Author: RR

ERSPC Final Analysis: Long-Term PSA Screening Reduces Prostate Cancer Deaths

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SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 313,780 new cases of prostate cancer will be diagnosed in 2025 and 35,770 men will die of the disease. Prostate cancer remains one of the most pressing global cancer burdens, with mortality rates projected to double by 2040 as populations age and life expectancy increases.

PSA is one of the most widely used prostate cancer biomarkers, and the widespread use of PSA testing in the recent years has resulted in a dramatic increase in the diagnosis and treatment of prostate cancer. PSA-based screening is widely debated due to false positives, overdiagnosis, and overtreatment.

The question of how and in whom to implement early detection strategies, continues to challenge clinicians and public health systems. The European Randomized Study of Screening for Prostate Cancer (ERSPC), initiated in 1993, represents the most comprehensive effort to evaluate whether population-based Prostate-Specific Antigen (PSA) screening reduces prostate cancer mortality. Now, with more than two decades of follow-up completed for over 160,000 men, the ERSPC provides its final unified analysis, offering critical insights into both the enduring benefits and ongoing challenges of PSA-based screening.

Study Overview and Screening Approach

The ERSPC spanned eight European countries and included a predefined core cohort of men aged 55–69 years at randomization. Participants were assigned to organized repeated PSA screening or to usual care without screening invitations. Screening protocols varied modestly by country, but all centers relied on standardized PSA assays and risk-based biopsy thresholds. Most participants received screening every four years, although the interval ranged from two to seven years. The Primary outcome was prostate cancer mortality.

  • Population: 162,236 men (55–69 yrs)
    • Screening group: 72,888
    • Control group: 89,348
  • Screening Protocol: Repeated PSA, 2–8 invitations, biopsies for elevated PSA
  • Follow-Up: Median 23 years
  • Outcomes:
    • Relative reduction in prostate cancer death: 13%
    • Absolute risk reduction: 0.22%

Key Points for Clinical Practice:

Three decades after its inception, the ERSPC provides unequivocal evidence that PSA-based screening reduces prostate cancer mortality. However, it also highlights that how screening is implemented may matter, as much as whether it is implemented at all.

  • PSA-based screening reduces prostate cancer mortality by ~13% over 23 years; absolute benefit continues to rise with long-term follow-up.
  • Overdiagnosis and overtreatment remain central harms. Risk-adapted strategies (MRI, biomarkers, active surveillance) mitigate these risks.
  • Screening should ideally start at age 50 for maximal benefit and continue based on life expectancy rather than age alone.
  • Modern guidelines support selective biopsy only in patients with high-risk features and conservative management/active surveillance for low-risk disease, to optimize the harm–benefit ratio.
  • Individualized decision-making and cessation of screening is essential, particularly for older men or those with competing health risks.

Such strategies aim to preserve the mortality benefit demonstrated in ERSPC while minimizing harms associated with overdiagnosis and overtreatment.

Conclusion

The final unified analysis of the ERSPC confirms that PSA screening offers a sustained reduction in prostate cancer mortality that becomes more pronounced over long-term follow-up. While screening continues to carry risks, particularly through detection of indolent disease, its harm–benefit balance has improved with time and can be further optimized through modern, risk-adapted approaches. As prostate cancer incidence continues to rise worldwide, these data provide essential guidance for developing screening policies that maximize benefit, reduce harm, and ensure evidence-based care for patients at risk.

European Study of Prostate Cancer Screening-23-Year Follow-up. Roobol MJ, de Vos II, Månsson M, et al for the ERSPC Investigators. N Engl J Med 2025;393:1669-1680.

Precision Medicine in Practice: Timely Use of Tumor NGS Remains Suboptimal in Common Cancers

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SUMMARY: Next-generation sequencing (NGS) has revolutionized the management of advanced cancers by enabling identification of tumor-specific genomic alterations for which targeted therapies are now available. National guidelines recommend early and routine NGS testing for patients with advanced or metastatic solid tumors to inform treatment decisions. In the United States, the five most prevalent advanced or metastatic solid tumors include advanced Non-Small Cell Lung Cancer (aNSCLC), metastatic Breast Cancer (mBC), metastatic Prostate Cancer (mPC), advanced Colorectal Cancer (aCRC), and metastatic Pancreatic Cancer (mPanC). For these malignancies, the integration of NGS has become increasingly critical in guiding targeted therapy selection and improving survival outcomes. Despite the approval of multiple targeted therapies for these malignancies, real-world utilization of NGS remains inconsistent.

In this study presented at the 2025 ASCO Annual Meeting, Chehade and colleagues,  evaluated patterns in NGS testing and its timing, relative to patient mortality.

Study Overview: This retrospective analysis leveraged the Flatiron Health EHR-derived de-identified database across 280 cancer clinics, spanning data from 2011 onward. The study included patients with a diagnosis of aNSCLC, mBC, mPC, aCRC, or mPanC, all of whom had records of NGS testing and a documented date of death. The researchers identified 86,536 patients with advanced non-small cell lung cancer, 36,000 with metastatic breast cancer, 35,702 with advanced colorectal cancer, 24,105 with metastatic prostate cancer and 14,964 with metastatic pancreatic cancer. About a third of patients from each cancer group received NGS testing (NSCLC, 36.3%; breast cancer, 32.1%; colorectal cancer, 41%; prostate cancer, 30.9%; and pancreatic cancer, 35.4%).

Patients were categorized based on the interval between receipt of NGS results and death:

  • More than 3 months before death
  • Within 3 months of death
  • After death

Key Findings Across cancer types, only 30% to 40% of patients received NGS testing. Among those who were tested and had a recorded date of death, the timing of NGS was as follows:

Timing of First NGS aNSCLC (N=19,958) mBC (N=5,689) mPC (N=3,397) aCRC (N=8,553) mPanC (N=3,957)
>3 mo before death          72.3%        81.6%        85.4%        85.0%         71.1%
Within 3 mo of death          25.6%        16.9%        13.5%        13.7%         26.5%
After death          2.1%        1.5%        1.1%        1.3%         2.4%

Notably, up to one in four patients with NSCLC or pancreatic cancer received their first NGS results within 3 months of death, a timeframe often too late for actionable therapeutic intervention.

Interpretation and Implications Despite advances in molecularly targeted therapies and growing guideline support for comprehensive genomic profiling, real-world testing patterns remain suboptimal:

  • Low uptake: Only about a third of eligible patients undergo NGS testing.
  • Late testing: A substantial proportion of tested patients receive results within 3 months of death.
  • Missed opportunities: Many patients are never tested—or are tested too late to benefit from life-extending therapies.

These findings highlight ongoing gaps in precision oncology implementation, especially in community-based settings.

Next Steps & Recommendations To improve the utility of NGS in oncology, efforts should focus on:

  • Earlier testing: At diagnosis or at first progression of advanced disease.
  • Workflow integration: Embedding NGS into routine clinical pathways.
  • Education: Raising awareness among clinicians and patients about the benefits of timely testing.
  • Health system support: Addressing barriers such as reimbursement, turnaround times, and tissue availability.

Conclusion: Real-World Data from this large retrospective analysis reveal late-stage testing and underutilization of life-prolonging genomic profiling. This study underscores an urgent need to optimize the timing and uptake of NGS testing in patients with advanced solid tumors. Earlier and broader testing is essential to ensure patients have access to the most effective, personalized treatment strategies, and to avoid the missed potential of life-extending therapies.

Utilization and timing of first tumor next-generation sequencing testing (NGS) in patients (pts) with five most common cancers in the USA. Chehade CH, Jo Y, Ozay ZI, et al. Doi: 10.1200/JCO.2025.43.16_suppl.11014. Abstract # 11014. Presented at: ASCO Annual Meeting; May 30-June 3, 2025; Chicago.

Low Dose Aspirin Reduces Recurrence in Colorectal Cancer Patients with PI3K Pathway Alterations

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SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 154,270 new cases of CRC will be diagnosed in the United States in 2025 and about 52,900 patients will die of the disease. The lifetime risk of developing CRC is about 1 in 23. Among patients with Stage II-III CRC, 20-40% will develop metastatic disease.

The majority of CRC cases (about 75 %) are sporadic whereas the remaining 25 % of the patients have a family history of the disease. Only 5-6 % of patients with CRC with a family history background are due to inherited mutations in major CRC genes, while the rest are the result of accumulation of both genetic mutations and epigenetic modifications of several genes. Colorectal Cancer is a heterogeneous disease classified by its genetics, and even though the diagnosis of Colorectal Cancer in the US is dropping among people 65 years and older, the incidence has been rising in the younger age groups, with 12% of Colorectal Cancer cases diagnosed in people under age 50.

Aspirin (AcetylSalicylic Acid) has been studied as a chemopreventive agent for several decades and the temporal relationship between systemic inflammation and cancer has been a topic of ongoing investigation. The US Preventive Services Task Force (USPSTF) found adequate evidence that Aspirin use reduces the incidence of CRC in adults after 5-10 years of use, and recommends initiating low-dose Aspirin use for the primary prevention of CardioVascular Disease (CVD) and CRC, in adults aged 50-69 years, who have a 10% or greater 10-year CVD risk, are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose Aspirin daily for at least 10 years.

Aspirin has been shown to lower the incidence of adenomas and CRC in high-risk patients. Additionally, observational studies suggest that treatment with Aspirin following diagnosis improves Disease-Free Survival (DFS) in unselected populations. Furthermore, retrospective findings indicate that somatic PIK3CA mutations predict treatment response to Aspirin. However this has not been validated in randomized trials.

The ALASCCA trial was designed to find the impact of Aspirin, on the recurrence of CRC with PI3K pathway mutations. The ALASCCA trial is a randomized, double-blind, multicenter, placebo-controlled trial conducted across 33 hospitals in Sweden, Denmark, Finland, and Norway. Researchers screened 3,508 patients diagnosed with Stage II or III colon cancer or Stage I, II, or III rectal cancer and identified 1,103 individuals with PI3K pathway mutations. Participants were categorized into two groups:

• Group A (N=515): Patients with a PIK3CA mutation in exon 9 and/or 20.
• Group B (N=588): Patients with other PI3K mutations, including PIK3CA mutations outside exon 9/20 or mutations in PIK3R1 or PTEN genes.

Of the 626 patients (419 with colon cancer and 207 with rectal cancer) who continued participation in this trial, 157 and 156 patients in Groups A and B respectively, received Aspirin 160 mg daily for 3 years, whereas 157 and 156 patients in each respective group received placebo. The median age was 66 years, 52% of patients were female, and majority of patients were white. Fifty percent of patients with both rectal and colon cancer had received neoadjuvant therapy. The Primary end point was Time to CRC recurrence (TTR) in Group A patients. Secondary end points included Disease Free Survival (DFS) and Overall Survival (OS) in Group A, DFS and OS in Group B, and Safety.

The study met its Primary end point and demonstrated that Aspirin use significantly reduced the risk of CRC recurrence. After 3 years of follow up in Group A, patients taking Aspirin had a 51% lower recurrence risk compared to the placebo group (HR=0.49; P=0.044). In Group B, patients taking Aspirin experienced a 58% reduction in recurrence risk versus the placebo group (HR=0.42; P=0.013). Overall, across all groups, Aspirin was associated with a 55% reduced risk of recurrence compared to placebo. There was no statistically significant difference in 3-year DFS rates among those who received Aspirin versus placebo in Group A (88.5% versus 81.4%, respectively; HR=0.61; P =0.091). There was however significantly improved DFS rates in Group B with Aspirin use (89.1% versus 78.7%, respectively; HR=0.51; P=0.17). Severe side effects of daily Aspirin use were rare.

The researchers concluded that this landmark study provides compelling evidence for the role of low-dose Aspirin in reducing colorectal cancer recurrence in patients with PI3K pathway mutations. By integrating precision medicine with a widely available drug, the ALASCCA trial sets the stage for a new standard in colorectal cancer management.

Low-Dose Aspirin for PI3K-Altered Localized Colorectal Cancer. Martling A, Myrberg IH, Nilbert M, et al.,  for the ALASCCA Study Group. N Engl J Med 2025;393:1051-1064.

Durvalumab + FLOT Establishes New Benchmark in Curative-Intent Therapy for Gastric and GEJ Cancers

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SUMMARY: The American Cancer Society estimates that in the US about 30,300 new gastric cancer cases will be diagnosed in 2025 and about 10,780 people will die of the disease. It is one of the leading causes of cancer-related deaths in the world. Several hereditary syndromes such as Hereditary Diffuse Gastric Cancer (HDGC), Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer) and Familial Adenomatous Polyposis (FAP) have been associated with a predisposition for gastric cancer. Additionally, one of the strongest risk factors for gastric adenocarcinoma is infection with Helicobacter pylori (H.pylori), which is a gram-negative, spiral-shaped microaerophilic bacterium.

Despite the intent of cure in resectable gastric and GastroEsophageal Junction (GEJ) cancers, long-term survival remains suboptimal, with fewer than half of patients alive at five years. Current perioperative chemotherapy strategies, such as the FLOT regimen (5-FU, Leucovorin, Oxaliplatin, and Docetaxel), are widely accepted as the standard of care, particularly in Western countries. However, recurrence remains a frequent challenge, underscoring the need for enhanced systemic control.

The global, randomized, double-blind Phase 3 MATTERHORN trial evaluated whether adding the immune checkpoint inhibitor Durvalumab to FLOT could improve clinical outcomes in patients with resectable, locally advanced gastric or GEJ adenocarcinoma. This approach leverages prior success of immunotherapy in metastatic settings, where checkpoint inhibitors are already approved in combination with chemotherapy, but expands the strategy into the curative-intent, perioperative context.

Durvalumab (IMFINZI®) is a human immunoglobulin G1 monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumor’s immune-evading tactics, and unleashes the T cells.

Trial Design and Treatment Protocol
In this study, a total of 948 treatment-naïve patients with Stage II to IVa resectable gastric or GEJ adenocarcinoma were randomized 1:1 to receive either Durvalumab plus FLOT (N=474) or placebo plus FLOT (N=474).  Treatment consisted of Durvalumab 1500 mg or Placebo every 4 weeks (Q4W) on Day 1 + FLOT (5-Fluorouracil, Leucovorin, Oxaliplatin and Docetaxel) on Days 1 and 15 for 4 cycles (2 cycles each neoadjuvant/adjuvant), followed by Durvalumab 1500 mg or Placebo on Day 1 Q4W for 10 cycles. Participants were enrolled across Asia, Europe, North America, and South America, reflecting the global burden of disease. Key stratification factors included geographic region (Asia vs non-Asia), nodal status, and PD-L1 expression. The median age was approximately 62 years, and around 70% of patients had gastric tumors, with the remainder involving the GEJ. Most patients (70%) had node-positive disease at baseline. Treatment groups were well balanced. Treatment was administered perioperatively, consisting of two neoadjuvant and two adjuvant cycles. Durvalumab or placebo was continued post-chemotherapy as monotherapy for 10 additional cycles. The Primary endpoint was Event-Free Survival (EFS), with Secondary endpoints including Overall Survival (OS), pathologic Complete Response (pCR), and Safety.

Efficacy Findings
At a median follow-up of 31.5 months, the addition of Durvalumab to FLOT significantly improved EFS compared to placebo. The median EFS had not yet been reached in the Durvalumab arm, whereas it was 32.8 months in the placebo group (Hazard Ratio [HR] 0.71; 95% CI, 0.58–0.86; P<0.001), translating to a roughly 30% reduction in the risk of progression, recurrence, or death. Importantly, Durvalumab did not delay surgery or adjuvant therapy initiation. Notably, 24-month EFS rates were higher with Durvalumab (67.4%) compared to placebo (58.5%), indicating a durable benefit. Subgroup analyses consistently favored the Durvalumab combination across clinical and demographic variables, including PD-L1 expression status, nodal involvement, and geographic region, although some subgroups lacked sufficient power for statistical significance.

An early OS analysis, though not yet mature, suggested a favorable trend for the Durvalumab arm (HR 0.78; 95% CI, 0.62–0.97), with median OS not reached in that group compared to 47.2 months in the placebo group.

In addition to EFS, the Durvalumab-containing regimen improved pathologic Complete Response rates as well as Major Pathological Response, suggesting more effective eradication of micrometastatic disease with immunotherapy-enhanced perioperative treatment.

The final Overall Survival results from the MATTERHORN trial were presented at the ESMO Congress 2025. In this definitive analysis, perioperative Durvalumab added to FLOT chemotherapy delivered a statistically significant and clinically meaningful survival advantage over placebo plus FLOT (HR=0.78; 95% CI, 0.63–0.96; P=0.021). Notably, the OS benefit was observed across PD-L1 expression levels, with comparable hazard ratios in both the TAP <1% and TAP ≥1% subgroups, suggesting that the activity of Durvalumab in the perioperative setting is not restricted to PD-L1–positive disease.

Durvalumab also enhanced pathological response metrics. Patients treated with Durvalumab achieved substantially higher nodal negativity rates (ypN0, 58.2% vs 44.8%), indicating deeper locoregional tumor clearance and supporting the biologic premise that checkpoint inhibition can potentiate chemotherapy-mediated cytoreduction. Improvements in Event-Free Survival were consistent across the spectrum of pathological response categories including partial, major, and complete responders, highlighting that meaningful clinical benefit extends beyond patients achieving ypCR.

Safety and Tolerability
The addition of Durvalumab did not compromise surgical outcomes or delay the initiation of adjuvant therapy. The incidence of grade 3/4 adverse events was similar between arms (72% with Durvalumab vs 71% with placebo), as were rates of serious adverse events (48% vs 44%) and treatment-related deaths (5% vs 4%). These findings reinforce the safety of incorporating immunotherapy into the perioperative setting without increasing toxicity burden or interfering with multimodal management.

Biomarker Insights and Future Directions
Approximately 90% of patients were PD-L1–positive in both groups, and 5% had MicroSatellite Instability–High (MSI-H) tumors (lower than the rates of 7% to 9% commonly seen). Although these biomarker-defined subpopulations are known to respond favorably to immunotherapy, their relatively small representation in the study suggests the observed benefits were driven by broader immunomodulatory effects rather than biomarker enrichment alone.

The optimal duration of adjuvant Durvalumab remains an open question. In MATTERHORN, Durvalumab was continued for 10 cycles post-chemotherapy, but further investigation may determine whether shorter courses or biomarker-guided de-escalation could yield similar benefits while minimizing toxicity and cost.

Clinical Implications

The MATTERHORN findings reinforce that integrating Durvalumab into the perioperative FLOT regimen confers durable improvements in both Overall and Event-Free Survival for patients with resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma. Importantly, the magnitude of benefit remained stable across key clinical and biological subgroups, including PD-L1 status and nodal involvement, underscoring the robustness and generalizability of the treatment effect.

Combined with the earlier JCO publication detailing significant gains in Event-Free Survival, these results strengthen the rationale for incorporating immunotherapy into curative-intent treatment pathways for early-stage upper gastrointestinal cancers. Durvalumab + FLOT is poised to emerge as a new global standard of care, reflecting the broader paradigm shift toward perioperative immune-checkpoint blockade in resectable solid tumors.

Final overall survival (OS) and the association of pathological outcomes with event-free survival (EFS) in MATTERHORN: A randomised, phase III study of durvalumab (D) plus 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) in resectable gastric / gastroesophageal junction (G / GEJ) adenocarcinoma. Tabernero J, Al-Batran, Wainberg ZA, et al. LBA81- Presented at ESMO Congress 2025, Berlin.

FDA Approves KOMZIFTI® for Relapsed or Refractory Acute Myeloid Leukemia with a NPM1 mutation

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SUMMARY: The FDA on November 13, 2025, approved Ziftomenib (KOMZIFTI&reg;), a menin inhibitor, for adults with relapsed or refractory Acute Myeloid Leukemia (AML) with a susceptible Nucleophosmin 1 (NPM1) mutation who have no satisfactory alternative treatment options.

The American Cancer Society estimates that in 2025, 22,010 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 11,090 patients will die of the disease. AML is one of the most common types of leukemia in adults and can be considered as a group of molecularly heterogeneous diseases with different clinical behavior and outcomes. With the understanding of molecular pathology of AML, personalized and targeted therapies are becoming an important part of the AML treatment armamentarium.

NPM1 mutations present in up to 30% of newly diagnosed adult AML define a unique disease subset recognized by both the WHO and the International Consensus Classification. Although NPM1-mutated AML often responds well to initial intensive therapy, outcomes deteriorate sharply after relapse or refractory disease. Patients in this setting frequently face limited therapeutic options and dismal response rates with conventional salvage strategies.

Mounting evidence shows that NPM1-mutated and KMT2A-rearranged (KMT2A-r) leukemias rely on an aberrant transcriptional program maintained through the interaction between menin and KMT2A. This dependency includes pathologic overexpression of HOX and MEIS1, which reinforce leukemic self-renewal and block differentiation. Inhibiting the menin–KMT2A complex has therefore emerged as a compelling therapeutic strategy capable of reversing leukemic transcriptional programs.

Ziftomenib, a potent and selective oral menin inhibitor, disrupts this interaction and restores myeloid differentiation in preclinical models. The registrational Phase II portion of the KOMET-001 study provides the most definitive evidence to date of its clinical potential in relapsed/refractory NPM1-mutated AML, and was used for the primary efficacy analysis and formed the basis for the FDA approval.

Mechanistic Rationale for Menin Inhibition

Menin serves as a scaffold protein essential for recruitment of the KMT2A/MLL methyltransferase complex to chromatin. This interaction drives leukemogenic transcriptional circuits in both KMT2A-r and NPM1-mutated AML, promoting expression of HOXA9, MEIS1, PBX3, and downstream effectors such as FLT3 and BCL2.

Key mechanistic insights include:

  • Menin–KMT2A blockade releases mutant NPM1 from chromatin, reducing HOX/MEIS1 signaling and triggering differentiation.
  • Ziftomenib promotes terminal maturation of AML blasts, rather than direct cytotoxicity, consistent with its differentiation-based mechanism.
  • NPM1 cytoplasmic mislocalization, a hallmark of the mutation, creates vulnerabilities that can be exploited through menin inhibition and related targeted approaches.

This biology underpins the therapeutic activity observed in KOMET-001 and supports the broader pursuit of menin inhibition across multiple AML subtypes.

KOMET-001 Trial Overview

KOMET-001 is a global, multicenter Phase I/II study evaluating single-agent Ziftomenib in adults with relapsed/refractory NPM1-mutated or KMT2A-rearranged AML. The Phase II portion which serves as the registrational dataset, focused on patients with relapsed/refractory NPM1-mutated disease treated at the recommended monotherapy dose of Ziftomenib 600 mg once daily.

Among the 92 patients with relapsed/refractory NPM1-mutated AML included in Phase II:

  • Median age: 69 years (range 33–84); 64% were ≥65 years
  • Median prior therapies: 2 lines (range 1–7)
  • Prior venetoclax exposure: 59%
  • Prior allogeneic transplantation: 24%
  • Common co-mutations: FLT3 (56%), IDH1/2 (33%)
  • ECOG 0–1: 83%

Efficacy was established based on the rate of Complete Remission (CR) plus CR with partial hematological recovery (CRh), the duration of CR plus CRh, and the rate of conversion from transfusion dependence to transfusion independence. The median follow-up was 4.2 months.

This heavily pretreated population reflects real-world patients with few remaining therapeutic options and particularly poor expected outcomes.

Efficacy Findings

Ziftomenib met its Primary endpoint with a CR/CRh rate of 22% (95% CI 14–32; P=0.0058), exceeding the historical 12% benchmark for this setting.

Key efficacy results:

  • CR/CRh rate: 22% (14% CR; 8% CRh)
  • Composite CR rate: 26%
  • Overall Response Rate (ORR): 33%
  • Median time to first response: 1.9 months
  • Median duration of response: 4.6 months
  • MRD negativity: 61% of evaluable CR/CRh responders
  • Median Overall Survival (OS): 6.6 months
  • Median OS among responders: 18.4 months

Two responders were successfully bridged to allogeneic stem cell transplantation and resumed Ziftomenib maintenance afterwards.

Efficacy was maintained across clinically relevant subgroups:

  • Age <65 vs ≥65: 21% vs 22% CR/CRh
  • Prior venetoclax exposure: 22% CR/CRh
  • Prior HSCT: 23% CR/CRh
  • FLT3 co-mutations: 13% (ITD), 33% (TKD)
  • IDH1/2 co-mutations: 50% and 31%, respectively

The activity in Venetoclax-exposed patients is particularly noteworthy given real-world salvage CR rates as low as 4% in this population.

Transfusion Independence

  • RBC independence conversion: 23%
  • Platelet independence conversion: 15%
  • Overall transfusion independence conversion: 20%

These improvements reflect meaningful clinical benefit and enhanced quality of life.

Safety and Tolerability

Ziftomenib demonstrated a favorable safety profile with low rates of treatment-related discontinuation (3%). Most adverse events were consistent with underlying AML or expected from differentiation-based therapies. Common Grade ≥3 TEAEs included febrile neutropenia (26%), anemia (20%) and thrombocytopenia (20%). Differentiation Syndrome occurred in 25% (15% grade 3; none grade 4–5) managed effectively using protocol-defined measures including cytoreduction and steroid prophylaxis, reinforcing the necessity of early recognition and continued therapy through differentiation-associated changes. Overall, ziftomenib showed no clear intrinsic myelosuppression, minimal cardiac toxicity, and a manageable safety profile appropriate for a predominantly older patient population.

Clinical Implications

The KOMET-001 data establish Ziftomenib as a meaningful therapeutic advance for patients with relapsed/refractory NPM1-mutated AML, an area historically characterized by low response rates and short survival. The durability of responses, high rate of MRD clearance, and consistent efficacy across age groups, co-mutational backgrounds, and prior therapies position Ziftomenib as a valuable monotherapy option and a potential bridge to curative transplantation. These results also strengthen the biological rationale for integrating menin inhibitors earlier in the treatment course. Ongoing frontline trials including the global Phase III KOMET-017 study will clarify the role of Ziftomenib-based combinations in newly diagnosed fit and unfit patients with NPM1-mutated or KMT2A-rearranged AML.

Conclusion

Ziftomenib, a first-in-class oral menin inhibitor, demonstrated clinically meaningful activity and durable responses in heavily pretreated relapsed/refractory NPM1-mutated AML, meeting its registrational Phase II endpoint. With a manageable safety profile including low myelosuppression, minimal QTc effects, and predictable differentiation syndrome, Ziftomenib represents an important new targeted therapy for a genetically defined AML subset.

The KOMET-001 results mark a significant step forward in addressing an area of profound unmet need, and they lay the foundation for expanding menin inhibition into earlier lines of therapy with the goal of transforming long-term outcomes for patients with NPM1-mutated AML.

Ziftomenib in Relapsed or Refractory NPM1-Mutated AML. Wang ES, Montesinos P, Foran J, et al. J Clin Oncol. 2025;43:3381-3390

Updated ASCO–ASTRO–SSO Guideline Clarifies Indications and Best Practices for Postmastectomy Radiation Therapy in Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 316,950 new cases of female breast cancer will be diagnosed in 2025, and about 42,170 women will die of the disease, largely due to metastatic recurrence.

Background

Postmastectomy radiation therapy (PMRT) remains a cornerstone of curative-intent treatment for many patients with invasive breast cancer, significantly reducing the risk of locoregional recurrence (LRR) and improving Disease-Specific Survival. However, with evolving systemic therapies, less extensive axillary surgery, and modern radiation techniques, the benefit of PMRT now varies widely across patient subgroups. Recognizing the need to update clinical decision-making in this context, the American Society for Radiation Oncology (ASTRO), American Society of Clinical Oncology (ASCO), and Society of Surgical Oncology (SSO) have released a comprehensive new guideline to replace the 2016 version.

The new recommendations jointly published in Journal of Clinical Oncology, Practical Radiation Oncology, and Annals of Surgical Oncology provide refined guidance on when and how PMRT should be applied in both upfront surgical and post-neoadjuvant settings.

Development and Scope

A multidisciplinary task force representing Radiation, Medical, and Surgical Oncology collaborated with experts from the European Society for Radiotherapy and Oncology. The group conducted a systematic review of evidence published between 2005 and 2024 and used structured consensus methods to determine recommendation strength and evidence quality.
The guideline addresses four primary clinical domains:

  1. Indications for PMRT after upfront mastectomy.
  2. Indications for PMRT following Neoadjuvant Systemic Therapy (NAST).
  3. Appropriate treatment volumes and dose-fractionation schedules.
  4. Optimal delivery techniques and normal tissue sparing strategies.

The recommendations are intended for adult patients with breast cancer undergoing mastectomy and are directed toward Radiation, Surgical, and Medical Oncologists, as well as other oncology professionals involved in multidisciplinary breast cancer management.

Key Recommendations

  1. PMRT After Upfront Mastectomy
  • Node-positive disease: PMRT is strongly recommended for most patients with pathologically positive axillary lymph nodes to reduce recurrence and breast cancer–specific mortality.
  • pT4 tumors: Strong recommendation for PMRT regardless of nodal status.
  • pT3N0 tumors: PMRT is conditionally recommended; omission or volume reduction may be appropriate when clinicopathologic features are favorable.
  • pT1–2N0 tumors: PMRT is generally not recommended but may be considered in the presence of multiple high-risk factors (e.g., triple-negative biology, LVI, young age, high grade, or central/medial tumor location).
  • Positive margins: In patients with positive surgical margins but no other PMRT indication, treatment limited to the chest wall or reconstructed breast alone is conditionally advised.
  1. PMRT After Neoadjuvant Systemic Therapy
  • Locally advanced disease (cT4 or cN2–3): PMRT is strongly recommended irrespective of pathologic response.
  • Residual nodal disease (ypN+): Strong recommendation for PMRT to the chest wall and regional nodes.
  • Pathologic complete response (ypN0) after cT1–3N1 or cT3N0 disease: PMRT is conditionally recommended for patients with high-risk features (young age, lymphovascular invasion, high residual cancer in breast); omission may be appropriate for select patients with favorable features.
  • cT1–2N0 disease with ypN0 response: PMRT is generally not indicated unless multiple high-risk factors are present such as young age, lymphovascular invasion, and high residual cancer in breast.
  • Positive post-neoadjuvant margins: PMRT is strongly recommended.
  1. Treatment Volumes and Dose-Fractionation
  • Target volumes: Irradiation should encompass the ipsilateral chest wall or reconstructed breast and regional lymphatics (axillary, supraclavicular, and internal mammary nodes). For selected pT3N0 cases, chest wall treatment alone or reconstructed breast alone may be reasonable.
  • Internal mammary coverage: Should be individualized based on tumor location, nodal burden, and risk features.
  • Fractionation: Moderate hypofractionation is preferred for most patients, including those with reconstruction, while conventional fractionation remains acceptable in select circumstances.
  • Boost therapy: A boost to the chest wall or scar may be considered for patients with T4 disease or close/positive margins. A nodal boost is recommended when residual nodal disease is suspected and surgical clearance is incomplete.
  1. Recommended Techniques for PMRT Delivery
  • Planning and delivery: CT-based volumetric planning using 3-dimensional conformal radiation therapy (3D-CRT) is the standard approach.
  • Advanced modalities: Intensity-Modulated Radiation Therapy (IMRT) or Volumetric Modulated Arc Therapy (VMAT) is advised when 3D-CRT cannot meet dosimetric goals; daily image guidance is recommended.
  • Cardiopulmonary sparing: Deep inspiration breath hold (DIBH) should be used whenever it reduces dose exposure to the heart and lungs, supported by real-time monitoring and image verification.
  • Bolus use: Routine use of tissue-equivalent bolus is not recommended. However, bolus may be selectively applied in cases with skin involvement, positive superficial margins, dermal lymphatic invasion, or extensive lymphovascular invasion.

Implementation Considerations

The guideline emphasizes individualized, multidisciplinary decision-making that weighs recurrence risk against treatment-related toxicities.

  • For patients with limited nodal disease (e.g., T1–2N1), omission of PMRT may be reasonable if the expected absolute benefit is low.
  • Patient preferences and quality-of-life considerations should inform discussions, especially regarding reconstructive implications and late toxicity risks.
  • The recommendations endorse shared decision-making across disciplines, highlighting the importance of coordinated care between surgeons, radiation oncologists, and medical oncologists.

Clinical Perspective

The expert panel acknowledged that radiation therapy after mastectomy can meaningfully reduce recurrence and improve survival, but the benefit must be balanced with the individual’s disease profile and values. The update also acknowledges persistent evidence gaps, particularly regarding patients who achieve nodal pathologic complete response after neoadjuvant therapy, underscoring the need for ongoing prospective research.

Postmastectomy Radiation Therapy: An ASTRO-ASCO-SSO Clinical Practice Guideline. Jimenez RB, Abdou Y, Anderson P, et al. J Clin Oncol, 2025;43:3292-3311

Amivantamab–Lazertinib Combination Improves Overall Survival in EGFR-Mutated Advanced NSCLC

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2025, about 226,650 new cases of lung cancer will be diagnosed and 124,730 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers and Adenocarcinoma is now the most frequent histologic subtype of lung cancer. Approximately 10-15% of Caucasian patients and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR mutations, and 90% of these mutations are either exon 19 deletions or L858R substitution mutation in exon 21.

Epidermal Growth Factor Receptor (EGFR) plays an important role in regulating cell proliferation, survival and differentiation, and is overexpressed in a variety of epithelial malignancies. EGFR targeted Tyrosine Kinase Inhibitors (TKIs) such as Gefitinib, Erlotinib, Afatinib, Dacomitinib and Osimertinib (TAGRISSO®) target the EGFR signaling cascade. However, patients eventually develop drug resistance due to new EGFR mutations. Another important cause of drug resistance to TKIs is due to the activation of parallel RTK (Receptor Tyrosine Kinase) pathways such as Hepatocyte Growth Factor/Mesenchymal-Epithelial Transition factor (HGF/MET) pathway, thereby bypassing EGFR TKI inhibitors. These patients are often treated with platinum-based chemotherapy as the next line of therapy, resulting in a median Progression Free Survival of about 5 months.

Amivantamab (RYBREVANT®) is a fully human bispecific antibody directed against EGFR and MET receptors. Amivantamab binds extracellularly and simultaneously blocks ligand-induced phosphorylation of EGFR and c-MET, inhibiting tumor growth and promoting tumor cell death. Further, Amivantamab down regulates receptor expression on tumor cells thus preventing drug resistance mediated by new emerging mutations of EGFR or c-MET. By binding to the extracellular domain of the receptor protein, Amivantamab can bypass primary and secondary TKI resistance at the active site. Amivantamab also engages effector cells such as Natural Killer cells, monocytes, and macrophages via its optimized Fc domain. Amivantamab demonstrated activity against a wide range of activating and resistance mutations in EGFR-mutated NSCLC, and in patients with MET exon 14 skip mutations, as well as patients with EGFR exon 20 insertion mutations, whose disease progressed on or after platinum-based chemotherapy.

Lazertinib (LAZCLUZE®) is a highly selective, third-generation TKI that penetrates the CNS, with demonstrated efficacy in activating EGFR mutations and acquired T790M “gatekeeper” point mutation. Combining Amivantamab with Lazertinib has been shown to provide a synergistic benefit by targeting the extracellular and catalytic EGFR domains. The combination of Amivantamab plus Lazertinib has shown clinically meaningful and durable antitumor activity in patients with previously untreated or Osimertinib-pretreated EGFR-mutated advanced NSCLC, with clinical activity against a broad spectrum of secondary EGFR and MET molecular alterations and even in tumors of patients without an identified resistance mechanism.

The MARIPOSA trial is an international, randomized Phase 3 study, conducted to assess the efficacy and safety of a combination of Amivantamab and Lazertinib as compared with Osimertinib alone, as first-line treatment in patients with EGFR-mutated advanced NSCLC. In this study, a third arm evaluated Lazertinib monotherapy, to dissect the individual contributions of each component in the combination. This study included 1074 patients (N=1074) with untreated EGFR-mutated advanced NSCLC who were randomly assigned in a 2:2:1 ratio to receive Amivantamab plus Lazertinib (N=429), Osimertinib monotherapy (N=429), or Lazertinib monotherapy (N=216). Amivantamab was administered weekly at a dose of 1050 mg IV (or 1400 mg IV in patients with a body weight of 80 kg or more) for the first 4 weeks (cycle 1), with the first infusion split over a period of 2 days (with 350 mg given on cycle 1, day 1, and the remainder given on cycle 1, day 2). Starting at cycle 2, the same Amivantamab dose was administered every 2 weeks. Osimertinib 80 mg and Lazertinib 240 mg were taken orally daily respectively. The median age was 63 years, majority of patients were Asian women or White and had never smoked. Approximately 60% had EGFR exon 19 deletions and 40% had exon 21 L858R mutations. Randomization was stratified according to EGFR mutation type (ex19del or L858R), Asian race (yes or no), and history of brain metastases (yes or no). Crossover was not included in this trial design. The Primary end point was Progression-Free Survival (PFS) in the Amivantamab plus Lazertinib group as compared with the Osimertinib group, as assessed by Blinded Independent Central Review. Secondary end points included Overall Survival (OS), Objective Response (defined as a Complete or Partial Response), Duration of Response, and Safety.

The authors previously reported that the median PFS (Primary endpoint), was significantly longer in the Amivantamab plus Lazertinib group at 23.7 months compared to 16.6 months in the Osimertinib group ((HR for progression or death = 0.70; P<0.001).

The researchers in this publication reported the results of the protocol-specified final Overall Survival analysis.

The combination of Amivantamab plus Lazertinib demonstrated a significant Overall Survival (OS) advantage over Osimertinib in patients with previously untreated, EGFR-mutated advanced NSCLC. After a median follow-up of 37.8 months, treatment with Amivantamab–Lazertinib reduced the risk of death by 25% compared with Osimertinib (HR=0.75; 95% CI, 0.61–0.92; P=0.005). Estimated 3-year OS rates were 60% with the combination versus 51% with Osimertinib, while 24-month OS was 75% and 70%, respectively. These findings were supported by multiple parametric modeling approaches, indicating a projected survival benefit exceeding one year.

A greater proportion of patients in the Amivantamab–Lazertinib arm remained on treatment at data cutoff (38% vs 28%). The combination also prolonged time to symptomatic progression, time to treatment discontinuation, and time to next therapy relative to Osimertinib. Notably, most patients in both groups who discontinued study therapy received subsequent anticancer treatment, primarily chemotherapy-based regimens.

The superior outcomes observed with Amivantamab–Lazertinib are thought to stem from its dual targeting of EGFR and MET pathways, enabling proactive suppression of key resistance mechanisms. This regimen was also associated with a lower frequency of complex acquired resistance (28% vs 43%) and potentially beneficial immune-mediated activity.

Among participants with baseline brain metastases (approximately 40% in each group), intracranial outcomes favored Amivantamab–Lazertinib and were consistent with those from the MARIPOSA-2 trial, supporting its efficacy in CNS disease.

As expected, Grade ≥3 adverse events were more frequent with Amivantamab–Lazertinib (80% vs 52%), most commonly dermatologic reactions, venous thromboembolism, and infusion-related events. However, no new safety signals emerged. Emerging evidence from other studies, such as COCOON, suggests that prophylactic strategies (enhanced dermatologic care, anticoagulation, and optimized infusion protocols) can substantially reduce these toxicities. Furthermore, a newly approved subcutaneous formulation of Amivantamab markedly lowers infusion-related reactions (13% vs 66%) and reduces administration time from hours to minutes while maintaining efficacy.

Overall, the MARIPOSA trial establishes Amivantamab–Lazertinib as a superior first-line, chemotherapy-free option for patients with EGFR-mutated advanced NSCLC, offering meaningful improvements in both Progression-Free and Overall Survival compared with Osimertinib.

Overall Survival with Amivantamab–Lazertinib in EGFR-Mutated Advanced NSCLC. Yang JC, Lu S, Hayashi H, et al. for the MARIPOSA Investigators. N Engl J Med 2025;393:1681-1693.

 

Educational Message: Precision Medicine in mCRC: Navigating Complexity in the Era of Targeted Therapy

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Written by: David Cosgrove, MD
Sponsored by: Takeda

Treatment algorithms for patients with metastatic colorectal cancer (mCRC) have become increasingly complex in recent years, as new drug approvals have created additional therapeutic avenues for specific subsets of patients.1 Traditionally, mCRC patients who are fit enough for active therapy would undergo combination cytotoxic chemotherapy utilizing a fluoropyrimidine backbone, until disease progression or unacceptable toxicity. There were a limited number of effective agents available, and specific combinations were selected primarily based on patient comorbidity and toxicity risk, rather than on any tumor-specific factors. Predictably, within this model, response rates were modest and long-term outcomes remained grim.

Today, the majority of mCRC patients will still receive initial treatment with cytotoxic chemotherapy, but diagnostic testing is often incorporated to uncover actionable tumor-specific genomic and/or immune signatures, and these insights may be leveraged to guide the use of specific targeted therapies with improved patient outcomes.2,3,4 Information on tumor mismatch repair status (or microsatellite instability), specific mutations within KRAS/NRAS/BRAF, POLE/POLD-1, overexpression of HER2, and fusions within the NTRK gene all now contribute to treatment decisions at the time of diagnosis and at the time of disease progression where a treatment plan change is indicated. In addition to the recent approval of drugs to target these molecular signatures, an accompanying shift in drug formulation has impacted the mCRC treatment landscape.

Traditional mCRC anticancer agents were formulated for intravenous administration and delivered in an oncology office or hospital infusion suite. Dosing choices, supportive care medications, and treatment adjustments were typically decided by the treating oncologist, in conjunction with infusion nurses and the supporting clinical team; pharmacists played a role in dose confirmation, drug-drug interaction checks and admixture, but direct input beyond that was limited. Today, a majority of the new FDA-approved mCRC therapies are formulated for oral administration. Oral formulations free patients from being tethered to an infusion suite and alter the frequency and personnel involved in treatment touchpoints. The shift to oral formulations has expanded the role of pharmacy teams in patient education, dosing input, dispensing and toxicity assessment, while maintaining their role in drug safety.

Most oncology clinics have had to adapt their staffing and patient flow model to account for this new dynamic. Patient education is a key component to chemotherapy delivery – with traditional intravenous agents, infusion room nurses and oncology nurse educators typically took on this role, performing toxicity assessments and managing side effects chair-side. Traditionally, cytotoxic agents within the same drug class and mechanism of action often exhibited similar toxicity profiles, further simplifying toxicity risk assessments and corresponding patient education. With today’s newer, oral formulations, mechanisms of action and toxicity profiles are more varied – some retain cytotoxic effects, such as capecitabine or tipiracil/trifluridine, whereas others carry very specific toxicity profiles.

As patients may no longer receive treatment in an infusion suite, a significant portion of the responsibility for providing patient-level therapeutic education has been transferred to the pharmacist and pharmacy team. This educational role may be replicated through a series of subsequent treatments, as newer agents are typically delivered sequentially to these patients in later lines of therapy, depending on patient functional status, and suitability for ongoing treatment. Equally as important as pre-treatment education, on-therapy toxicity assessments and potential dose adjustments are now typically shared responsibilities between the treating physician and pharmacy team, and often incorporate patient reported outcomes (PROs) or electronic patient reported outcomes (ePROs)5, as the patient is taking these medications at home, and not under the direct supervision of an infusion nurse team as with the intravenous therapies.

Today’s mCRC treatment model requires close collaboration between the treating oncologist, who has typically developed a long-term therapeutic relationship with the patient and has knowledge of patient-specific factors that will influence treatment tolerance and potential side effects, and the pharmacy team. Lack of a robust communication system and/or improper delegation of tasks pose significant risks to the vulnerable mCRC patient population. To this end, many centers have developed Medically Integrated Pharmacies (MIP) for specialized oncology drugs, which provide direct oversight of quality and safety metrics, enhance adherence, reduce the risk of access delays and deliver appropriate patient-centered care. In our practice, we have seen countless examples of the MIP team lowering barriers to access, expediting delivery and intervening with dose adjustments or concomitant medication changes to ensure our mCRC patients glean as much benefit from their therapies as possible, while maintaining their desired quality of life in the face of a devastating illness.

As crucial as these aspects of care are for the treatment team, financial risk is a major concern for the mCRC patients themselves. Most of the newer therapies approved in the mCRC space in recent years are high-cost agents, and unlike intravenous agents, which were delivered in a medical facility and therefore covered under the medical benefit portion of a patient’s health insurance plan, oral formulation drugs fall under the pharmacy benefit. While we have seen fewer outright denials of coverage for clinically appropriate drugs, challenges remain such as prior authorization, onerous paperwork and especially patient co-payment requirements.

Unfortunately, a number of my patients have also faced barriers from their insurance-mandated, Limited Distribution Network (LDN), which incorporates an external Pharmacy Benefit Manager (PBM) and requires dispensing through a mail-order specialty pharmacy.6 The inability to communicate closely with LDNs and PBM-mandated third-party decision makers has proven challenging – without an on-site team to understand the specifics of a patient’s case, treating providers have limited ability to control dosing adjustments, maintain drug supply and limit care delays. Care delays pose very serious risks, especially in the later stages of mCRC during which dosing flexibility is critical and the majority of patients require dose holds or adjustments on a regular basis. While this issue remains to be solved, having an active MIP in a treatment center with dedicated staff to facilitate co-pay assistance and access to manufacturer- or foundation-level support has proven instrumental in many practices. This resource helps alleviate financial burden and ensures the patient is not forced to make therapy choices based on ability to pay when facing this illness.

In summary, therapeutic management of mCRC has become increasingly complex in recent years. The introduction of new therapeutic agents offers renewed hope for patients dealing with this devastating disease, while simultaneously requiring oncology practices to adjust treatment team infrastructure, and has shifted the onus of delivering patient education to the pharmacy team, who must work in close collaboration with the treating physician. Today’s shift to oral drug formulations introduces financial risks for patients, as at-home medications fall under a prescription drug benefit which may introduce additional barriers such as may PBM-mandated LDNs or specialty pharmacy requirements. The creation of MIPs has significantly enhanced provider communication, reduced barriers to access, expedited therapy delivery, and supported timely dose adjustments or medication changes to help mCRC patients gain the most benefit from treatment. MIPs have also been essential in building a broader administrative team focused on ensuring patients receive maximum benefit from breakthrough anticancer agents, while minimizing both physical and financial toxicity.

References:

  1. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf
  2. Yaeger R, Weiss J, Pelster M, et al. Adagrasib with or without Cetuximab in colorectal cancer with mutated KRAS G12C. N Engl J Med 2023;388:44-54
  3. Kopetz S, Yoshino T, Cutsem EV, et al. Encorafenib, cetuximab and chemotherapy in BRAF-mutant colorectal cancer: a randomized phase 3 trial. Nat Med 2025
  4. Overman MJ, Lonardi S, Wong K, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol 2018;36:773-779
  5. Basch E, Deal A, et al. Overall survival results of a trial assessing patient-reported outcomes for symptom monitoring during routine cancer treatment. JAMA 2017 July 11;318(2):197-198
  6. https://www.ncoda.org/oold/

Endocrine Therapy Omission in ER-Low Early Stage Breast Cancer Linked to Worse Survival Outcomes

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 316,950 new cases of female breast cancer will be diagnosed in 2025, and about 42,170 women will die of the disease, largely due to metastatic recurrence.

Background
Approximately 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors. Adjuvant Endocrine Therapy (ET) is a cornerstone in managing Estrogen Receptor (ER)–positive early-stage breast cancer, contributing significantly to reduced recurrence and improved Overall Survival (OS). However, its role in patients with ER-low disease, defined as tumors with 1%-10% ER positivity by ImmunoHistoChemistry (IHC), remains unclear and controversial.

Study Objective
The present study was conducted to determine the association between ET omission and OS in high-risk, ER-low early-stage breast cancer patients who received chemotherapy, leveraging Real-World Data from the National Cancer Database (NCDB).

Methods
A retrospective cohort analysis was conducted using the 2021 NCDB Participant User File, focusing on female patients diagnosed with Stage I–III ER-positive breast cancer between 2018 and 2020. ER-low status was defined as 1%-10% ER expression per ASCO/CAP guidelines. Progesterone Receptor (PR)–positive disease was defined as 1% or more receptor expression. This study included patients who received neoadjuvant or adjuvant chemotherapy, reflecting a high-risk population with aggressive tumor features. The study excluded male patients, Stage IV disease, noninvasive cancers, and cases with incomplete treatment or outcome data. The final cohort comprised 7,018 ER-low patients who received chemotherapy.

Key Findings

  • Endocrine Therapy (ET) Usage Patterns:
    Among patients with ER-low breast cancer receiving chemotherapy, 42% did not initiate ET within 12 months post-surgery. ET omission was more prevalent in tumors that were:

    • Progesterone Receptor (PR)–negative
    • HER2–negative
    • High grade (2 or 3)
    • High proliferative index (Ki67 ≥20%)
    • Treated with NeoAdjuvant Chemotherapy (NAC)
  • Survival Impact:
    Over a median follow-up of 3 years, 586 deaths occurred. ET omission was associated with significantly poorer OS:

    • Overall HR: 1.23 (95% CI, 1.04–1.46; P =0.02)
    • ER 1%-5% subgroup: HR 1.15 (95% CI, 0.91–1.45; P =0.24)
    • ER 6%-10% subgroup: HR 1.42 (95% CI, 1.00–2.02; P =0.048)
  • Effect in Residual Disease (RD) After NAC:
    • For patients with RD, ET omission led to worse OS (HR, 1.26; 95% CI, 1.00–1.57; P =0.046)
    • No OS difference was observed in patients who achieved pathologic Complete Response (pCR) (HR, 1.06; P =0.84)
  • 3-Year OS Estimates:
    • With ET: 92.3% (95% CI, 91.3–93.3%)
    • Without ET: 89.1% (95% CI, 87.8–90.5%)

Clinical Implications
These findings suggest that omission of ET in ER-low breast cancer is associated with an increased risk of mortality, particularly in patients with:

  • Residual disease after neoadjuvant chemotherapy
  • Tumors with higher ER expression (6%-10%)

This supports the clinical value of ET even in ER-low disease subsets, which have historically been managed more like Triple-Negative Breast Cancer (TNBC) due to their aggressive features and ambiguous endocrine responsiveness.

Guideline and Research Context
The 2010 ASCO/CAP guidelines established 1% or more ER positivity as the threshold for ET eligibility. Yet, international variation remains. Swedish guidelines, for instance, never adopted the lower threshold, and recent European discourse suggests reverting to 10% or more. Compounding the uncertainty, clinical trials often exclude ER-low tumors or treat them as TNBC. Retrospective studies from Sweden and China have shown mixed results regarding ET’s benefit in ER-low disease, further emphasizing the need for prospective data.

Discussion
Despite the relatively small proportion of ER-low tumors (3% of ER-positive breast cancer), the findings could impact the care of tens of thousands of patients globally. The biologic heterogeneity of ER-low tumors, often resembling basal-like subtypes, complicates treatment decisions. Still, evidence from this large cohort supports offering ET, particularly in patients with residual disease post-neoadjuvant chemotherapy, or tumors on the higher end of the ER-low spectrum. Additionally, the data align with emerging strategies to escalate therapy in ER-low BC, including use of CDK4/6 inhibitors (e.g., Abemaciclib, Ribociclib), which have demonstrated benefit even in this subgroup.

Limitations

  • Lack of data on ET adherence, recurrence, or cause of death
  • Short follow-up (3 years)
  • Potential confounding due to observational design
  • Lack of molecular characterization to distinguish responders

Nevertheless, sensitivity analyses confirmed the robustness of findings.

Conclusion
Omission of endocrine therapy in ER-low, early-stage breast cancer, especially following chemotherapy, is linked to inferior Overall Survival. The strongest signal of benefit is in patients with residual disease post- neoadjuvant chemotherapy and those with ER expression closer to 10%. Until randomized trials clarify endocrine sensitivity in this population, clinicians should counsel patients on the potential survival benefit of ET, even in cases with limited ER expression.

Key Takeaway for Oncologists:
In the absence of prospective trial data, Real-World Evidence supports continued use of endocrine therapy in patients with ER-low early-stage breast cancer, particularly those with residual disease after neoadjuvant chemotherapy or higher ER expression within the 1%-10% range.

Endocrine Therapy Omission in Estrogen Receptor–Low (1%-10%) Early-Stage Breast Cancer. Choong GM, Hoskin TL, Boughey JC, et al. J Clin Oncol 2025;43:1875-1885.

Precision Medicine in Practice: Timely Use of Tumor NGS Remains Suboptimal in Common Cancers

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SUMMARY: Next-generation sequencing (NGS) has revolutionized the management of advanced cancers by enabling identification of tumor-specific genomic alterations for which targeted therapies are now available. National guidelines recommend early and routine NGS testing for patients with advanced or metastatic solid tumors to inform treatment decisions. In the United States, the five most prevalent advanced or metastatic solid tumors include advanced Non-Small Cell Lung Cancer (aNSCLC), metastatic Breast Cancer (mBC), metastatic Prostate Cancer (mPC), advanced Colorectal Cancer (aCRC), and metastatic Pancreatic Cancer (mPanC). For these malignancies, the integration of NGS has become increasingly critical in guiding targeted therapy selection and improving survival outcomes. Despite the approval of multiple targeted therapies for these malignancies, real-world utilization of NGS remains inconsistent.

In this study presented at the 2025 ASCO Annual Meeting, Chehade and colleagues,  evaluated patterns in NGS testing and its timing, relative to patient mortality.

Study Overview: This retrospective analysis leveraged the Flatiron Health EHR-derived de-identified database across 280 cancer clinics, spanning data from 2011 onward. The study included patients with a diagnosis of aNSCLC, mBC, mPC, aCRC, or mPanC, all of whom had records of NGS testing and a documented date of death. The researchers identified 86,536 patients with advanced non-small cell lung cancer, 36,000 with metastatic breast cancer, 35,702 with advanced colorectal cancer, 24,105 with metastatic prostate cancer and 14,964 with metastatic pancreatic cancer. About a third of patients from each cancer group received NGS testing (NSCLC, 36.3%; breast cancer, 32.1%; colorectal cancer, 41%; prostate cancer, 30.9%; and pancreatic cancer, 35.4%).

Patients were categorized based on the interval between receipt of NGS results and death:

  • More than 3 months before death
  • Within 3 months of death
  • After death

Key Findings Across cancer types, only 30% to 40% of patients received NGS testing. Among those who were tested and had a recorded date of death, the timing of NGS was as follows:

Timing of First NGS aNSCLC (N=19,958) mBC (N=5,689) mPC (N=3,397) aCRC (N=8,553) mPanC (N=3,957)
>3 mo before death          72.3%        81.6%        85.4%        85.0%         71.1%
Within 3 mo of death          25.6%        16.9%        13.5%        13.7%         26.5%
After death          2.1%        1.5%        1.1%        1.3%         2.4%

Notably, up to one in four patients with NSCLC or pancreatic cancer received their first NGS results within 3 months of death, a timeframe often too late for actionable therapeutic intervention.

Interpretation and Implications Despite advances in molecularly targeted therapies and growing guideline support for comprehensive genomic profiling, real-world testing patterns remain suboptimal:

  • Low uptake: Only about a third of eligible patients undergo NGS testing.
  • Late testing: A substantial proportion of tested patients receive results within 3 months of death.
  • Missed opportunities: Many patients are never tested—or are tested too late to benefit from life-extending therapies.

These findings highlight ongoing gaps in precision oncology implementation, especially in community-based settings.

Next Steps & Recommendations To improve the utility of NGS in oncology, efforts should focus on:

  • Earlier testing: At diagnosis or at first progression of advanced disease.
  • Workflow integration: Embedding NGS into routine clinical pathways.
  • Education: Raising awareness among clinicians and patients about the benefits of timely testing.
  • Health system support: Addressing barriers such as reimbursement, turnaround times, and tissue availability.

Conclusion: Real-World Data from this large retrospective analysis reveal late-stage testing and underutilization of life-prolonging genomic profiling. This study underscores an urgent need to optimize the timing and uptake of NGS testing in patients with advanced solid tumors. Earlier and broader testing is essential to ensure patients have access to the most effective, personalized treatment strategies, and to avoid the missed potential of life-extending therapies.

Utilization and timing of first tumor next-generation sequencing testing (NGS) in patients (pts) with five most common cancers in the USA. Chehade CH, Jo Y, Ozay ZI, et al. Doi: 10.1200/JCO.2025.43.16_suppl.11014. Abstract # 11014. Presented at: ASCO Annual Meeting; May 30-June 3, 2025; Chicago.