Author: Rodrigo Arrangoiz MS, MD, FACS, FSSO

• Truncating CHEK2 mutations (such as the c.1100delC mutation):
  • Are considered rare, moderate penetrance mutations
• The lifetime risk of developing breast cancer with these mutations:
  • Is 3 times higher than the general population:
    • This means that the majority of patients with these mutations will not develop breast cancer, and many of the cancers that do develop may be sporadic and not related to the mutation:
      • Patients with these mutations should be counseled about their risk and the available risk management strategies
• Those with a significant family history of breast cancer:
  • Should be counseled regarding high risk breast cancer screening:
    • Annual mammogram with consideration of annual MRI starting at age 40 or modified to an earlier age based on family history
  • Should be counseled regarding prevention strategies, including:
    • Chemoprevention and prophylactic surgery
• It should be emphasized that there is less absolute risk-reduction benefit with prophylactic surgery compared to high-penetrance mutations like BRCA mutations, and recommendations should be based on patient’s family history
• National Comprehensive Cancer Network guidelines:
  • Should be followed with recommendation for high-risk screening, including colon cancer screening recommendations among individuals with a CHEK2 mutation
• References
  • Stratton MR, Rahman N. The emerging landscape of breast cancer susceptibility. Nat Genet. 2008;40(1):17-22.
  • Desmond A, Kurian AW, Gabree M, Mills MA, Anderson MJ, Kobayashi Y, et al. Clinical actionability of multigene panel testing for hereditary breast and ovarian cancer risk assessment. JAMA Oncol. 2015;1(7):943-951.
  • Weiss A, Garber JE, King T. Breast cancer surgical risk reduction for patients with inherited mutations in moderate penetrance genes. JAMA Surg. 2018;153(12):1145-1146.
  • Tung N, Domchek SM, Stadler Z, Nathanson KL, Couch F, Garber JE, et al. Counselling framework for moderate-penetrance cancer-susceptibility mutations. Nat Rev Clin Oncol. 2016;13(9):581-588.

• Recognizing family history patterns associated with specific gene mutations is important
• A family history of invasive lobular cancer and gastric cancer may be associated with CDH1 mutations:
  • These mutations confer a 6.6 times greater risk of breast cancer than the general population and are associated with a high risk of hereditary diffuse gastric cancer (55% to 80%)
• Patients with CDH1 mutations:
  • Should be offered prophylactic gastrectomy and consideration of bilateral prophylactic mastectomy based on family history
  • If surgery is not pursued, guidelines for screening for gastric cancer include:
    • Yearly endoscopic surveillance with random mucosal biopsies
  • Breast screening consists of:
    • Annual mammogram and breast MRI
• References
  • Hansford S, Kaurah P, Li-Chang H, Woo M, Senz J, Pinheiro H, et al. Hereditary diffuse gastric cancer syndrome: CDH1 mutations and beyond. JAMA Oncol.2015;1(1):23-32.
  • Weiss A, Garber JE, King T. Breast cancer surgical risk reduction for patients with inherited mutations in moderate penetrance genes. JAMA Surg. 2018;153(12):1145-1146
  • van der Post RS, Vogelaar IP, Carneiro F, Guilford P, Huntsman D, Hoogerbrugge N, et al . Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers. J Med Genet. 2015;52(6):361-374.
  • National Comprehensive Cancer Network Guidelines. Genetic/familial high-risk assessment: breast and ovarian, Version 1/2018. https://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf. Accessed November 9, 2019.

• The Gail model:
  • Which is based on age, race/ethnicity, age at menarche, age at first live birth, number of prior breast biopsies, personal history of atypical hyperplasia, and family history of breast cancer in first-degree relatives:
    • Does not address and is not appropriate for patients with lobular carcinoma in situ (LCIS)
• The Tyrer-Cuzick model:
  • Incorporates age, nulliparity, family history, and LCIS
  • In addition, the Tyrer-Cuzick model incorporates:
    • BMI, age at menarche, age at menopause, hormone replacement therapy use, and prior breast biopsies
  • However, while the Tyrer-Cuzick model does incorporate personal history of atypical ductal hyperplasia and LCIS:
    • Data has emerged showing that this model appears to overestimate risk and has poor concordance among populations of women with high-risk breast lesions
  • This model does not accurately predict invasive breast cancer risk and should be avoided even if it may be the most accurate in assessing risk secondary to family history, among women with LCIS
  • Breast cancer risk among women with LCIS has been shown to be approximately 2% per year and modified by volume of LCIS
• BRCAPRO and BOADICEA:
  • Are both Mendelian models that estimate breast cancer risk based on the probability that the individual carries a mutation in a major breast cancer susceptibility gene, such as BRCA1 or BRCA2
  • The BOADICEA model incorporates 3rd-degree relatives, whereas the BRCAPRO only incorporates 1st- and 2nd-degree relatives
  • Neither of these models incorporate nulliparity or LCIS into the calculation
• References:
  • Gail MH, Brinton LA, Byar DP, Corle DK, Green SB, Schairer C, et al. Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst. 1989;81(24):1879-1886.
  • Tyrer J, Duffy SW, Cuzick J. A breast cancer prediction model incorporating familial and personal risk factors. Stat Med. 2004;23(7):1111-1130. [See comment in Stat Med. 2005;24:1610-1612; erratum appears in Stat Med. 2005;24:156].
  • Valero M, Zabor E, Park A, Gilbert E, Newman A, King TA, et al. The Tyrer-Cuzick Model inaccurately predicts invasive breast cancer risk in women with LCIS. Ann Surg Oncol. 2020;27(3):736-740.
  • Boughey JC, Hartmann LC, Anderson SS, Degnim AC, Vierkant RA, Reynolds CA, et al. Evaluation of the Tyrer-Cuzick (International Breast Cancer Intervention Study) model for breast cancer risk prediction in women with atypical hyperplasia. J Clin Oncol. 2010;28(22):3591-3596.
  • King TA, Pilewskie M, Muhsen S, Patil S, Mautner SK, Park A, et al. Lobular carcinoma in situ: a 29-year longitudinal experience evaluating clinicopathologic features and breast cancer risk. J Clin Oncol. 2015;33(33):3945-3952.
  • Berry DA, Parmigiani G, Sanchez J, Schildkraut J, Winer E. Probability of carrying a mutation of breast-ovarian cancer gene BRCA1 based on family history. J Natl Cancer Inst. 1997;89(3):227-238.
  • Antoniou AC, Pharoah PP, Smith P, Easton DF. The BOADICEA model of genetic susceptibility to breast and ovarian cancer. Br J Cancer. 2004;91(8):1580-1590.

• A combination of two HER2-targeted drugs – tucatinib and ado-trastuzumab emtansine (T-DM1), extended progression-free survival among patients with unresectable, locally advanced, or metastatic HER2-positive breast cancer compared with T-DM1 alone, according to results from the HER2CLIMB-02 trial presented at the 2023 San Antonio Breast Cancer Symposium (Abstract GS01-10).
• Study Background
  • T-DM1 is an antibody-drug conjugate consisting of trastuzumab and the cytotoxic drug emtansine. It was approved by the U.S. Food and Drug Administration for use as a monotherapy in 2013 for patients with late-stage HER2-positive breast cancer, and in 2019 for patients with early-stage HER2-positive breast cancer. However, not all patients have durable responses to T-DM1, and a combination approach may boost the drug’s efficacy.
• Tucatinib, a small-molecule inhibitor of HER2, has been shown to delay disease progression in the central nervous system, unlike most other HER2-targeted drugs. For patients with brain metastases, such a drug can make a significant difference.
  • HER2-positive breast cancer has a predilection to spread to the brain, and when this occurs, prognosis is poor.
  • Few options exist for the successful management of breast cancer brain metastases, making this an area of unmet need.
• HER2CLIMB and HER2CLIMB-02:
  • A previous trial, HER2CLIMB, found that the addition of tucatinib to a regimen containing the HER2-targeted antibody trastuzumab and the chemotherapy capecitabine significantly improved progression-free and overall survival in heavily pretreated patients, including those with brain metastases. This trial led to the 2020 approval of tucatinib, trastuzumab, and capecitabine by the U.S. Food and Drug Administration.
• In the phase III HER2CLIMB-02 trial, 463 patients with unresectable, locally advanced, or metastatic HER2-positive breast cancer were enrolled and randomly assigned to receive tucatinib plus T-DM1 (n = 228) or placebo plus T-DM1 (n = 235). Among these patients, 44.1% had brain metastases at baseline.
  • The median time to disease progression or death was 9.5 months for patients in the tucatinib arm and 7.4 months for patients in the placebo arm, with tucatinib plus T-DM1 reducing the risk of disease progression or death by 24.1%.
  • Among patients who had brain metastases at baseline, the median time to disease progression or death was 7.8 months for those in the tucatinib arm and 5.7 months for those treated in the placebo arm, with tucatinib plus T-DM1 reducing the risk of disease progression or death by 36.1%.
  • The overall survival data remain immature after a median of 24.4 months of follow-up.
  • The rate of certain treatment-related side effects, especially those related to liver and gastrointestinal function, was higher among patients treated with tucatinib than those treated with placebo, resulting in a higher rate of dose adjustments and treatment discontinuation in the tucatinib arm.
    • However, these effects were largely manageable with monitoring and clinical intervention.
  • This study is one of very few large breast cancer studies prospectively designed to evaluate novel systemic therapies in patients with brain metastases.
  • While there is much interest in improving outcomes for patients with HER2-positive breast cancer brain metastases, most studies evaluating systemic agents have been limited by a small size, a retrospective design, or an exploratory analysis of a larger study.
• Limitations of this study include as-yet immature overall survival data.
  • Further, the study was not designed to compare tucatinib plus T-DM1 to tucatinib plus trastuzumab and capecitabine or any regimens containing the antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (T-DXd).

• When patients are told they have a variant of unknown significance (VUS):
  • It can often lead to anxiety and overtreatment
• It is important to counsel patients that a VUS:
  • Is not clinically actionable and the majority of VUS are reclassified as benign
• Patients should be counseled to update their genetic counselors as their family history changes and keep contact information up to date as variant reclassification does occur
• The American College of Medical Genetics has recommended that genetic testing classify genetic variants using the following classification schema:
  • Deleterious (pathogenic)
  • Suspected deleterious (likely pathogenic)
  • Variant of Uncertain Clinical Significance
  • Genetic variant, favor polymorphism (likely benign)
  • Polymorphism (benign)
• While deleterious and suspected deleterious mutations of BRCA mutations:
  • Are known to be associated with an increased risk of breast and ovarian cancer:
    • It is unknown whether a BRCA VUS mutation is associated with an increased risk due to limited available data
    • As the use of genetic testing increases and as more of the population is tested, the knowledge base regarding variant pathogenicity constantly grows
• Given the amount of data available from many years of BRCA1 / BRCA 2 testing:
  • The prevalence of VUS among this population has declined to 2% to 5%:
    • However, among moderate and low penetrance genes:
      • The number of VUS continues to rise
    • As the data expand and knowledge regarding a variant evolves, a variant may be reclassified
• In a study reported in the Journal of the American Medical Association:
  • 25.4% of patients initially diagnosed with a VUS were reclassified over a 12-year period
  • Of these patients, 97% were downgraded to benign or likely benign
  • Three percent of patients were upgraded to pathogenic or likely pathogenic variants
• Given this low risk of reclassification to pathogenic mutation, risk-reducing mastectomy, salpingo-oophorectomy, or genetic testing of family members are not indicated for this patient
• There is currently no established effective screening protocol for pancreatic cancer, even among patients with a deleterious BRCA 2 mutation
• References:
  • Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424.
  • Hall MJ, Reid JE, Burbidge LA, Pruss D, Deffenbaugh AM, Frye C, et al. BRCA1 and BRCA2 mutations in women of different ethnicities undergoing testing for hereditary breast-ovarian cancer. Cancer. 2009;115(10):2222-2233.
  • Mersch J, Brown N, Pirzadeh-Miller S, Mundt E, Cox HC, Brown K, et al. Prevalence of variant reclassification following hereditary cancer genetic testing. JAMA. 2018;320(12):1266-1274.

• Receipt of mantle field radiation before the age of 30:
  • Is associated with a significantly increased risk of breast cancer compared to the general population
• Patients with a history of Hodgkin’s lymphoma treated with mantle field radiation therapy:
  • Are more likely to be diagnosed with breast cancer at a younger age, have hormone receptor negative breast cancer, and have a second breast cancer
  • Because the increased risk of breast cancer has been seen as early as 8 years following receipt of radiation therapy:
    • High risk screening after mantle field radiation therapy should begin at the age of 25 or 8 years after radiation therapy, whichever occurs later
  • The estimated cumulative incidence of breast cancer by the age of 50 among patients with a history of Hodgkin’s lymphoma treated with mantle field radiation therapy:
    • Is 35%
• Among all women at high risk for breast cancer:
  • Lifetime risk greater than 20%:
    • Annual screening MRI:
      • Has been associated with 77% to 100% sensitivity for detecting a new cancer
    • While mammography is associated with 16% to 40% sensitivity
• In 2007, the American Cancer Society convened an expert panel to review the evidence on MRI screening as an adjunct to annual mammography for women at high risk of developing breast cancer:
  • Annual screening MRI is recommended for patients with:
    • A clinical history of chest radiation between the ages of 10 and 30 years
    • Women with a known BRCA mutation
    • Untested first-degree relatives of BRCA mutation carriers
    • Those with other genetic mutations increasing breast cancer risk
    • Women with a greater than 20% lifetime risk secondary to family history
• The addition of bilateral breast ultrasound to a screening regimen of mammography and MRI:
  • Is associated with a substantial increase in false positives leading to additional biopsies with no incremental benefit over mammography and MRI alone
• There is insufficient evidence to recommend for or against annual screening breast MRI in women who have a history of:
  • Lobular carcinoma in situ
  • Atypical lobular hyperplasia
  • Atypical ductal hyperplasia
• There is no evidence to support MRI in women with:
  • Less than 15% lifetime risk of breast cancer
  • Dense breast tissue
  • Personal history of breast cancer
• References:
  • Veit-Rubin N, Rapiti E, Massimo U, Benhamou S, Vinh-Hung V, Vlastos G, et al. Risk, characteristics, and prognosis of breast cancer after Hodgkin’s lymphoma.Oncologist. 2012;17(6):783-791.
  • Henderson TO, Amsterdam A, Bhatia S, Hudson MM, Meadows AT, Neglia JP, et al. Systematic review: surveillance for breast cancer in women treated with chest radiation for childhood, adolescent, or young adult cancer. Ann Intern Med. 2010;152(7):444-455; w144-454.
  • Moskowitz CS, Chou JF, Wolden SL, Bernstein JL, Malhotra J, Novetsky Friedman D, et al. Breast cancer after chest radiation therapy for childhood cancer. J Clin Oncol.2014; 32(21):2217-2223.
  • Saslow D, Boetes C, Burke W, Harms S, Leach MO, Lehman CD, et al. American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin. 2007;57(2):75-89.
  • National Comprehensive Cancer Network. Breast Cancer Screening and Diagnosis, Version 1.2019. https://www.nccn.org/professionals/physician_gls/pdf/breast-screening.pdf. Accessed February 23, 2020.
  • Riedl CC, Luft N, Bernhart C, Weber M, Bernathova M, Tea MK, et al. Triple-modality screening trial for familial breast cancer underlines the importance of magnetic resonance imaging and questions the role of mammography and ultrasound regardless of patient mutation status, age, and breast density. J Clin Oncol. 2015;33(10):1128-1135.
  • van Zelst JCM, Mus RDM, Woldringh G, et al. Surveillance of Women with the BRCA1 or BRCA2 Mutation by Using Biannual Automated Breast US, MR Imaging, and Mammography. Radiology. 2017;285(2):376-388.

• Intraparotid lymph node metastases from an extraparotid tumor, usually skin neoplasms (e.g., basal cell carcinoma, melanoma, squamous cell carcinoma, Merkel cell carcinoma, etc.)
  • Regardless of the lobe in which the metastasis is found, but strictly necessary in those located in the deep lobe
• Intraparotid lymph node metastasis from a primary tumor of the parotid gland:
  • Regardless of the lobe in which the metastasis is identified, but strictly necessary in those located in the deep lobe
• Primary parotid gland tumor with metastasis to regional cervical nodes [N+]
• High-grade malignant primary tumor of the parotid gland with known high risk of regional lymph node metastasis
• Malignant primary tumor of the deep lobe of the parotid gland
• Benign primary tumor of the superficial lobe with extension to the deep lobe:
  • The latter scenario is usually managed, in most cases, by superficial parotidectomy associated with a partial excision of the deep lobe
• Benign primary tumor of the deep lobe requiring a superficial parotidectomy “of necessity” for excision (in other words, those in which it is not possible to perform a deep parotidectomy while preserving the superficial lobe)
• Malignant primary tumor of the parotid gland with invasion of surrounding soft tissues
• Primary tumor of the parotid gland with a high rate of multifocality (to ensure complete removal, e.g., oncocytomas).
• Bibliography:

1. Olsen KD, Moore EJ. (2014) Deep lobe parotidectomy: clinical rationale in the management of primary and metastatic cancer. Eur Arch Otorhinolaryngol. 271(5):1181-5.
2. Olsen KD, Quer M, de Bree R, Vander Poorten V, Rinaldo A, Ferlito A. (2017) Deep lobe parotidectomy-why, when, and how? Eur Arch Otorhinolaryngol. 274(12):4073-4078.
3. Thom JJ, Moore EJ, Price DL, Kasperbauer JL, Starkman SJ, Olsen KD. (2014) The Role of Total Parotidectomy for Metastatic Cutaneous Squamous Cell Carcinoma and Malignant Melanoma. JAMA Otolaryngol Head Neck Surg. 140(6):548-54.

• Ligation of Whartons duct in the mylohyoid-hyoglossal hiatus during submaxillectomy requires prior exposure of the lingual and hypoglossal nerves
• Landmarks:
  • 1. Submandibular canal
  • 2. Hypoglossal nerve
  • 3. Lingual nerve
  • 4. Eardrum cord
  • 5. Mylohyoid nerve
  • 6. Submental artery
  • 7. Frog veins (“of the hypoglossus”)
  • 8. Hyoglossal muscle (floor of the submandibular triangle)
  • 9. Anterior belly of the digastric muscle
  • 10. Facial artery
  • 11. Facial vein
  • 12. Posterior belly of the digastric muscle
  • 13. Projection of Jaffe’s mandibular marginal nerve
  • 14. Hayes-Martin manoeuvre
  • 15. Platysma muscle
  • 16. Sector of the venous vascular lamina over the hyoglossal muscle

• A small trial headed by MD Anderson Cancer Center, Houston, has helped to further identify women who can safely skip surgery after neoadjuvant therapy for early breast cancer.
• Among 50 women in the study with cT1, cT2, cN0, cN1, M0 triple negative or HER2-positive disease:
  • 31 (62%) had a complete pathologic response (pCR) to neoadjuvant therapy on image-guided vacuum-assisted core biopsy (VACB)
• They went onto whole breast radiation with a boost, but given their response to neoadjuvant treatment and the accuracy of VACB, the women did not have surgery
• So far, it seems to have been the right call:
  • At 3 years, there’s been no tumor recurrences and disease-free and overall survival are both 100%
• Eliminating breast surgery in highly-selected patients with image-guided VACB-determined pCR following” neoadjuvant systemic therapy has “very promising 3-year results:
  • This was presented by Henry M. Kuerer, MD, PhD, a breast cancer surgeon at MD Anderson, who presented the findings at the European Society for Medical Oncology (ESMO) 2023 annual meeting.
• The study speaks to a trend in breast cancer toward deescalation of treatment:
  • Particularly surgery:
    • To save women from the side effects of treatments they don’t need
• With the success of modern systemic therapy, it’s only natural that we think this way:
  • This study is really important:
    • It’s addressing a very important question whether we can omit surgery in certain groups of patients:
      • We do want to deescalate surgery, and the study results are “very good:
      • However, larger trials with longer follow-up are needed to draw any firm conclusions.

Study details

• Women in the trial were a median of 60.4 years old
• 58% had HER2-positive and the rest triple-negative unicentric breast cancer
• Mean baseline tumor size was 2.8 cm
• Just 12% of the participants had lymph node involvement
• Neoadjuvant systemic therapy was clinician’s choice
• Breast lesions had to shrink to less than 2 cm on imaging after systemic therapy to be eligible for the study
• A minimum of 12 cores had to be obtained on VACB
• The 38% of women in the study with residual disease after systemic treatment went on to surgery
• Two patients were circulating tumor cell (CTC)-positive at baseline, two were positive at 6 months, and one at 12 months
• No patients had CTCs detected at more than one timepoint
• The work was funded by the National Cancer Institute

Samadder NJ, et al. JAMA Oncol. 2021;7(2):230‑237. doi:10.1001/jamaoncol.2020.6252

More than 1 in 4 patients with inherited variants in high‑risk cancer genes had changes to medical management based on their test results, including chemotherapy and surgical decisions.⁶

If a patient has cancer, a positive result^6‑8:

• May open the door for more personalized care options that can be tailored for your particular cancer
• May provide access to clinical trials
• May help to estimate risk for developing another cancer, which may impact care or screening recommendations for patients both now and in the future