heightened suspicion even when guidelines do not mandate advanced imaging; that suspending surgery when frozen section reveals something unexpected can preserve diagnostic accuracy and prevent undertreatment; and that multidisciplinary collaboration, staged surgery, and guideline-conformant individualized therapy can deliver excellent long-term outcomes even in a cancer this rare and this easy to miss.

Subject of Research: Primary breast angiosarcoma diagnosis and treatment in a postmenopausal woman

Article Title: Primary Mammary Angiosarcoma in a Postmenopausal Woman: A Case Report

Article References: Liu, T., Xu, Y., Wang, Q., Yu, S., Lin, H., Ye, Z., Zheng, Z., Yang, C., & Hong, T. (2026). Primary Mammary Angiosarcoma in a Postmenopausal Woman: A Case Report. Cancer Reports, 9(9), Article e70653. https://doi.org/10.1002/cnr2.70653

Image Credits: AI Generated

DOI: 10.1002/cnr2.70653

Keywords: breast angiosarcoma, primary breast angiosarcoma, postmenopausal, BI-RADS, fibroadenoma, frozen section pathology, immunohistochemistry, CD31, sentinel lymph node biopsy, adjuvant chemotherapy, R0 resection, rare cancer

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

Colorectal cancer remains one of the most common malignancies worldwide, and while radical surgery is highly effective when the disease has not spread to distant organs, stage III disease, defined by lymph node involvement, carries a recurrence rate of 20 to 30 percent. Adjuvant chemotherapy after surgery has been proven in randomized controlled trials to reduce this risk and improve survival. However, the picture becomes murkier in patients aged 70 and older. As people age, comorbidities accumulate and organ function declines, making chemotherapy harder to tolerate and raising the risk of serious adverse events. Notably, there is no consistent evidence that adding oxaliplatin provides additional benefit in this age group, suggesting that the therapeutic effect of adjuvant chemotherapy may be limited for many elderly patients.

This uncertainty creates a real clinical dilemma. Physicians must weigh the possibility of a survival benefit against the substantial burden chemotherapy can impose on an older body. The Japanese research team, led by Tomoya Tago and Yasuyuki Takamizawa, set out to determine whether simple blood-derived markers, calculated from tests already ordered in routine care, could identify which elderly patients are most likely to benefit from postoperative chemotherapy and which might safely avoid it.

The study included patients aged 70 or older who underwent radical resection of pathologically confirmed stage III colorectal adenocarcinoma at the National Cancer Center Hospital between January 2000 and December 2017. After excluding those with other primary cancers, prior neoadjuvant therapy, or incomplete data, 308 patients remained, of whom 177 received adjuvant chemotherapy and 131 did not. Because patients selected for chemotherapy were significantly younger and likely healthier than those who were not, the researchers used propensity score matching to balance the two groups on sex, age, body mass index, comorbidities, tumor location and stage, histology, and preoperative tumor marker levels. This produced 78 matched pairs with well-balanced baseline characteristics.

The survival benefit of adjuvant chemotherapy held up after matching. The five-year recurrence-free survival rate was 76.6 percent in the chemotherapy group versus 62.8 percent in the non-treatment group, with a hazard ratio of 0.537. Five-year overall survival was 84.1 percent versus 73.9 percent, with a hazard ratio of 0.495. Both differences were statistically significant, confirming that adjuvant chemotherapy remains worthwhile for properly selected elderly patients overall.

The most striking findings emerged when the researchers stratified the matched cohort by nine preoperative and postoperative immuno-nutritional and inflammatory markers, including the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, prognostic nutritional index, geriatric nutritional risk index, controlling nutritional status score, Glasgow Prognostic Score, and modified Glasgow Prognostic Score. Two postoperative markers showed significant interactions with chemotherapy benefit: the lymphocyte-to-monocyte ratio and the C-reactive protein-to-albumin ratio.

In patients with a high postoperative LMR, defined by the study’s cut-off of 5.27, adjuvant chemotherapy produced a dramatic improvement. Five-year recurrence-free survival reached 84.4 percent in the treated group versus just 53.0 percent in the untreated group, a hazard ratio of 0.27. Overall survival showed an even starker contrast: 92.1 percent versus 68.0 percent, with a hazard ratio of 0.16. Yet in patients with a low postoperative LMR, chemotherapy provided essentially no advantage, with five-year recurrence-free survival of 69.2 percent versus 72.9 percent, and overall survival of 76.9 percent versus 80.4 percent, both comparisons statistically indistinguishable.

The CAR told a similar story. Patients with a high postoperative CAR, above the cut-off of 0.026, derived marked benefit from chemotherapy, with five-year recurrence-free survival of 79.0 percent versus 47.8 percent and overall survival of 88.0 percent versus 62.4 percent. In those with a low CAR, the survival curves of treated and untreated patients were nearly superimposable. The biological rationale is rooted in tumor-host interactions: lymphocytes mount anti-tumor immune responses and their preservation is associated with better drug responsiveness, whereas systemic inflammation, marked by elevated C-reactive protein relative to albumin, reflects a cytokine-driven state regulated by interleukin-1, interleukin-6, and tumor necrosis factor-alpha that generally portends poorer outcomes. Because postoperative samples in this study were collected uniformly four to eight weeks after surgery, once acute inflammatory responses from the operation had subsided, the markers likely captured the patient’s intrinsic baseline immunity at the moment chemotherapy would begin, rather than residual tumor-driven inflammation.

The clinical appeal of these markers lies in their simplicity and cost. Unlike circulating tumor DNA, which shows promise for predicting treatment efficacy but remains expensive and not yet widely implementable, LMR and CAR can be calculated from standard complete blood counts and chemistry panels already obtained in routine follow-up. The authors suggest that these values could serve as supplementary information alongside age, performance status, and comorbidities when the indication for adjuvant chemotherapy is being considered, helping individualize decisions rather than uniformly determine them.

The researchers acknowledge important limitations. The study was retrospective and single-center, so selection bias and institution-specific treatment practices cannot be fully excluded, and the derived cut-off values may not generalize elsewhere. Standardized comorbidity assessment tools such as the Charlson Comorbidity Index and Geriatric-8 were not consistently available, data on chemotherapy completion rates and adverse events were incomplete, and molecular information on RAS, BRAF, and microsatellite instability status was lacking for much of the study period. Even so, because the cohort included elderly patients with common comorbidities, it reflects a population closer to real-world practice than the highly selected patients enrolled in clinical trials. The authors conclude that postoperative LMR and CAR are promising predictors of adjuvant chemotherapy efficacy in this growing patient population and hope the work will spur development of novel biomarkers for guiding treatment decisions in elderly cancer care.

Subject of Research: Predicting adjuvant chemotherapy efficacy in elderly stage III colorectal cancer patients using immuno-nutritional and inflammatory blood markers

Article Title: Predicting the Efficacy of Adjuvant Chemotherapy Using Immuno‐Nutritional and Inflammatory Markers in Elderly Patients With Stage III Colorectal Cancer

Article References: Tago, T., Takamizawa, Y., Kato, T., Nagata, H., Moritani, K., Tsukamoto, S., & Kanemitsu, Y. (2026). Predicting the Efficacy of Adjuvant Chemotherapy Using Immuno‐Nutritional and Inflammatory Markers in Elderly Patients With Stage III Colorectal Cancer. Annals of Gastroenterological Surgery, 10(5), 1575-1585. https://doi.org/10.1002/ags3.70235

Image Credits: AI Generated

DOI: 10.1002/ags3.70235

Keywords: colorectal cancer, adjuvant chemotherapy, elderly patients, lymphocyte-to-monocyte ratio, C-reactive protein-to-albumin ratio, immuno-nutritional markers, inflammatory markers, propensity score matching, recurrence-free survival, biomarkers, National Cancer Center Hospital, Annals of Gastroenterological Surgery