Author: Rodrigo Arrangoiz MS, MD, FACS, FSSO

• The staging of primary tumors of the oral cavity:
  • As published by the AJCC and UICC is widely accepted
• In its most recent revision (eighth edition of the AJCC Staging Manual):
  • Depth of invasion (DOI):
    • Is added to the surface dimensions and local extent of the tumor:
      • As the required parameters for primary tumor staging in the oral cavity

• Accurate assessment of DOI by clinical examination is not possible:
  • However, the staging system stratifies DOI by 5 mm increments, and thus clinical estimates of DOI can be categorized into:
    • Thin (less than 5 mm)
    • Thick (5 to 10 mm)
    • Very thick (greater than 10 mm)
      • By palpation to assign clinical T stage

• The stage distribution of patients with squamous cell carcinoma of the oral cavity at the Memorial Sloan Kettering Cancer Center in New York is shown in the graph:

• The most important histologic feature of the primary tumor:
  • That affects selection of treatment and eventual prognosis:
    • Is its depth of invasion (DOI)
• Thin and superficially invasive lesions:
  • Have a lower risk of regional lymph node metastasis
  • Are highly curable
  • Offer an excellent prognosis
• Thicker lesions that deeply infiltrate the underlying soft tissues:
  • Have a significantly increased incidence of regional lymph node metastasis and an adverse impact on prognosis
• The risk of lymph node metastasis and survival rates in relation to the DOI of the primary lesion for T1 and T2 squamous carcinomas of the oral tongue and floor of mouth are shown in Figure:
  • Although it would be ideal to know the exact DOI of the lesion before surgical intervention, having that information before surgical excision and histopathologic examination of the primary tumor is not possible
• In general, however, estimate of DOI by assessing thickness of the lesion as appreciated by palpation:
  • Is a reasonably good indicator of deeply invasive lesions versus superficial lesions:
    • To estimate the extent of soft tissue and / or bone resection for the primary lesion and to decide on the need for elective dissection of the regional lymph nodes at risk in a clinically negative neck

• Several retrospective studies have identified DOI of the primary tumor:
  • As an important determinant of prognosis:
    • Thus DOI is now included in T staging of primary tumors of the oral cavity

• The clinical features of primary tumors arising from the mucosal surface of the oral cavity are:
  • Variable
• The tumor may be:
  • Ulcerative
  • Exophytic
  • Endophytic
• The gross characteristics of the lesion:
  • Are usually sufficient to raise the index of suspicion regarding the need for a biopsy to establish tissue diagnosis
• Ulcerative lesions:
  • Usually are accompanied by an irregular edge and induration of the underlying soft tissues

• Exophytic lesions may present either as a:
  • Cauliflower-like irregular growth or as flat, pink to pinkish white proliferative lesions
  • Occasionally, a red to pink velvety flat lesion is the only manifestation of superficially invasive or in situ carcinoma

• Squamous cell carcinomas (SCC) with excessive keratin production and verrucous carcinomas:
  • Present as white heaped-up keratotic lesions with varying degrees of keratin debris on the surface

• Papillary projections:
  • Often are seen in lesions that are accompanied or preceded by a squamous papilloma

• Endophytic lesions:
  • Have a very small surface component:
    • But a substantial amount of soft-tissue involvement beneath the surface

• What DOI is (and why it matters):
  • Depth of invasion (DOI) is the vertical depth of tumor invasion:
    • Measured from the basement membrane of the adjacent normal mucosa to the deepest point of invasion:
      • It is not the same as “tumor thickness”
  • DOI is now a core determinant of T category in AJCC 8th and 9th oral cavity SCC:
    • AJCC 8 DOI cut points (oral cavity):
      • T1:
        • ≤ 2 cm and DOI ≤ 5 mm
      • T2:
        • ≤ 2 cm with DOI > 5 to 10 mm OR > 2 to 4 cm with DOI ≤ 10 mm
      • T3:
        • DOI >10 mm (or tumor > 4 cm) 
  • Clinical implication:
    • A small “T1 by size” lesion can become T2 / T3 purely based on DOI:
      • Changing risk counseling and neck strategy
• Risk of occult nodal metastasis vs DOI (tongue and floor of mouth):
  • Big picture (consistent across studies):
    • DOI is one of the strongest predictors of occult cervical lymph node metastasis (CLNM) in cN0 oral cavity SCC
    • A commonly used operative decision threshold is:
      • DOI ~ 3 to 4 mm:
        • But subsite matters, and FOM often carries higher nodal risk at the same DOI

• Evidence supporting ≥ 4 mm as an elective neck dissection (END) trigger (early OCSCC):
  • Multiple analyses suggest DOI ≥ 4 mm is an effective cutoff where END improves regional control / survival compared with observation in early-stage OCSCC
  • Recent work continues to evaluate / validate a 4 mm threshold, acknowledging imperfect sensitivity / specificity
  • Meta-analytic evidence shows higher lymph node metastasis (LNM) risk when DOI > 4 mm (RR ~2.18 in one large study, alongside other adverse pathologic factors)
  • Floor of mouth nuance:
    • At the same DOI:
      • FOM cancers may metastasize more frequently than tongue cancers in some datasets:
        • Implying that a single universal DOI cutoff across all subsites can be overly simplistic 
• Prognosis vs DOI (local control, survival, and upstaging):
  • DOI correlates with:
    • Higher probability of nodal metastasis:
      • Including occult disease
    • Worse disease-specific outcomes:
      • It is sufficiently prognostic that it was incorporated into AJCC 8 edition T staging 
      • DOI > 10 mm is particularly important because it upstages to pT3 (even if tumor is small in surface dimension):
        • Reflecting its association with advanced / aggressive behavior
  • Key point for counseling:
    • DOI is not just a “neck decision tool”:
      • It is a global biologic aggressiveness marker and a staging variable
• Elective neck management in cN0 tongue / FOM SCC:
  • Guideline-consistent approach:
    • NCCN guidance (summarized in literature):
      • Consider elective neck dissection (END) in early oral cavity SCC when DOI exceeds ~3 mm (often framed as “consider END”)
    • Many institutions operationalize:
      • Tongue:
        • END commonly at ≥ 4 mm
      • FOM:
        • Lower threshold and / or stronger lean toward END due to higher nodal propensity in several series 
• END vs sentinel lymph node biopsy (SLNB) vs observation:
  • Elective Neck Dissection (END):
    • Typical for cN0 early tongue / FOM:
      • Selective neck dissection levels I to III ± IV based on institutional practice, DOI, and risk factors:
        • Benefit is maximizing regional control and avoiding “salvage neck failure” biology
  • Sentinel Lymph Node Biopsy (SLNB):
    • Valid alternative to END for T1 to T2 cN0 oral cavity SCC in experienced centers:
      • Especially when trying to reduce morbidity
    • Practical pearl:
      • SLNB is most attractive when DOI is low / intermediate and imaging is negative:
        • But your workflow must support reliable mapping / pathology
  • Observation:
    • Reasonable primarily for very thin lesions (e.g., ≤ 2 mm) without other high-risk features and with reliable follow-up
    • Remember:
      • DOI cutoffs have imperfect test characteristics:
        • A “thin” tumor can still metastasize
• A pragmatic surgeon algorithm (tongue + floor of mouth, cN0):
  • Pre-op:
    • High-quality exam + imaging
    • Estimate DOI if possible:
      • US / MRI can help in some settings
    • If DOI likely > 10 mm (or bulky lesion):
      • Treat the neck (END)
    • If DOI 4 to 10 mm:
      • Strong default to END (levels I to III) or SLNB if program is robust
    • If DOI 2 to 4 mm:
      • Individualized:
        • Subsite matters – FOM pushes toward END; add PNI / LVI / grade / budding into decision
    • If DOI ≤ 2 mm:
      • Consider observation vs SLNB:
        • Depending on subsite / risk factors and follow-up reliability
          

• There is a sequence of disease progression from:
  • Atypia / dysplasia, to in situ carcinoma, to invasive cancer
• Leukoplakia and erythroplakia:
  • Are terms given to clinically identifiable lesions:
    • That may harbor invasive cancer or undergo malignant transformation
• Precursor lesions may present as:
  • Small patches or as a large verrucous plaques
  • The surface can be:
    • Brown to red (erythroplakia) or may have circumscribed whitish plaques (leukoplakia):
      • White spots may ulcerate
• Leukoplakia:
  • Develops as a result of chronic irritation of the mucous membranes by carcinogens
    • This irritation stimulates proliferation of epithelial and connective tissue
  • Histopathologic examination reveals:
    • Underlying hyperkeratosis associated with epithelial hyperplasia
  • In the absence of underlying dysplasia:
    • Leukoplakia rarely (less than 5 %) is associated with progression to malignancy (Ridge, 2013; Massano et al., 2006; Thompson, 2003)
• Erythroplakia:
  • Red spots, that are friable adjacent to normal mucosa:
    • Characterize erythroplakia
  • It is associated with underlying epithelial dysplasia and has a much greater potential for malignancy than leukoplakia:
    • Carcinoma is found in nearly 40 % of the cases of erythroplakia (Ridge, 2013)
• The classification of the world health organization (WHO) of precursor lesions is as follows (Barnes, 2005):
  • Squamous cell hyperplasia:
    • Hyperplasia describes an increase in the number of cells:
      • This can be in the spinous layer (acanthosis), and / or in the layers of basal / parabasal cells (progenitor compartment) called basal cell hyperplasia
  • Dysplasia:
    • Is characterized by cellular atypia, loss of normal cellular maturation, and loss of epithelial stratification:
      • Mild dysplasia:
        • Squamous intraepithelial neoplasia 1
      • Moderate dysplasia:
        • Squamous intraepithelial neoplasia 2
      • Severe dysplasia or carcinoma in situ:
        • Squamous intraepithelial neoplasia 3
    • The probability of developing a carcinoma depends on the degree of dysplasia:
      • In the case of severe dysplasia:
        • Up to 24% of patients may have an occult invasive squamous cell cancer (Ridge, 2013)

• Background:

  • Oral leukoplakia (OL):

    • Is a white patch or plaque that cannot be rubbed off, cannot be characterized clinically or histologically as any other condition:

      • It is not associated with any physical or chemical causative agent except tobacco:

    • • • Therefore, a process of exclusion establishes the diagnosis of the disease

• In general, the term leukoplakia implies:

  • Only the clinical feature of a persistent, adherent white plaque or patch:

    • Therefore, reserve the term for idiopathic lesions when investigations fail to reveal any cause:

  • • • The term carries absolutely no histologic connotation:

        • Although, inevitably, some form of disturbance of the surface epithelium is characteristic

• Follow-up studies suggest that cancer is more likely to occur in individuals with idiopathic leukoplakia:

  • Than in individuals who do not have this condition:

  • • Thus, idiopathic leukoplakia:

    • • Is considered a premalignant lesion

• Pathophysiology:

  • The etiology of most cases of OL is unknown (idiopathic)

  • In other cases, the initiation of the condition may depend on:

    • Extrinsic local factors and / or intrinsic predisposing factors:

    • Factors most frequently blamed for the development of idiopathic leukoplakia include:

      • Tobacco use, alcohol consumption, chronic irritation, candidiasis, vitamin deficiency, endocrine disturbances, and possibly a virus

• Epidemiology:OL occurs in fewer than 1% of individuals
  • OL is considered to be potentially malignant:With a transformation rate in various studies and locations:That range from 0.6% to 20%
    • • A long-term follow-up study by Fan et al:Indicated that oral leukoplakia can increase the risk of esophageal squamous cell carcinoma
  • OL is more common in men than in women:With a male-to-female ratio of 2:1
  • Most cases of OL occur in persons in their fifth to seventh decade of life:Approximately 80% of patients are older than 40 years

• The following three stages of OL have been described:

  • The earliest lesion is:

    • Nonpalpable, faintly translucent, and has white discoloration

  • Next, localized or diffuse, slightly elevated plaques with an irregular outline develop:

    • These lesions are opaque white and may have a fine, granular texture

  • In some instances, the lesions progress to thickened, white lesions, showing induration, fissuring, and ulcer formation

• Clinically, OL falls into one of the following two main groups:

  • The most common are uniformly white plaques (homogenous OL):

    • Prevalent in the buccal mucosa:

      • Which usually have low premalignant potential

  • Far more serious is speckled or verrucous leukoplakia:

    • Which has a stronger malignant potential than homogenous leukoplakia:

      • Speckled leukoplakia:

        • Consists of white flecks or fine nodules on an atrophic erythematous base

    • These lesions can be regarded as a combination of or a transition between leukoplakia and erythroplasia:

      • Which is flat or depressed below the level of the surrounding mucosal red patch:

        • Is uncommon in the mouth, and carries the highest risk of malignant transformation

Rodrigo Arrangoiz MS, MD, FACS

Here are some publications on oral cavity cancer:

• Oral Tongue Cancer: Literature Review and Current Management https://www.oatext.com/pdf/CRR-2-153.pdf
• Understand Cancer: Research and Treatment Oral Cavity Cancer: Literature Review and Current Management. https://www.researchgate.net/publication/303366031_Understand_Cancer_Research_and_Treatment_Oral_Cavity_Cancer_Literature_Review_and_Current_Management

Training:

• General surgery:

• Michigan State University:

• 2004 al 2010

• Surgical Oncology / Head and Neck Surgery / Endocrine Surgery:

• Fox Chase Cancer Center (Filadelfia):

• 2010 al 2012

• Masters in Science (Clinical research for health professionals):

• Drexel University (Filadelfia):

• 2010 al 2012

• Surgical Oncology / Head and Neck Surgery / Endocrine Surgery:

• IFHNOS / Memorial Sloan Kettering Cancer Center:

• 2014 al 2016

• Oral cavity leukoplakia:
  • Is a clinical diagnosis defined by the WHO as:
    • A “white plaque of questionable risk having excluded other known diseases or disorders that carry no increased risk for cancer”
• It is the most common oral potentially malignant disorder (OPMD) in North America and Europe:
  • With a prevalence ranging from 0.1% to 33%
• Definition:
  • Oral leukoplakia (OL) is a predominantly white patch or plaque on the oral mucosa:
    • That cannot be characterized clinically or pathologically as any other disorder
  • It is a diagnosis of exclusion:
    • Conditions such as:
      • Frictional keratosis, lichen planus, candidiasis, and other identifiable white lesions must be ruled out before the term is applied
  • A final diagnosis of leukoplakia in cases with an identifiable causative factor (e.g., friction, tobacco):
    • Can only be made in retrospect after failure to resolve within 4 to 8 weeks of eliminating the suspected cause
• Pathophysiology:
  • Leukoplakia represents a spectrum of epithelial alterations:
    • Driven by accumulating somatic – genomic alterations
  • The molecular progression model involves:
    • Sequential loss of heterozygosity (LOH) at specific chromosomal loci:
      • Early losses at 9p21 (p16 inactivation) and 3p21, followed by 17p13 (p53 mutation), 11q13 (cyclin D1 amplification), and later losses at 4q, 8p, 13q, and 14q
    • Tumor progression from OL:
      • OIs promoted by somatic genomic alterations, immune evasion, and abrogation of effective immune responses against cancer cells
    • Overexpression of p53 and deletions /mutations in KMT2C, p16INK4a, and p14ARF genes have been identified:
      • Particularly in proliferative verrucous leukoplakia (PVL)
    • Microbial dysbiosis:
      • May also contribute to a chronic inflammatory microenvironment favoring epithelial transformation
• Etiology and Risk Factors:
  • Tobacco and alcohol consumption:
    • Are the most common risk factors
  • However, OL can also occur in non-smokers — notably:
    • Most patients with PVL have never smoked:
      • Yet PVL carries the highest malignant transformation rates (70% to 100%)
  • Additional risk factors include:
    • Betel quid / areca nut use
    • Immunosuppression:
      • HIV-positive patients with OL are more likely to develop oral cancer
• Clinical Presentation:
  • OL typically presents as:
    • A white, adherent plaque that cannot be scraped off:
      • Lesions are largely asymptomatic
  • Two clinical subtypes are recognized:
    • Homogeneous leukoplakia:
      • Uniformly white, flat, thin plaques with a smooth or slightly wrinkled surface
      • These carry a lower risk of malignant transformation
    • Nonhomogeneous leukoplakia:
      • Mixed red-and-white lesions (erythroleukoplakia), nodular, verrucous, or speckled variants
      • These carry a significantly higher risk of malignant transformation
  • Common sites include:
    • The lateral / ventral tongue, floor of mouth, soft palate, buccal mucosa, and gingiva
  • Proliferative verrucous leukoplakia (PVL):
    • A distinct aggressive subtype, is characterized by multifocal keratotic plaques with progressive expansion, high recurrence, and strong malignant potential
• Histology:
  • Histopathology of leukoplakia can reveal a range of findings:
    • Hyperkeratosis (orthokeratosis or parakeratosis) without dysplasia:
      • The most common finding:
        • Represents benign epithelial thickening
    • Epithelial dysplasia:
      • Classified as:
        • Mild, moderate, or severe
      • Characterized by:
        • Architectural disturbance with blunt rete pegs, increased basal layer width, dyskeratosis (premature individual cell keratinization), nuclear enlargement, pleomorphism, hyperchromasia, and increased / atypical mitoses
    • Carcinoma in situ or invasive squamous cell carcinoma:
      • May be found on biopsy of clinically apparent leukoplakia
      • Importantly, frank dysplasia is more frequently found in isolated (unifocal) leukoplakia than in PVL:
        • Yet PVL has a much higher malignant transformation rate (~ 50% vs. ~ 9.5%), underscoring that histologic grade alone does not fully predict risk
• Management:
  • Management is guided by histopathologic findings and clinical risk factors:
    • All leukoplakias should be biopsied regardless of clinical impression:
      • As the decision to biopsy based on visual assessment alone has low sensitivity (59.6%) and low specificity (62.1%) for identifying cancer
    • Benign (no dysplasia):
      • Active surveillance with periodic clinical examination, or treatment with topical therapy
      • Risk factor modification (tobacco and alcohol cessation) is essential
    • Dysplastic lesions: 
      • Surgical excision:
        • Scalpel or laser ablation – is the standard approach
        • CO₂ laser ablation and photodynamic therapy have also been used
      • Chemoprevention:
        • Vitamin A, retinoids, beta-carotene, and lycopene have shown some short-term efficacy in clinical resolution of lesions but no treatment has been proven to prevent long-term malignant transformation in RCTs
        • Relapses and adverse effects are common
  • Close follow-up is mandatory regardless of treatment, as recurrence rates are high (37.5% in one series) and malignant transformation can occur even after complete excision:
    • The American Dental Association (2026) recommends routine clinical oral examination for all adults, including systematic visual inspection and palpation to detect OPMDs early
• Prognosis and Malignant Transformation:
  • The mean malignant transformation rate of OL is approximately:
    • 3.5% (range 0.13% to 34%) across studies:
      • With an estimated annual rate of ~1.5% to 2% per year
  • A large population-based cohort study (n = 4,886) found a 5-year absolute risk of oral cancer of 3.3% overall, stratified by dysplasia grade:
    • No dysplasia: 2.2%
    • Mild dysplasia: 11.9%
    • Moderate dysplasia: 8.7%
    • Severe dysplasia: 32.2%
  • Critically, 39.6% of cancers arose from biopsied leukoplakias without dysplasia:
    • Highlighting that absence of dysplasia does not eliminate risk
  • Risk factors for malignant transformation include:
    • Female sex
    • Lesion area > 200 mm²
    • Epithelial dysplasia
    • Nonhomogeneous type
    • Tongue location
    • Immunosuppression
• References:
• Common Tongue Conditions in Primary Care. Straub L, Schettini P, Myrex P. American Family Physician. 2024;110(5):467-475.
• Oncological Outcomes of Patients With Oral Potentially Malignant Disorders. Villa A, Lodolo M, Ha P. JAMA Otolaryngology– Head & Neck Surgery. 2025;151(1):65-71. doi:10.1001/jamaoto.2024.3719.
• Oral Leukoplakia, the Ongoing Discussion on Definition and Terminology. van der Waal I. Medicina Oral, Patologia Oral Y Cirugia Bucal. 2015;20(6):e685-92. doi:10.4317/medoral.21007.
• Molecular Markers of the Risk of Oral Cancer. Lippman SM, Hong WK. The New England Journal of Medicine. 2001;344(17):1323-6. doi:10.1056/NEJM200104263441710.
• Head and Neck Cancer. Forastiere A, Koch W, Trotti A, Sidransky D. The New England Journal of Medicine. 2001;345(26):1890-900. doi:10.1056/NEJMra001375.
• Microbial Dysbiosis and Host-Microbe Interactions in Proliferative Verrucous Leukoplakia: Insights Into Carcinogenic Potential. Špiljak B, Ozretić P, Brailo V, et al. Archives of Microbiology. 2025;208(1):65. doi:10.1007/s00203-025-04611-w. Head and Neck Cancer. Dunn LA, Ho AL, Pfister DG. JAMA. 2025;:2842834. doi:10.1001/jama.2025.21733.
• Oral Leukoplakia and Oral Cavity Squamous Cell Carcinoma. Bewley AF, Farwell DG. Clinics in Dermatology. 2017 Sep – Oct;35(5):461-467. doi:10.1016/j.clindermatol.2017.06.008.
• Oral Potentially Malignant Disorders. Wetzel SL, Wollenberg J. Dental Clinics of North America. 2020;64(1):25-37. doi:10.1016/j.cden.2019.08.004.
• Proliferative Verrucous Leukoplakia: An Expert Consensus Guideline for Standardized Assessment and Reporting. Thompson LDR, Fitzpatrick SG, Müller S, et al. Head and Neck Pathology. 2021;15(2):572-587. doi:10.1007/s12105-020-01262-9.
• Leukoplakia-a Diagnostic and Management Algorithm. Villa A, Woo SB. Journal of Oral and Maxillofacial Surgery : Official Journal of the American Association of Oral and Maxillofacial Surgeons. 2017;75(4):723-734. doi:10.1016/j.joms.2016.10.012.
• Potentially Malignant Disorders of the Oral Cavity and Oral Dysplasia: A Systematic Review and Meta-Analysis of Malignant Transformation Rate by Subtype. Iocca O, Sollecito TP, Alawi F, et al. Head & Neck. 2020;42(3):539-555. doi:10.1002/hed.26006.
• Clinical Management Update of Oral Leukoplakia: A Review From the American Head and Neck Society Cancer Prevention Service. Gates JC, Abouyared M, Shnayder Y, et al. Head & Neck. 2025;47(2):733-741. doi:10.1002/hed.28013.
• Oral Leukoplakia and Risk of Progression to Oral Cancer: A Population-Based Cohort Study. Chaturvedi AK, Udaltsova N, Engels EA, et al. Journal of the National Cancer Institute. 2020;112(10):1047-1054. doi:10.1093/jnci/djz238.
• Randomized Controlled Trials for Oral Leukoplakia. Lodolo M, Valor J, Villa A. Oral Diseases. 2025;. doi:10.1111/odi.15399.
• Management of Oral Leukoplakia by Ablative Fractional Laser-Assisted Photodynamic Therapy: A 3-Year Retrospective Study of 48 Patients. Yao YL, Wang YF, Li CX, Wu L, Tang GY. Lasers in Surgery and Medicine. 2022;54(5):682-687. doi:10.1002/lsm.23534.
• Interventions for Treating Oral Leukoplakia to Prevent Oral Cancer. Lodi G, Franchini R, Warnakulasuriya S, et al. The Cochrane Database of Systematic Reviews. 2016;7:CD001829. doi:10.1002/14651858.CD001829.pub4.
• Living evidence-informed guideline on the early detection of oral squamous cell carcinoma and potentially malignant disorders. Olivia Urquhart. American Dental Association (2026).
• Long-Term Outcome of Non-Surgical Treatment in Patients With Oral Leukoplakia. Kuribayashi Y, Tsushima F, Morita KI, et al. Oral Oncology. 2015;51(11):1020-1025. doi:10.1016/j.oraloncology.2015.09.004.

• RxPONDER (SWOG S1007):
  • Changed adjuvant decision-making for patients with HR-positive, HER2-negative early breast cancer with 1 to 3 positive axillary nodes:
    • By showing that the value of chemotherapy depends heavily on menopausal status:
      • When the 21-gene recurrence score (Oncotype DX RS) is 0 to 25
  • The key practice-changing message is that postmenopausal women with RS 0 to 25:
    • Generally do not benefit from adjuvant chemotherapy:
      • Whereas premenopausal women with the same RS range do appear to benefit
• Trial design:
  • RxPONDER was a prospective randomized phase III trial enrolling more than 5,000 women with HR-positive, HER2-negative breast cancer, 1 to 3 positive lymph nodes, and an RS of 25 or lower
  • Patients were randomized to endocrine therapy alone or chemoendocrine therapy
  • The central goal was to determine whether recurrence score could identify node-positive patients who could safely avoid chemotherapy
• Main result:
  • In the overall study population, the effect of chemotherapy differed by menopausal status:
    • Among postmenopausal women:
      • Adding chemotherapy did not improve invasive disease–free survival
    • Among premenopausal women:
      • Chemotherapy did improve invasive disease–free survival and distant relapse–free survival:
        • This interaction is the most important clinical takeaway from the study
  • Postmenopausal patients:
    • For postmenopausal patients with 1 to 3 positive nodes and RS 0 to 25:
      • Chemotherapy can usually be omitted without compromising outcomes:
        • This is the group in which RxPONDER most clearly supports de-escalation
      • For the surgeon, this means that limited nodal positivity alone no longer automatically implies a chemotherapy recommendation in HR-positive / HER2-negative disease
  • Premenopausal patients:
    • For premenopausal patients with 1 to 3 positive nodes and RS 0 to 25:
      • Chemotherapy was associated with a statistically significant benefit
      • The trial did not prove whether that benefit came from cytotoxic therapy itself, chemotherapy-induced ovarian suppression, or both:
        • So multidisciplinary interpretation remains important
      • Current NCCN educational guidance reflects this nuance:
        • Noting that in premenopausal patients the assay may help frame discussion of alternatives such as ovarian function suppression, but chemotherapy and ovarian suppression are not yet proven interchangeable
• What it means for the surgical oncologist:
  • RxPONDER matters because it directly affects postoperative counseling after lumpectomy or mastectomy when final pathology shows 1 to 3 positive nodes
  • The surgeon should anticipate genomic testing in appropriate ER-positive / HER2-negative patients and should understand that:
    • Node-positive does not automatically mean chemotherapy
    • Menopausal status is central to interpretation:
      • In postmenopausal patients with RS 0 to 25:
        • Chemotherapy can often be avoided
      • In premenopausal patients with RS 0–25:
        • Chemotherapy is still generally recommended unless the medical oncology discussion supports a different endocrine-based strategy
• Practical surgical takeaway:
  • For a surgical oncologist:
    • RxPONDER shifts the conversation from “How many nodes are positive?” to “What is the biology, and is the patient premenopausal or postmenopausal?”
    • In modern breast practice, a patient with 1 to 3 positive nodes and favorable genomics may still avoid chemotherapy if she is postmenopausal:
      • But a similar premenopausal patient usually still merits strong consideration of chemotherapy
• Bottom line:
  • RxPONDER showed that for HR-positive, HER2-negative early breast cancer with 1 to 3 positive nodes and Oncotype DX RS 0 to 25, postmenopausal women do not derive meaningful chemotherapy benefit, while premenopausal women do:
    • That is the key message that should guide surgical counseling and multidisciplinary adjuvant planning
• Key references:
  • Kalinsky K, Barlow WE, Gralow JR, et al. 21-Gene Assay to Inform Chemotherapy Benefit in Node-Positive Breast Cancer. N Engl J Med. 2021;385:2336-2347. 
  • NCCN educational update on biomarkers in early-stage breast cancer, summarizing current use of the 21-gene assay in node-positive disease.