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Risk Factors for Cutaneous Melanoma II

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • The increasing incidence rates of cutaneous melanoma in the United States projected for 2025 are influenced by several key risk factors:
    • With ultraviolet (UV) exposure and demographic changes playing significant roles
  • Ultraviolet (UV) Exposure:
    • UV radiation from sunlight and artificial sources like tanning beds is the primary risk factor for melanoma
    • Both intermittent intense exposure (e.g., sunburns) and chronic cumulative exposure contribute to melanoma risk
    • The American Cancer Society emphasizes that reducing UV exposure through protective measures such as:
      • Sunscreen use, wearing protective clothing, and avoiding tanning beds can mitigate this risk
  • Demographic Factors:
    • Skin Type:
      • Individuals with fair skin, light hair, and light eye color are at higher risk:
        • Due to lower melanin levels:
          • Which provide less natural protection against UV radiation
    • Age:
      • Melanoma incidence increases with age, particularly in older adults:
        • Due to cumulative UV exposure over a lifetime
      • However, it is also common in younger adults, especially women:
        • Likely due to higher use of tanning beds and intentional sun exposure
    • Gender:
      • Men have higher melanoma incidence rates than women, particularly after age 40:
        • This may be due to differences in sun exposure behaviors and lower rates of skin self-examination among men
    • Genetic Factors:
      • A family history of melanoma increases risk, as does the presence of numerous or atypical nevi (moles)
      • Genetic predispositions, such as mutations in the CDKN2A gene:
        • Also contribute to higher melanoma risk
    • Other Factors:
      • Immunosuppression, whether due to medical conditions like HIV or medications post-organ transplantation:
        • Increases melanoma risk
      • Additionally, socioeconomic factors, such as higher income and access to dermatologic care, can lead to higher diagnosis rates due to increased diagnostic scrutiny
  • In summary, the rising incidence of cutaneous melanoma in the United States is driven by UV exposure, demographic changes, genetic predispositions, and other factors:
    • Effective prevention strategies focusing on reducing UV exposure and early detection are crucial to managing this growing public health concern
  • References:

Risk Factors for Melanoma

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • Estimating an individual’s risk of developing melanoma:
    • Can be clinically useful in determining primary prevention strategies and in directing the level of screening
  • Patients identified as being at high risk for melanoma:
    • May also be recruited to prevention trials
  • Multiple factors are associated with risk for developing melanoma:
    • Some factors are modifiable while others are inherent to the individual
  • Skin type:
    • Caucasians have at least 20 times the melanoma incidence of African Americans and five times the melanoma incidence of American Hispanics
    • In addition, white patients with red or blond hair, fair complexion, or blue eyes:
      • Are at increased risk for melanoma
  • Age and Gender:
    • The incidence of melanoma increases with age
    • The incidence of melanoma is:
      • 1.7-fold higher for women than men before 49 years of age
      • Over age 70:
        • The incidence of melanoma is 2.4-fold higher for men than women
    • In general, the incidence of melanoma is:
      • Higher in men than in women:
        • Specifically, a man’s lifetime risk of melanoma development is approximately:
          • 1.5 times greater than a woman’s risk
  • Overexposure to ultraviolet radiation (UVR) from the sun:
    • Overexposure of UVR from the sun:
      • Has been associated with an increased risk of melanoma
    • Genetic sequencing data:
      • Also support the role of UV melanomagenesis
    • Known to be a tumor with one of the highest mutational loads:
      • A seminal report of the melanoma effort within The Cancer Genome Atlas Program:
        • Revealed that most somatic mutations in melanoma indeed have a “UV signature”
    • Data support that damage from sunburns in childhood or even in adulthood are associated with increased risk:
      • A correlation has been identified between the number of severe and painful sunburn episodes and the risk of melanoma:
        • Individuals who have a history of more than 10 severe sunburns are more than twice as likely to develop a melanoma compared those who have no history of sunburns
  • Use of indoor tanning devices:
    • Multiple studies support that indoor tanning device use is strongly associated with increased risk of melanoma
    • A systematic review by the International Agency for Research on Cancer (IARC):
      • Demonstrated a 15% increased relative risk of melanoma in individuals who had ever used a sunbed versus those who had never (RR 1.15; 95% CU 1.00 to 1.31)
    • The dangers of indoor tanning have been corroborated by subsequent U.S. and Australian groups
    • Young age of onset and higher frequency of use are key risk factors that are associated with even greater risk of melanoma
    • Indeed, a well-designed Minnesota case–control study showed increased risk with number of years, hours, and sessions of indoor tanning, independent of outdoor sun exposure:
      • These researchers also found that 97% of women diagnosed with melanoma before age 30 had indoor tanned
    • Young patients who use indoor tanning devices more than 10 times annually have more than 7 times the melanoma risk compared to individuals who do not indoor tan
    • A meta-analysis estimated a 1.8% increased melanoma risk for each additional tanning bed session
    • Since 2009, the World Health Organization lists tanning beds as a Class I carcinogen
  • Previous melanoma:
    • Individuals with a personal history of melanoma have an increased risk of developing a second melanoma of approximately:
      • 3% to 7%
  • Benign nevi:
    • Although a benign nevus is most likely not a precursor of melanoma:
      • The presence of large numbers of nevi has been consistently associated with an increased risk of melanoma:
        • Persons with ≥ 50 nevi, all of which are > 2 mm in diameter:
          • Have 5 to 17 times the melanoma risk of persons with fewer nevi
  • Individuals who tend to develop freckles:
    • Also have an increased risk of melanoma
  • Family history:
    • Approximately 10% of individuals diagnosed with melanoma:
      • Have a family member with a history of melanoma
    • A family history of melanoma:
      • Increases an individual’s risk of melanoma three- to eightfold
    • Furthermore, persons who have two or more family members with melanoma:
      • Are also at a particularly high risk
    • When available, these patients should be referred to genetic counseling
  • Genetic predisposition:
    • Approximately 8% to 12% of melanomas:
      • Occur in individuals with a genetic predisposition
    • Specific genetic alterations have been implicated in the pathogenesis of melanoma
  • Atypical mole and melanoma syndrome:
    • Previously known as dysplastic nevus syndrome, atypical mole and melanoma syndrome:
      • Is characterized by the presence of multiple, large (> 5 mm) atypical dysplastic nevi generally in nonexposed areas of skin that represent a distinct clinicopathologic type of melanocytic lesion
      • Melanomas can originate from either normal skin or from a dysplastic nevus
      • Since the actual frequency of an atypical mole progressing to melanoma is small:
        • Resection of all dysplastic nevi is not indicated
      • However, new, changing, or symptomatic lesions that appear suspicious for melanoma on clinical and / or dermoscopic examination should be evaluated histologically

Surgical Margins in Melanoma

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • The standards set for wide excision of melanoma:
    • Are well-studied and are the result of:
      • Five randomized, prospective trials
  • Randomized trials:
    • The French Cooperative Group Trial and the Swedish Melanoma Trial Group:
      • Analyzed melanomas 2 mm in depth
      • Comparing 2-cm and 5-cm margins
      • The findings of these studies demonstrated:
        • No increased risk of local or distant recurrence associated with the smaller margin
  • The World Health Organization (WHO) Melanoma Trial number 10:
    • Analyzed patients with melanomas 2 mm in thickness:
      • But compared 1-cm and 3-cm margins
    • It also demonstrated no difference in overall survival:
      • Although among the patients with a melanoma of 1- to 2-mm thickness:
        • The rate of local recurrence was slightly higher when a 1-cm margin was used:
          • The difference was not statistically significant, however:
            • And the recommendation from this trial was that a 1-cm margin was safe for lesions 2 mm Breslow thickness:
              • Although the rate of local recurrence in the 1- to 2-mm subgroup may be higher with this margin
  • The Intergroup Melanoma Trial:
    • Analyzed all patients with a melanoma of intermediate thickness (1 to 4 mm)
    • The authors compared 2-cm and 4-cm margins and, despite the inclusion of patients with melanomas 2 mm thick:
      • No difference was seen in overall survival or local recurrence
    • This trial demonstrated that a 2-cm margin of excision was safe for patients with a melanoma of up to 4 mm thick:
      • But did not address patients who had a lesion greater than 4 mm thick
  • The British Cooperative Group Trial:
    • Analyzed patients with lesions greater than 2 mm in thickness and randomly assigned them to 1-cm margins or 3-cm margins
    • This trial demonstrated a greater risk of recurrence among patients who had a 1-cm margin of excision:
      • However, importantly, this trial did not include SLN biopsy, and the greatest incidence of recurrence was regional:
        • When accounting for regional recurrence, the differences between groups were no longer statistically significant
      • Given this limitation, the application of these results to the standards in regions where SLN is routinely applied becomes somewhat ambiguous
      • Finally, the overall survival in both arms was not statistically different
  • Margins are measured grossly, not microscopically:
    • Therefore pathologic analysis after resection does not require repeat resection (except in the setting of positive margins) to ensure the appropriate distance
    • There is no role for compromise of these standards, i.e., biopsy margins cannot be added to planned surgical margins to obtain a total excision margin (i.e., 5 mm plus 5 mm):
      • Therefore, wide excision is planned around the biopsy site or the known primary lesion with the appropriate margin at the time of definitive wide excision:
        • In areas of anatomic or functional constraint, such as the hand or the face:
          • Margins may be compromised from the set standards:
          • In settings where margins must be compromised:
            • Local recurrence does not appear to have an impact on overall survival
  • Sentinel lymph node biopsy:
    • Should be discussed and offered for patients with melanoma greater than or equal to 0.8 mm in thickness
    • Melanomas less than 0.8 mm thick with the presence of high-risk features such as:
      • The presence of ulceration
  • Ultrasound surveillance of the regional lymph node basin(s):
    • Would be indicated only in the instance of a primary tumor that failed to localize on preoperative lymphoscintigraphy
  • Reference
    • Balch CM, Houghton AN, Sober AJ, et al, eds. Cutaneous Melanoma. 5th ed. St. Louis, MO: Quality Medical Publishing; 2009.
    • National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Melanoma. Available at http://www.nccn.org.
    • Morton DL, Cochran AJ, Thompson JF, et al. Sentinel node biopsy for early stage melanoma: accuracy and morbidity in MSLT-I, an international multicenter trial. Ann Surg. 2005;242:302-311.

Ribociclib Plus Endocrine Therapy for Early Breast Cancer: NATALEE Trial

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • Practice Guideline:
    • The NATALEE trial was an open-label, multicenter, randomized phase III trial:
      • That evaluated the addition of ribociclib to standard endocrine therapy (ET) in patients with stage II to III hormone receptor-positive, HER2-negative early breast cancer
    • The trial included 2,549 patients receiving ribociclib (400 mg once daily, 3 weeks on, 1 week off) plus ET and 2,552 patients receiving ET alone
    • At a median follow-up of 27.7 months:
      • Ribociclib plus ET significantly improved invasive disease-free survival (IDFS) compared to ET alone (HR, 0.75; 95% CI, 0.62 to 0.91; P = .003), with 3-year IDFS rates of 90.4% versus 87.1%, respectively
      • Additionally, ribociclib plus ET improved distant disease-free survival (DDFS) (HR, 0.74; 95% CI, 0.60 to 0.91)[1]
    • The American Society of Clinical Oncology (ASCO) recommends:
      • Considering ribociclib in combination with ET for patients with stage II to III hormone receptor-positive, HER2-negative early breast cancer:
        • Particularly those with high-risk features
      • This recommendation is based on the significant IDFS benefit observed in the NATALEE trial
      • However, ASCO suggests that ribociclib may not provide meaningful clinical benefit to all eligible patients:
        • Especially those with lower-risk disease, and emphasizes the importance of individual patient factors in decision-making
  • The NATALEE trial was a pivotal phase III study that evaluated the efficacy and safety of ribociclib in combination with endocrine therapy (ET) in patients with stage II to III hormone receptor-positive, HER2-negative early breast cancer
    • The trial included 5,101 patients who were randomized to receive either ribociclib (400 mg/day, 3 weeks on/1 week off for 3 years) plus a nonsteroidal aromatase inhibitor (NSAI) or NSAI alone
    • Premenopausal women and men also received Goserelin
    • The primary endpoint of the trial was invasive disease-free survival (iDFS)
    • At a median follow-up of 33.3 months:
      • Ribociclib plus ET demonstrated a significant improvement in iDFS compared to ET alone:
        • With a hazard ratio (HR) of 0.749 (95% CI, 0.628-0.892; P = 0.0012)
      • The 3-year iDFS rates were 90.7% for the ribociclib plus ET group versus 87.6% for the ET alone group
      • This benefit was consistent across various subgroups, including those with different stages and nodal statuses[2][3][4]
      • Secondary endpoints, such as distant disease-free survival (DDFS) and recurrence-free survival (RFS), also favored the ribociclib plus ET group
      • No new safety signals were observed, and the treatment was generally well-tolerated [2][3][4]
  • Based on the NATALEE trial results, ribociclib in combination with ET is indicated for patients with stage II to III hormone receptor-positive, HER2-negative early breast cancer, particularly those at high risk of recurrence:
    • This includes patients with node-positive disease and those with additional high-risk features
  • The trial’s findings support the use of ribociclib as an effective adjuvant therapy to improve iDFS and reduce the risk of recurrence in this patient population [2][3][4]
  • References:

Epidemiology of Cutaneous Melanoma

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • Cutaneous melanoma:
    • Is a malignancy arising from melanocytes of the skin:
      • Its incidence has been increasing globally:
        • Particularly in fair-skinned populations
    • The incidence of invasive cutaneous melanoma:
      • Continues to be a major public health concern in the United States:
        • It has been increasing faster than that of nearly any other cancer over the last 30 years
  • In 2020, there were an estimated 325,000 new cases and 57,000 deaths due to melanoma worldwide:
    • The highest incidence rates are observed in Australia and New Zealand:
      • With rates of 42 per 100,000 person-years for males and 31 per 100,000 person-years for females
    • Western Europe, North America, and Northern Europe also have high incidence rates
    • While melanoma remains rare in most African and Asian countries
  • The incidence of melanoma is closely linked to:
    • Ultraviolet (UV) radiation exposure:
      • Both from natural sunlight and artificial sources like tanning beds
      • This exposure is a significant risk factor, particularly in populations with lighter skin pigmentation
  • The incidence rates have been rising by approximately 3% to 7% annually over the past decades in white populations:
    • Driven by changes in outdoor activities and sun exposure behaviors
  • Mortality rates for melanoma:
    • Have shown stabilization or decline in some regions, such as the USA, Australia, and parts of Europe:
      • Likely due to early detection and advances in treatment:
        • Including the use of immune checkpoint inhibitors and targeted therapies
    • However, mortality rates remain highest in regions with the highest incidence, such as New Zealand, where they peak at 5 per 100,000 person-years
  • Projections indicate that if current trends continue:
    • The global burden of melanoma will increase to 510,000 new cases and 96,000 deaths by 2040, underscoring the need for effective prevention and early detection strategies
  • According to the analysis by Garbe et al:
    • Melanoma incidence among US whites is predicted to rise to 56.1 per 100,000 males and 36.2 per 100,000 females by 2036, with a significant portion of this increase expected to occur by 2025
    • This trend is driven by factors such as increased UV exposure and improved detection methods
  • Guy et al. projected that melanoma incidence rates would continue to increase for white males and females through 2019, with death rates remaining stable:
    • Although this projection does not extend to 2025, it supports the trend of rising incidence rates observed in other studies
  • Whiteman et al. also noted that melanoma rates in US whites increased at more than 3% annually between 1982 and 2011 and are projected to continue rising until at least 2022:
    • With annual new cases expected to rise significantly due to aging populations and high age-specific rates in the elderly
  • The American Cancer Society (ACS) projects that in 2025:
    • There will be approximately 106,110 new cases of melanoma and 7,180 deaths due to melanoma in the United States
    • The incidence rates for melanoma have been rising by about 2% to 3% annually, driven by changes in sun exposure behaviors and the aging population
  • Overall, the lifetime risk of being diagnosed with melanoma is about:
    • 2.5% (1 in 40) for whites, 0.1% (1 in 1,000) for blacks, and 0.5% (1 in 200) for Hispanics
  • The major environmental risk factor, exposure to ultraviolet (UV) radiation, is reflected in geographic and ethnic patterns of melanoma rates
  • There have also been changes in the distribution and stage of melanoma at diagnosis:
    • With an overall trend toward thinner T1 / T2 melanomas
  • References:

Combining Ribociclib With Hormone Therapy Improves Patient Outcomes in Early-Stage Breast Cancer: NATALEE

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • Targeted treatment with ribociclib plus hormone therapy:
    • Provided significant invasive disease–free survival benefits in patients with early-stage hormone receptor–positive, HER2-negative breast cancer at risk of disease recurrence
  • Results from the phase III NATALEE trial, led by researchers at The University of Texas MD Anderson Cancer Center, were presented at the 2023 San Antonio Breast Cancer Symposium (Abstract GS3-03)
  • Patients who received the combination regimen experienced significantly extended invasive disease–free survival compared to those who received hormone therapy alone:
    • Which corresponds to a 25% reduction in the risk of recurrence
    • The invasive disease–free survival rates at 3 years were:
      • 90.7% with the combination and 87.6% with only hormone therapy
  • The current treatments we have for hormone receptor–positive, HER2-negative early-stage breast cancer:
    • Only help a small group of patients, which leaves many people with limited options to lower the chances of their cancer coming back
  • NATALEE trail shows the continued disease-free survival improvement for patients receiving ribociclib with hormone therapy and showed a benefit across clinically relevant subgroups
  • Study Background
    • According to the National Cancer Institute, hormone receptor–positive, HER2-negative breast cancer is the most common subtype of the malignancy:
      • Accounting for nearly 70% of all breast cancer cases in the United States
    • Approximately one-third of individuals diagnosed with stage II hormone receptor–positive, HER2-negative breast cancer:
      • Face a risk of recurrence:
        • Despite receiving standard-of-care treatment
    • Among those with stage III disease:
      • More than half experience a recurrence
  • Ribociclib:
    • Belongs to a category of targeted therapies known as:
      • Small-molecule inhibitors
    • It specifically targets the CDK4 and CDK6 proteins:
      • Which play a crucial role in regulating cell growth and promoting the growth of breast cancer cells
    • In 2018, the U.S. Food and Drug Administration granted approval for ribociclib’s use:
      • In treating advanced hormone receptor–positive, HER2-negative breast cancer
    • While previous research demonstrated the survival advantages of ribociclib in treating metastatic breast cancer:
      • The NATALEE trial provided evidence that it could improve outcomes for patients with early-stage breast cancer that hasn’t spread to the lymph nodes
  • NATALEE Methodology:
    • The NATALEE trial (ClinicalTrials.gov identifier NCT03701334) enrolled 5,101 men and pre- and postmenopausal women from 20 different countries with:
      • Stage IIA, IIB, or III hormone receptor–positive, HER2-negative breast cancer at risk for recurrence
    • Participants were randomly assigned to receive either adjuvant ribociclib for 3 years with hormonal therapy for at least 5 years or hormonal therapy alone for at least 5 years.
    • The primary endpoint was invasive disease–free survival, and the secondary efficacy endpoints were recurrence-free survival, distant disease–free survival, and overall survival
  • Results:
    • Researchers observed consistent benefits across patient subgroups, including those with:
      • Node-negative, stage II, and stage III disease
    • Analyses of secondary endpoints of distant disease–free survival and recurrence-free survival supported ribociclib with hormone therapy compared to ribociclib alone
    • The overall survival data remains incomplete as of now, with 84 events in the ribociclib plus hormone therapy group and a total of 88 events in the hormone therapy alone group
    • No new safety signals were observed since the prior interim analysis, and side effects were consistent with the known safety profile of ribociclib and nonsteroidal aromatase inhibitors
    • Researchers will continue to evaluate how adding ribociclib to hormonal therapy impacts quality of life and will follow patients to observe long-term outcomes

Cyclin-Dependent Kinase 4/6 (CDK4/6) Inhibitors in Early Breast Cancer Practice Guideline

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors:
    • Are indicated in early breast cancer primarily for patients with:
      • Hormone receptor-positive
      • HER2-negative
      • Node-positive breast cancer:
        • At high risk of recurrence
  • The American Society of Clinical Oncology (ASCO) recommends:
    • The use of abemaciclib in combination with endocrine therapy (ET) for these patients:
      • Particularly those who meet the criteria of the intention-to-treat (ITT) population from the monarchE trial:
        • This includes patients with resected breast cancer with:
          • ≥ 4 positive axillary lymph nodes (ALNs) or 1 to 3 positive ALNs plus additional high-risk features such as grade 3 disease, tumor size ≥ 5 cm, or a Ki-67 index ≥ 20% [1]
        • The rationale for this recommendation is based on the sustained improvement in invasive disease-free survival (IDFS) observed in the monarchE trial:
          • With a hazard ratio (HR) of 0.680 and a 5-year absolute improvement in IDFS of 7.6% compared to ET alone [1]
        • The FDA has expanded the approval of abemaciclib to include patients without the Ki-67 testing requirement:
          • Acknowledging benefits across the broader ITT population [1]
  • Ribociclib:
    • Is another CDK4/6 inhibitor evaluated in the NATALEE trial:
      • Which included patients with:
        • Stage II to III hormone receptor-positive
        • HER2-negative early breast cancer
    • However, ASCO’s panel suggests that ribociclib may not provide meaningful clinical benefit to all eligible patients:
      • Especially those with lower-risk disease, and recommends considering individual patient factors such as risks, benefits, costs, and preferences when deciding on its use [1]
  • The indications for cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in early breast cancer are:
    • Primarily for patients with hormone receptor-positive (HR+), HER2-negative breast cancer who are at high risk of recurrence
    • This includes patients with:
      • Node-positive disease and additional high-risk features
    • The monarchE trial:
      • Demonstrated a significant invasive disease-free survival (iDFS) benefit with the use of abemaciclib in combination with endocrine therapy (ET) in patients with:
        • Node-positive early breast cancer, leading to its approval for this indication [2]
    • The NATALEE trial:
      • Evaluated ribociclib in combination with ET in a broad population of patients with:
        • Stage II or III HR+, HER2-negative early breast cancer
      • The trial showed a significant iDFS benefit:
        • With a 25.2% lower risk of invasive disease, recurrence, or death compared to ET alone [2]
      • Ribociclib was administered at a dose of 400 mg per day:
        • Which was associated with a lower incidence of dose-dependent toxic effects compared to the higher dose used in advanced breast cancer [2]
  • The efficacy of CDK4/6 inhibitors in early breast cancer has been variable across different trials:
    • While the PALLAS and PENELOPE-B trials did not show a significant benefit with palbociclib, the monarchE and NATALEE trials demonstrated significant iDFS benefits with abemaciclib and ribociclib, respectively [2][3]
  • These findings highlight the importance of patient selection and the specific characteristics of the trials in determining the benefit of CDK4/6 inhibitors in early breast cancer
  • References:
Mechanisms of Action and Resistance in Estrogen Receptor (ER)–Targeted Therapy.
Burstein HJ. Systemic Therapy for Estrogen Receptor-Positive, HER2-Negative Breast Cancer. The New England Journal of Medicine. 2020;383(26):2557-2570. doi:10.1056/NEJMra1307118.
The mechanisms of action and resistance in estrogen receptor (ER)-targeted therapy, including the role of CDK4/6 inhibitors in inhibiting cell cycle progression in ER-positive breast cancer. This figure underscores the biological rationale for using CDK4/6 inhibitors in combination with endocrine therapy to improve outcomes in early breast cancer.

Common Patient Groups that Experience a Biochemical Incomplete Response in the Context of Dynamic Risk Stratification for Differentiated Thyroid Cancer (DTC)

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • Common patient groups that experience a biochemical incomplete response in the context of dynamic risk stratification for differentiated thyroid cancer (DTC) include:
  • Low-Risk Patients:
    • Approximately 11% to 19% of patients initially classified as low-risk by the American Thyroid Association (ATA) experience a biochemical incomplete response
    • These patients typically have persistently abnormal thyroglobulin (Tg) values or rising anti-Tg antibodies without structural evidence of disease
  • Intermediate-Risk Patients:
    • This group has a higher incidence, with 21% to 22% of patients experiencing a biochemical incomplete response
    • These patients often have more aggressive disease features, such as larger tumor size or lymph node involvement, which contribute to the incomplete biochemical response
  • High-Risk Patients:
    • Even among high-risk patients, 16% to 18% experience a biochemical incomplete response
    • These patients are more likely to have advanced disease at diagnosis, including distant metastases or extensive lymph node involvement
  • Patients with BRAFV600E Mutation:
    • The presence of the BRAFV600E mutation is significantly associated with a biochemical incomplete response
    • This mutation is linked to more aggressive disease and a higher likelihood of persistent biochemical evidence of disease
  • Patients with Higher Preablative Stimulated Tg Levels:
    • Patients with higher preablative stimulated Tg levels (≥ 12.30 ng/mL) are more likely to experience a biochemical incomplete response
    • This marker is a robust predictor of persistent disease
  • These groups highlight the variability in response to initial therapy and underscore the importance of dynamic risk stratification in guiding follow-up and management strategies for DTC patients
  • References:

Biochemical Incomplete Response (BIR) in Thyroid Cancer

Rodrigo Arrangoiz MS, MD, FACS, FSSO

Implications and Management of a Biochemical Incomplete Response in Dynamic Risk Stratification

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • A biochemical incomplete response is defined as:
    • Negative imaging with elevated thyroglobulin (Tg) or anti-Tg antibodies:
      • During follow-up after initial treatment for differentiated thyroid cancer (DTC)
  • This response category reflects persistent biochemical evidence of disease:
    • Without structural correlates
    • The prognosis for patients with a biochemical incomplete response:
      • Is generally favorable but variable:
        • Approximately 30% of patients spontaneously achieve no evidence of disease (NED)
        • An additional 20% achieve NED with further therapy
        • 20% progress to structural disease
          • Disease-specific mortality is rare, occurring in less than 1% of cases
  • Risk Factors and Predictors:
    • Several factors influence the likelihood of a biochemical incomplete response and its progression:
      • BRAFV600E mutation:
        • Is significantly associated with biochemical incomplete response, with studies showing a higher prevalence of this mutation in affected patients
        • This mutation also correlates with an increased risk of progression to structural disease
      • Patients with a biochemical incomplete response have a higher recurrence risk compared to those with an excellent response:
        • But their risk is lower than that of patients with a structural incomplete response
  • Management Strategies:
    • Management of a biochemical incomplete response:
      • Is guided by the trend in Tg or anti-Tg antibody levels and the absence of structural disease
    • Observation with TSH suppression:
      • For patients with stable or declining Tg levels, continued observation with ongoing TSH suppression is recommended:
        • The degree of TSH suppression should be individualized based on the patient’s risk profile and comorbidities
    • Rising Tg or anti-Tg antibody levels:
      • If Tg or anti-Tg antibody levels increase, further evaluation with imaging (e.g., neck ultrasound, cross-sectional imaging, or functional imaging such as RAI SPECT/CT or PET-CT) is warranted
      • Additional therapies, such as radioactive iodine (RAI) therapy, may be considered in select cases:
        • Particularly if Tg levels remain persistently elevated or if there is evidence of iodine-avid disease
    • Additional RAI therapy:
      • While not universally required, additional RAI therapy may be beneficial in patients with persistent biochemical evidence of disease:
        • Especially if Tg levels are significantly elevated or rising
        • Approximately 20% of patients achieve NED with further RAI therapy
  • Clinical Outcomes and Long-Term Follow-Up:
    • Long-term outcomes for patients with a biochemical incomplete response are generally favorable:
      • Most patients either achieve NED or remain biochemically stable without progression to structural disease
      • Approximately 60% of patients with a biochemical incomplete response have no evidence of disease over long-term follow-up
    • Dynamic risk stratification (DRS) allows for individualized follow-up and management adjustments based on evolving risk
    • This approach ensures that patients with stable disease are not overtreated, while those with evidence of progression receive timely intervention
  • Gaps in Evidence:
    • Despite the utility of DRS, there are gaps in the evidence regarding the management of biochemical incomplete response:
      • Limited prospective studies:
        • Most data on biochemical incomplete response are derived from retrospective studies
        • Prospective studies are needed to validate management strategies, particularly in patients treated without RAI

          – Patients treated without RAI:
          • The interpretation of Tg levels and the utility of DRS in patients treated with lobectomy or total thyroidectomy without RAI remain less well-defined, necessitating further research
  • In summary:
    • A biochemical incomplete response in DRS is associated with a generally favorable prognosis, though a subset of patients may progress to structural disease
    • Management involves close monitoring, TSH suppression, and selective use of additional therapies, with long-term outcomes guided by dynamic risk stratification
  • References:
Rodrigo Arrangoiz, MD (Oncology Surgeon)