Merkel Cell Carcinoma (MCC)

  • MCC:
    • Also known as primary small-cell carcinoma of the skin and anaplastic carcinoma of the skin:
      • Is a rare, aggressive cutaneous malignancy
  • Risk factors for MCC include:
    • Immunosuppression:
      • Human immunodeficiency virus (HIV) infection
      • Cancer
      • Organ transplant
    • Chemotherapy
    • Radiation
    • Arsenic
    • Sun exposure
  • Approximately 80% of Merkel cell tumors:
    • Harbor a polyoma virus:
      • But its role in pathogenesis remains unclear
  • The cornerstone of management for MCC is:
    • Wide local excision with a margin of 1 to 2 cm
    • Nodal staging in clinically node-negative patients:
      • Is a subject of controversy:
        • About one third of the patients with MCC will have a positive SLN:
          • SLN biopsy does not appear to have an impact on survival but does improve local control
        • On the basis of the current evidence, National Comprehensive Cancer Network guidelines:
          • Recommend routine SLN biopsy for clinically node-negative MCC
  • MCC is an extremely radiosensitive tumor:
    • A recent randomized study for stage 1 Merkel cell carcinoma:
      • Showed significant reduction on regional recurrence with radiation
    • A retrospective Surveillance, Epidemiology, and End Results (SEER) database study:
      • Demonstrated an improvement in survival for patients who received adjuvant radiation:
        • This effect was more pronounced in the 2 cm tumors
      • Recommendations for adjuvant radiation after appropriate surgical resection are still unclear:
        • However, adjuvant radiation therapy to the primary tumor site should be considered for:
          • Larger ( greater than 1 cm) tumors with adverse features such as:
            • Perineural invasion and lymphovascular invasion
        • In high-risk cases that omit a SLN biopsy:
          • Radiation to nodal basin is recommended
      • Regional lymph node dissection and / or nodal irradiation is recommended for patients with nodal metastases;
        • However, for resectable lesions there is no role for neoadjuvant radiation therapy
  • References:
    • Gupta SG, Wang LC, Peñas PF, Gellenthin M, Lee SJ, Nghiem P. Sentinel lymph node biopsy for evaluation and treatment of patients with Merkel cell carcinoma: The Dana-Farber experience and meta-analysis of the literature. Arch Dermatol. 2006;142:685-690.
    • Jouary T, Leyral C, Dreno B, et al. Adjuvant prophylactic regional radiotherapy versus observation in stage I Merkel cell carcinoma: A multicentric prospective randomized study. Ann Oncol. 2012;23:1074-1080.
    • Mehrany K, Otley CC, Weenig RH, Phillips PK, Roenigk RK, Nguyen TH. A meta-analysis of the prognostic significance of sentinel lymph node status in Merkel cell carcinoma. Dermatol Surg. 2002; 28:113-117.Mojica P, Smith D, Ellenhorn JD. Adjuvant radiation therapy is associated with improved survival in Merkel cell carcinoma of the skin. J Clin Oncol. 2007;25:1043-1047.

Lumpectomy Plus Tamoxifen With or Without Irradiation in Women Age 70 Years or Older With Early Breast Cancer: Long-Term Follow-Up of CALGB 9343

  • Radiation therapy (RT) after breast-conserving surgery (BCS):
    • Decreases the risk of ipsilateral breast recurrence (IBTR)
  • Several studies have suggested that there exists a favorable subgroup of patients:
    • In whom irradiation may not provide meaningful overall benefit, including but not limited to:
      • Older women with smaller estrogen receptor (ER)–positive cancers treated with anti-hormonal therapy
  • To test this hypothesis, the Cancer and Leukemia Group B (CALGB) initiated CALGB 9343
    • A randomized trial comparing the efficacy of:
      • Tamoxifen alone (Tam) with tamoxifen plus RT (TamRT) in older women with ER-positive, clinical stage I breast cancer
  • When reported in 2004 (median follow-up, 5 years):
    • The 5-year incidence of IBTR or regional nodal recurrence was:
      • 4% for patients receiving Tam
      • 1% for those receiving TamRT
    • There was no difference in:
      • Survival
      • Time to distant metastasis
      • Ultimate breast-preservation rate
    • Examining Medicare data through 2007, Soulis et al found:
      • That CALGB 9343 report:
        • Had little impact, with the use of irradiation:
          • Only slightly diminishing in this population:
            • Because it was possible that with longer-term follow-up the results of the CALGB 9343 trial might not persist:
              • The CALGB 9343 trial performed a longterm analysis to address these concerns
  • The methods of the CALGB 9343 trial study have been previously described:
    • CALGB 9343 was designed in cooperation with the Eastern Cooperative Oncology Group (ECOG) and Radiation Therapy Oncology Group (RTOG)
    • Local institutional review boards reviewed and approved the study in compliance with the Declaration of Helsinki
    • Written informed consent was obtained from all patients.
    • An independent data and safety monitoring committee provided oversight
    • The CALGB Statistical Center managed data collection, and data quality was ensured by the study chairperson and statistical center review
    • CALGB statisticians performed the statistical analyses
    • The CALGB quality-assurance program has been previously described
    • Patient Selection:
      • Women age 70 years or older with clinical stage I, ER-positive breast cancer and no history of cancer other than in situ cervical or non melanoma skin cancer within 5 years were eligible
      • Initial eligibility criteria included breast cancers up to 4 cm regardless of estrogen receptor status, but this was reduced in August 1996 to equal or less 2 cm (T1) with ER-positive or indeterminate receptor status
      • Patients were required to have clinically negative axillae
    • Treatment:
      • At entry, patients were randomly assigned (1:1 ratio) to receive Tam or TamRT
      • Random assignment was stratified by age (less 75 years vs equal or greater than 75 years) and axillary dissection (yes vs no)
      • Patients were observed every 4 months for 5 years and yearly thereafter
      • This study did not rigorously capture tamoxifen discontinuation
      • Local therapy:
        • All women underwent lumpectomy with a clear margin (absence of tumor at the inked margin)
        • Axillary node dissection was allowed but not encouraged
        • RT included tangential fields to the entire breast followed by an electron boost to the lumpectomy site
      • Tamoxifen:
        • All women received 20 mg of tamoxifen per day for 5 years:
          • Initiated either during or after irradiation
        • Adjuvant hormonal treatment beyond 5 years was discretionary
    • Study End Points:
      • The primary study end points were time to locoregional recurrence, frequency of mastectomy for recurrence, breast cancer–specific survival, time to distant metastasis, and overall survival (OS)
      • IBTR was defined as any cancer in the ipsilateral breast
      • Regional recurrence was defined as any recurrence in the ipsilateral supraclavicular, infraclavicular, or axillary nodes
      • Secondary end points were:
        • Cosmetic results, as judged by physician and patient, and adverse effects such as breast pain and skin changes
    • Actuarial Survival:
      • The expected proportion of women in this study who would be alive at each year after random assignment was found assuming the women were randomly sampled from women of the same age in the general population
      • They used the 2001 period life table of the US Social Security Administration (approximate middle of follow-up for this study)
      • They compared actual survival proportion and its confidence limits over time after random assignment of women in the study with their actuarial survival distribution
  • Results:
    • The study was initiated by the CALGB (July 1994) and by the RTOG and ECOG (December 1996)
    • Enrollment ended in February 1999 with 647 women:
      • CALGB, 307; ECOG, 112; and RTOG, 228 women
      • Eleven patients (2%) never began protocol treatment
      • Statistical analyses used a modified intent-to-treat approach that included all 636 patients who began protocol treatment:
        • 317 with TamRT and 319 with Tam
      • Before the eligibility change, 10 patients with ER-negative tumors and 13 patients with tumors greater than 2 cm were entered
      • Baseline characteristics of the women were similar in the two groups
      • As of January 2011, median follow-up was 12.6 years (maximum, 16.5 years)
      • Of the 636 treated patients:
        • 335 (53%) survived at least 10 years:
          • 227 of whom remain in active follow-up
      • Because the observed treatment effect was similar when assessed by both log-rank and multivariate methods, they quote the values from only the log-rank test
      • Time to Locoregional Recurrence:
        • As compared with the Tam group:
          • The TamRT group experienced a significantly longer time to locoregional recurrence (observed HR, 0.18; 95% CI, 0.07 to 0.42; < .001)
        • At 10 years:
          • 90% of patients in the Tam group (95% CI, 85% to 93%) compared with 98% in the TamRT group (95% CI, 96% to 99%):
            • Were free from locoregional recurrence
          • Thirty-two women in the Tam group experienced locoregional recurrence:
            • Of these, 20 had only IBTR
            • Six, IBTR with distant metastasis
            • Five, only axillary recurrence
            • One, both IBTR and axillary recurrence
          • Six women in the TamRT group experienced locoregional recurrence:
            • All six were IBTRs
        • At 10 years:
          • 91% in the Tam group (95% CI, 87% to 94%) compared with 98% in the TamRT group (95% CI, 96% to 99%) were free from local (IBTR) recurrence
          • There were no axillary recurrences among the 244 women who underwent initial axillary dissection
          • Among those who did not undergo axillary dissection:
            • There were no axillary recurrences in the TamRT group
            • There were six of 200 in the Tam group
      • Treatment of IBTR:
        • Six patients receiving TamRT and 27 receiving Tam had in-breast recurrences (IBTRs):
          • Of these, four (TamRT) and 10 (Tam) underwent mastectomy
          • One patient in the TamRT arm underwent lumpectomy without RT
          • 13 in the Tam arm underwent lumpectomy (four without RT, eight with RT, and one unknown RT)
      • Time to Mastectomy:
        • Time to mastectomy did not differ significantly between the two treatment groups (observed HR, 0.50; 95% CI, 0.17 to 1.48; 􏰅 .17)
        • The 10-year probability of not undergoing mastectomy was 98% (95% CI, 96% to 99%) in the TamRT group and 96% (95% CI, 93% to 98%) in the Tam group
      • Time to Distant Metastasis:
        • Time to distant metastasis did not differ significantly between the two treatment groups (< .50;); distant relapse occurred in 21 patients in the TamRT group (13 have died as a result of breast cancer) and 16 in the Tam group (eight have died as a result of breast cancer)
        • The 10-year probability of freedom from distant metastasis was 95%
      • Survival:
        • Of the 636 women in the trial, there were 334 deaths:
          • 166 in the TamRT arm and 168 in the Tam arm (HR, 0.95; 95% CI, 0.77 to 1.18)
          • The respective 10-year estimates of OS were:
            • 67% (95% CI, 62% to 72%) and 66% (95% CI, 61% to 71%)
          • Only 21 of the deaths (6.3%) resulted from breast cancer:
            • 13 in the TamRT arm and eight in the Tam arm (HR, 1.55; 95% CI, 0.64 to 3.74)
          • The respective 10-year breast cancer–specific survival estimates were:
            • 97% (95% CI, 94% to 99%) and 98% (95% CI, 95% to 99%)
  • Conclusion:
    • Long-term follow-up of CALGB 9343 confirms and extends the earlier report that in women age equal or greater than 70 years with clinical stage I, ER-positive breast cancer treated with lumpectomy followed by tamoxifen:
      • Irradiation adds no significant benefit in terms of survival, time to distant metastasis, or ultimate breast preservation, even though it provides a small decrease in IBTR

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Suprahyoid Muscles

  • The suprahyoid muscles are a group of four muscles:
    • Located superior to the hyoid bone of the neck
  • They all act to elevate the hyoid bone:
    • An action involved in swallowing
  • The arterial supply to these muscles:
    • Is via branches of the facial artery, occipital artery, and lingual artery
  • Stylohyoid muscle:
    • Is a thin muscular strip:
      • Which is located superiorly to the posterior belly of the digastric muscle
    • Attachments: 
      • Arises from the styloid process of the temporal bone
      • Attaches to the lateral aspect of the hyoid bone
    • Actions:
      • Initiates a swallowing action:
        • By pulling the hyoid bone in a posterior and superior direction
    • Innervation:
      • Stylohyoid branch of the facial nerve (CN VII)
        • This arises proximally to the parotid gland
  • The digastric muscle:
    • Is comprised of two muscular bellies:
      • Which are connected by a tendon:
        • In some cadaveric specimens, this tendon can be seen to pierce the stylohyoid muscle
    • Attachments: 
      • The anterior belly arises from the digastric fossa of the mandible
      • The posterior belly arises from the mastoid process of the temporal bone
    • The two bellies are connected by an intermediate tendon:
      • Which is attached to the hyoid bone via a fibrous sling
    • Actions:
      • Depresses the mandible and elevates the hyoid bone
    • Innervation:
      • The anterior belly is innervated by the inferior alveolar nerve:
        • A branch of the mandibular nerve:
          • Which is derived from the trigeminal nerve, CN V
      • The posterior belly:
        • Is innervated by the digastric branch of the facial nerve
  • Mylohyoid muscle:
    • Is a broad, triangular shaped muscle
    • It forms the floor of the oral cavity and supports the floor of the mouth
    • Attachments:
      • Originates from the mylohyoid line of the mandible
      • Attaches onto the hyoid bone
    • Actions:
      • Elevates the hyoid bone and the floor of the mouth
    • Innervation:
      • Inferior alveolar nerve:
        • A branch of the mandibular nerve:
          • Which is derived from the trigeminal nerve
  • Geniohyoid muscle:
    • Is located either side of the midline of the neck:
      • Deep to the mylohyoid muscle
    • Attachments:
      • Arises from the inferior mental spine of the mandible
      • It then travels inferiorly and posteriorly to attach to the hyoid bone
    • Actions:
      • Depresses the mandible and elevates the hyoid bone
    • Innervation:
      • C1 nerve roots that run within the hypoglossal nerve
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ATAC Trial

  • The Arimidex, Tamoxifen, Alone or in Combination trial (ATAC):
    • Was designed to compare the efficacy and safety of anastrozole (1 mg) with tamoxifen (20 mg):
      • As adjuvant treatment for postmenopausal women with early-stage breast cancer
    • Patients were treated every day for 5 years
    • The study was a double-blind, prospective, randomized trial:
      • With 9,366 postmenopausal women
    • A proportional hazards model was used to assess the:
      • Primary endpoints of:
        • DFS
      • Secondary endpoints of:
        • Time to recurrence
        • Time to distant recurrence
        • Overall survival
        • Death with or without recurrence
    • The combination arm of anastrozole and tamoxifen:
      • Was discontinued after the initial analysis as it was found to have no efficacy or tolerability benefits over tamoxifen alone
  • Long-term follow-up of 120 months:
    • Showed significant improvements in the anastrozole group versus the tamoxifen group for:
      • DFS
      • Time to recurrence
      • Time to distant recurrence
    • In hormone receptor-positive patients:
      • These benefits were seen to increase over time
    • Recurrence rates:
      • Were found to remain lower on anastrozole after treatment was completed
    • There was little difference in overall survival between anastrazole and tamoxifen:
      • Hazard ratio, 0.95; 95% confidence interval, 0.84–1.06; P=0.4
  • Fractures:
    • Were more frequent during the active treatment in patients receiving anastrozole:
      • But were similar between the two groups in post-treatment follow-up
  • Treatment-related serious adverse events were less common in the anastrozole group:
    • But were also found to be similar between the two groups after treatment completion
  • Anastrozole showed a non-significant increased incidence of colorectal cancer and lung cancers, and a decreased incidence of endometrial, melanoma, and ovarian cancers:
    • However, only the decrease in endometrial cancers remained statistically significant after Bonferroni correction (P<0.001)
  • Overall, anastrozole was found to have superior long-term efficacy and safety than tamoxifen:
    • As initial adjuvant therapy for postmenopausal women with hormone-sensitive early-stage breast cancer
  • Outcomes from the ATAC trial:
    • Made anastrozole the preferred treatment for postmenopausal women with localized hormone receptor-positive breast cancer
  • References
    • Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF, et al. Results of the ATAC (arimidex, tamoxifen, alone or in combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet. 2005;365(9453):60-62.
    • Cuzick J, Sestak I, Baum M, Buzdar A, Howell A, Dowsett M, et al; ATAC/LATTE Investigators. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol. 2010;11(12):1135-1141.

Melanoma of the Anal Canal

  • Melanoma of the anal canal:
    • Is rare:
      • Of all melanomas diagnosed:
        • Only 0.4% to 1.6% arise in the anal canal
  • Lesions tend to be diagnosed at an advanced stage:
    • With the onset of symptoms such as pruritus and bleeding
  • Often, these tumors are diagnosed in a delayed fashion:
    • Because of confusion with more common lesions of the anal canal:
      • Such as hemorrhoids
  • Once a biopsy specimen was evaluated, the histology and immunohistochemistry was diagnostic of an anal melanoma:
    • A staging work-up in the form of cross-sectional imaging:
      • Is the standard of care for determining whether distant or regional disease may be present
    • If staging studies are negative for metastatic disease:
      • Then the next step is to control the primary lesion:
        • There are two reasonable options for controlling the primary lesion in the setting of anal canal melanoma:
          • Abdominoperineal resection or local excision
        • Both are accepted practices; however, over the past several decades, there has been a trend toward less aggressive surgery:
          • In the form of local excision
        • The findings of retrospective studies support a less aggressive approach:
          • Because of a lack of difference in overall or disease-free survival between groups treated with either radical surgery or local excision:
            • Ross et al reported on 26 patients with anal melanoma treated with either radical surgery (abdominoperineal resection) or local excision and found no difference in overall and recurrence-free survival between the two groups
  • References:
    • Iversen K, Robins RE. Mucosal malignant melanomas. Am J Surg. 1980;139:660-664.
    • Nigro ND, Vaitkevicius VK, Considine B Jr. Combined therapy for cancer of the anal canal: a preliminary report. Dis Colon Rectum. 1974;17:354-356.
    • Ross M, Pezzi C, Pezzi T, Meurer D, Hickey R, Balch C. Patterns of failure in anorectal melanoma: a guide to surgical therapy. Arch Surg. 1990;125:313-316.

High Risk for Regional Recurrence for Melanoma Patients Who Underwent Lymphadenectomy

  • Patients considered at high risk for regional recurrence following lymphadenectomy for melanoma:
    • May be considered for adjuvant radiation:
      • Which may decrease regional recurrence:
        • By approximately 50%
  • High-risk patients include:
    • Those with extranodal spread
    • Multiple nodes involved:
      • ≥ 2 nodes in the neck or axilla
      • ≥ 3 nodes in the inguinal basin
    • Those with large positive nodes:
      • ≥ 3 cm nodes in the neck
      • ≥ 4 cm in the inguinal or axillary basins
  • While adjuvant radiation may decrease regional recurrence by approximately 50%:
    • There is no survival benefit seen
  • Radiation is known to increase the rate of lymphedema
  • References:
    • Burmeister BH, Henderson MA, Ainslie J, et al. Adjuvant radiotherapy versus observation alone for patients at risk of lymph-node field relapse after therapeutic lymphadenectomy for melanoma: a randomised trial. Lancet Oncol. 2012; 13(6): 589-97.

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Metastasectomy Metastatic Melanoma

  • Despite recent advances in systemic therapy for advanced melanoma:
    • This disease will eventually fail to respond to systemic therapies in the majority of patients with stage IV disease:
      • And surgical resection (metastasectomy) thus remains an important consideration
    • The findings of retrospective series and prospective registries:
      • Have confirmed that long-term survival is possible for a substantial minority of appropriately selected patients who have resection for stage IV disease
    • With appropriate patient selection, metastasectomy:
      • May be the initial preferred modality rather than systemic therapy
    • A history of significant autoimmune disease, such as colitis:
      • Could exclude a patient from consideration of checkpoint blockade drugs:
        • However, metastasectomy would be a reasonable consideration even in patients who are candidates for systemic treatment
  • Appropriate selection of candidates for metastasectomy is crucial:
    • Although solitary metastases are most favorable:
      • The presence of more than one nodule is not an absolute contraindication to resection
      • Selection factors include:
        • The extent of disease:
          • The number of metastases
          • The number of involved sites
        • The tumor growth rate or doubling time
        • The patient’s comorbidities
        • It must be possible to remove all evident disease:
          • As incomplete resection of metastases has not been beneficial in some patients relative to nonsurgical treatment
        • Palliative intent is another potential indication for surgery in stage IV melanoma:
          • But this is not the only indication for surgery
  • References:
    • Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-2616.
    • Morton DL, Foshag LJ, Hoon DS, et al. Prolongation of survival in metastatic melanoma after active specific immunotherapy with a new polyvalent melanoma vaccine. Ann Surg. 1992;216:463-482.
    • Ollila DW. Complete metastasectomy in patients with stage IV metastatic melanoma. Lancet Oncol. 2006;7:919-924.
    • Sosman JA, Moon J, Tuthill RJ, et al. A phase 2 trial of complete resection for stage IV melanoma: Results of Southwest Oncology Group Clinical Trial S9430. Cancer. 2011;117:4740-4746.
  • The NSABP P-2, or the Study of Tamoxifen and Raloxifene trial (STAR trial):
    • Enrolled 19,747 postmenopausal women:
      • With a 5-year Gail risk assessment score of 1.66%:
        • For the development of invasive breast cancer at 5 years
    • The women were randomized to receive:
      • 20 mg of tamoxifen plus placebo or 60 mg of raloxifene plus placebo
    • The updated results of the STAR trial:
      • Median follow-up 81 months
      • Reported more cases of invasive breast cancer in the raloxifene group than the tamoxifen group:
        • Risk ratio [RR]: 1.24; 95% confidence interval [CI]: 1.05–1.47:
          • Demonstrating that raloxifene is about 76% as effective as tamoxifen in reducing breast cancer risk
      • There were significantly fewer cases of invasive uterine cancer with raloxifene compared to tamoxifen:
        • RR: 0.55; 95% CI, 0.36–0.83
      • Thromboembolic events occurred less often in the raloxifene group:
        • RR: 0.75; 95% CI: 0.6–0.93
      • There were fewer cataracts and cataract surgeries in the women taking raloxifene:
        • RR: 0.79; 95% CI: 0.68–0.92
      • Importantly, there was no significant difference in mortality between the two groups.

References

1. Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS, Atkins JN, et al; for the National Surgical Adjuvant Breast and Bowel Project (NSABP). Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA. 2006;295(23):2727-2741.

2. Vogel VG. The NSABP Study of Tamoxifen and Raloxifene (STAR) trial. Expert Rev Anticancer Ther. 2009;9(1):51-60.

3. Mamounas EP, Wicherham DL, Fisher B, Geyer CE, Julian TB, Wolmark N. The NSABP experience. In: Kuerer HM, ed. Kuerer’s Breast Surgical Oncology. New York, NY: McGraw-Hill Companies; 2010:475-508.

Does Tamoxifen Work in ER Negative Tumors?

  • Several preclinical studies have demonstrated that tamoxifen acts:
    • Not only by blocking the ER pathway:
      • But also by modulating the production of:
        • Transforming growth factor-alpha
        • Transforming growth factor-beta
        • By increasing the levels of sex hormone-binding globulin in serum
        • Increasing natural killer cell counts
        • By decreasing insulin-like growth factor
  • The NSABP protocol B-23:
    • Was developed to determine whether:
      • Tamoxifen has a role in patients with ER negative cancer
    • Patients with ER negative tumors were randomized to:
      • Four cycles of adjuvant doxorubicin and cyclophosphamide (AC) or 6 cycles of adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) with or without tamoxifen
    • The results of B-23 demonstrated:
      • No significant improvement in DFS or overall survival (OS) with tamoxifen added to chemotherapy:
        • DFS:
          • CMF, 83%; CMF plus tamoxifen, 83%
          • AC, 83%; AC plus tamoxifen, 82%
        • OS:
          • CMF, 89%; CMF plus tamoxifen, 89%
          • AC, 90%; AC plus tamoxifen, 91%
      • Additionally, protocol B-23 confirmed the results of protocol B-15:
        • That found that four cycles of AC are equivalent to 6 cycles of CMF in terms of DFS and OS
  • NSABP B-24:
    • Also demonstrated the effectiveness of tamoxifen only on ER+ ductal carcinoma in situ (DCIS):
      • As did a study by Allred et al. on the risk reduction of a subsequent breast cancer in ER+ DCIS treated with tamoxifen

References

1. Fisher B, Anderson S, Tan-Chiu E, Wolmark N, Wickerham DL, Fisher ER,et al. Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-23. J Clin Oncol. 2001;19(4):931-942.

2. Wapnir IL, Dignam JJ, Fisher B, Mamounas EP, Anderson SJ, Julian TB, et al. Long-term outcomes of invasive ipsilateral breast tumor recurrences after lumpectomy in NSABP B-17 and B-24 randomized clinical trials for DCIS. J Natl Cancer Inst. 2011;103(6):478-488.

3. Allred DC, Anderson SJ, Paik S, Wickerham DL, Nagtegaal ID, Swain SM, et al. Adjuvant tamoxifen reduces subsequent breast cancer in women with estrogen receptor-positive ductal carcinoma in situ: a study based on NSABP protocol B-24. J Clin Oncol. 2012;30(12):1268-1273.

Atypical Lobular Hyperplasia (ALH)

  • ALH is generally an incidental finding:
    • Without specific defining characteristics on mammography, ultrasound, or MRI
  • A palpable breast mass which yields ALH at core needle biopsy:
    • Is not clinically concordant and should prompt further diagnostic workup with a second biopsy:
      • Either core or excisional
  • ALH alone confers a 4 to 5 fold increased risk of breast cancer
  • Risk reducing mastectomy (RRM):
    • Can be considered in patients with a lifetime risk of breast cancer ≥ 20% based on history of:
      • ADH / ALH or family history:
        • But this risk must be quantified using a risk assessment tool such as the Gail or Tyrer-Cuzick model
  • ALH should only be considered for observation:
    • When it is diagnosed incidentally and there is radiologic, pathologic, and clinical concordance
  • Relevant indications for genetic testing include:
    • Personal history of breast cancer ≤ 45 years of age
    • Triple negative breast cancer ≤ 60 years of age
    • A first-degree relative with breast cancer ≤ 50 years of age
    • Two or more first- or second-degree relatives with breast cancer at any age
    • Patient or relative with bilateral breast cancer
    • Male breast cancer in a relative at any age
  • The Gail Model:
    • Should only be used in patients ≥ 35 years of age:
      • May underestimate risk in patients with strong family history or non-Caucasian ethnicity
  • The Tyrer-Cuzick model:
    • May be more appropriate in this setting
  • References:
    • Morrow M, Schnitt SJ, Norton L. Current management of lesions associated with an increased risk of breast cancer. Nat Rev Clin Oncol. 2015; 12: 227-238. National Comprehensive Cancer Network (NCCN) Guidelines (Login Required): Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 1.2021. Breast Cancer Risk Reduction, Version 1.2020.