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• Patients present with a painless lump and are often unsure as to its duration:
  • The increased size of the goiter can lead to symptoms related to pressure effects on adjacent structures such as:
    • Dysphagia (from pharyngeal and/or esophageal compression)
    • Globus sensation
    • Hoarseness (from laryngeal or recurrent laryngeal nerve compression)
    • Shortness of breath (from tracheal deviation and compression)
• An incidental thyroid nodule (ITN) is one of the most common incidental findings on imaging studies that include the neck:
  • Guidelines have been developed to assist the medical provider in deciding when and how to investigate ITN

• The overall significant complication rate from sentinel lymph node dissection reported from the ACOSOG Z0010 trial:
  • Was low, with 32% of patients reporting at least one surgical side effect and less than 1% of patients requiring hospitalization
  • The most common surgical side effect was axillary paresthesia:
    • Affecting 307 (8.6%) of 3,573 patients
  • Allergic reaction was reported in less than 1% related to the administration of lymphazurin blue dye
  • Lymphedema in 7%
  • Brachial plexus injury in less than 1% of patients
  • Only one anaphylactic reaction to blue dye was reported
• References
  • Hunt KK, Ballman KV, McCall LM, Boughey JC, Mittendorf EA, Cox CE, et al. Factors associated with local-regional recurrence after a negative sentinel node dissection: results of the ACOSOG Z0010 trial. Ann Surg. 2012;256(3):428-436.
  • Boughey JC, Hunt KK. The ACOSOG experience. In: Kuerer HM, ed. Kuerer’s Breast Surgical Oncology. New York, NY: McGraw-Hill Companies; 2010:517-530.

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• Active transport of iodine (I-) into the thyroid follicular cells:
  • Is mediated by the Na/I symporter (NIS)
• Intracellular accumulated iodide ion is then passively translocated across the apical membrane into the colloid:
  • Via pendrin proteins and Cl channels
• The effluxed iodide ion becomes covalently attached to thyroglobulin:
  • Mediated by thyroperoxidase (TPO)
• Further iodinization of tyrosine molecules on the thyroglobulin glycoprotein then occurs via TPO forming:
  • Monoiodotyrosines (MIT) and diiodotyrosines (DIT):
    • Which are then coupled to create the bioactive thyroid hormones T4 and T3:
      • Again catalyzed via TPO
• Colloid is taken up into the follicular cell by:
  • Micropinocytosis
• Through digestion of this thyroglobulin by:
  • Lysosomal extracts and a resulting proteolytic breakdown of the thyroglobulin:
    • T4 and T3 are released into the cytoplasm
• Finally T4 and T3 are transported into the circulation by a hormone transporter:
  • Monocarboxylate transporter 8 (MCT8)

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• The 21-gene recurrence-score assay (e.g., Oncotype DX, Genomic Health):
  • Is one of several commercially available gene-expression assays:
    • That provide prognostic information in hormone-receptor-positive breast cancer
• The assay originally set cut points for:
  • Low risk at a recurrence score < 18
  • Intermediate risk at 18 to 30
  • High risk at > 31
• It is predictive of chemotherapy benefit when:
  • The recurrence score (RS) is high (> 26), and prognostic for very low rates of distant recurrence (2% at 10 years) when the RS is low (< 10)
• The TAILORx prospective randomized clinical trial:
  • Was completed to determine whether chemotherapy is beneficial for women:
    • With an intermediate RS of 11 to 25
  • The cutoffs for this trial were adjusted to ensure all patients in the intermediate range who may benefit were included
  • At 9 years of follow-up:
    • The endocrine therapy only and the chemo-endocrine therapy group:
      • Had similar rates of invasive disease-free survival:
        • 83.3% vs. 84.3% respectively
    • The endocrine therapy alone was noninferior to chemoendocrine therapy for all patients in the intermediate RS study group
    • The two groups also had similar outcomes in freedom from disease recurrence at a distant or locoregional sites
    • However, the chemotherapy benefit for invasive disease-free survival varied with the combination of recurrence score and age (P=0.004):
      • With some benefit of chemotherapy found in women 50 years old or younger with an RS of 16 to 25
      • In women less than 50 receiving chemotherapy demonstrated a lower rate of distant recurrence than endocrine therapy if RS was 16 to 20 (percentage-point difference, 0.8 at 5 years and 1.6 at 9 years) or 21 to 25 (percentage-point difference, 3.2 at 5 years and 6.5 at 9 years)
      • Overall survival however remained similar
  • For this reason, researchers conclude that the 21-gene assay can identify women with ER postive early-stage breast cancer:
    •  Who may be spared chemotherapy if they are over 50 years old with an RS of 25 or lower, as well as women 50 years or younger with RS of 15 or lower
• References
  • Sparano JA, Gray RJ, Makower DF, Pritchard K, Albain KS, Hayes DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018;379(2):111-121.

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• A multi-institution, prospective randomized trial:
  • From participating Cancer Care Ontario centers was performed from 1993 to 1996
• The study sought to determine whether:
  • Accelerated hypofractionated whole-breast irradiation (WBI) was as effective as conventional 5-week fractionation
• Included in the study were women who received:
  • Breast-conserving surgery (BCS) for invasive breast cancer with clear surgical margins and negative axillary nodes
• Participants were randomly assigned to receive:
  • WBI either at the standard dose of 50.0 Gy in 25 fractions over 35 days (control group), or at a dose of 42.5 Gy in 16 fractions over 22 days (hypofractionated-radiation group)
  • The control group included 612 patients and the hypofractionation group had 622 patients
• Results from this study indicated:
  • That the Canadian regimen was not inferior to the standard 5-week treatment regimen for women who received BCS for invasive breast cancer with clear surgical margins and negative axillary nodes
  • The risk of local recurrence at 10 years was:
    • 6.7% in the control group and 6.2% in the hypofractionated group
  • Cosmesis at 10 years was found to be comparable between the 2 groups:
    • With good or excellent outcomes for 71.3% of women in the control group and 69.8% in the hypofractionated-radiation group
  • There was also no difference between the 2 groups in overall survival and no increase in cardiac-related deaths was seen in the hypofractionated group
• References
  • Whelan TJ, Pignol J-P, Levine MN, Julian JA, MacKenzie R, Parpia S, et al. Long-term results of hypofractionated radiation therapy for breast cancer. N Engl J Med. 2010;362(6):513-520

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• The NCIC-CTG MA.20 trial:
  • Randomized 1,832 high-risk women who were treated with breast-conserving surgery and sentinel node biopsy (SLNB) or axillary lymph node dissection (ALND) to:
    • Either WBI alone or WBI plus regional nodal irradiation (RNI)
    • Axillary lymph node dissection was required for any patients with a positive SLN
    • RNI included the:
      • Internal mammary nodes
      • Supraclavicular nodes
      • High axillary nodes
  • The trial enrolled patients with node-positive or high-risk node-negative disease
  • Eighty-five percent of patients had 1 to 3 positive nodes, 5% had more than 4 positive nodes, and 10% were node negative
  • Node-negative patients:
    • With tumors greater than or equal to 2 cm who had fewer than 10 axillary nodes removedwere considered high risk if they had at least one of the following:
      • ER negative
      • Lymphovascular invasion
      • Nuclear grade 3
  • All patients had systemic therapy.
  • With a median follow-up of 10 years:
    • The addition of RNI improved:
      • Locoregional DFS from 92.2% to 95.2% (P=0.009)
      • Distant DFS from 82.4% to 86.3% (P=0.03)
    • There was no difference in OS from 81.8% to 82.8% (P=0.38)
    • The addition of RNI to WBI was associated with:
      • An increase in grade 2 or greater pneumonitis from 0.2% to 1.2% (P=0.01) and lymphedema from 4.5% to 8.4% (P=0.001)
• Similarly, European Organisation for Research and Treatment of Cancer (EORTC) 22922:
  • Randomized 4004 women undergoing breast-conserving surgery or mastectomy and ALND for histological stage I, II, or III breast cancer to:
    • RNI (supraclavicular and internal mammary nodal irradiation) or no regional nodal irradiation
  • At a median follow-up of 10.9 years:
    • The addition of regional nodal irradiation improved DFS from 69.1% to 72.1% (P=0.04)
    •  Again, there was a non-significant trend toward improvement in OS from 80.7% to 82.3% (P=0.06 among the RNI group.
• The results of NCIC-CTG MA.20:
  • Have led many to conclude that all patients with axillary nodal metastases, regardless of tumor size or extent of nodal involvement:
    • Should receive comprehensive nodal radiation therapy (RT)
• A major conundrum in current practice is resolving the apparently contradictory findings of American College of Surgeons Oncology Group (ACOSOG) Z0011 and After Mapping of the Axilla, Radiation or Surgery? (AMAROS) with those of MA.20
  • The modest benefit in DFS with nodal RT in MA.20 may reflect differences in patient populations between the studies:
    • Patients with clinically positive nodes were excluded from ACOSOG Z0011 and AMAROS (and not MA.20)
  • In addition, fewer than 10 nodes were removed in one-third of patients in the MA.20 study and the median node count was 12, compared to a median of 17 in the ALND arms of Z0011 and AMAROS
• The benefit of nodal RT:
  • Therefore may be limited to higher risk patients with more extensive nodal disease and perhaps more limited axillary surgery
• References
• Poortmans PM, Collette S, Kirkove C, Limbergen EV, Budach V, Struikmans H, et al. Internal mammary and medial supraclavicular irradiation in breast cancer. N Engl J Med. 2015;37(4)3:317-327.
• Pepels MJ, de Boer M, Bult P, van Dijck A, van Deurzen CH, Menke-Pluymers MB, et al. Regional recurrence in breast cancer patients with sentinel node micrometastases and isolated tumor cells. Ann Surg. 2012;255(1):116-121.
• Whelan TJ, Olivotto IA, Parulekar WR, Ackerman I, Chua BH, Nabid A, et al; MA.20 Study Investigators. Regional nodal irradiation in early-stage breast cancer. N Engl J Med.2015;373(4):307-316.

• The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial:
  • Was the first study to compare:
    • A 3rd-generation aromatase inhibitor (AI), anastrozole, with tamoxifen for the adjuvant treatment of early breast cancer
• The ATAC trial:
  • As 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, and 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.

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• Published in 2003 the evaluation of combination chemotherapy for breast cancer:
  • Given by both dose dense and sequential therapy
  • The goal of the study was to evaluate the best way to administer the chemotherapy regimen:
    • Doxorubicin (A), cyclophosphamide (C) followed by paclitaxel (T)
  • The study assessed chemotherapy administration in:
    • A dose dense fashion:
      • Two weeks vs. three weeks
    • Treatment sequence:
      • Concurrent versus sequential
  • The findings of the study showed:
    • That dose density improved clinical outcomes significantly
    • Sequential chemotherapy was as effective as concurrent chemotherapy:
      • But required a longer time period of administration
• Dose-dense chemotherapy:
  • Refers to decreasing the interval between cycles of treatment without the need of increasing doses and toxicity
• Sequential therapy:
  • Refers to the administration of treatments one at a time rather than concurrently
• National Cancer Institute’s Breast Intergroup INT C9741 and CALGB 9741 trial:
  • Was a prospective, randomized trial designed to study adjuvant chemotherapy treatment regimens:
    • In women with axillary node-positive breast cancer conducted from September 1997 to March 1999
  • Doxorubicin (A), paclitaxel (T), and cyclophosphamide (C) were chosen for this study
  • Using a 2 x 2 factorial design, patients were assigned to receive one of the following 4 regimens:
    • Sequential A then C followed by T x 4 cycles every 3 weeks
    • Dose-dense, sequential A then C then T x 4 cycles every 2 weeks with filgrastim
    • Concurrent AC x 4 cycles followed by T x 4 cycles every 3 weeks
    • Dose-dense, concurrent AC x 4 cycles followed by T x 4 cycles every 2 weeks with filgrastim

• Results showed that:
  • Dose-dense treatment improved the primary endpoints of:
    • Disease-free survival (DFS) and overall survival (OS):
      • Four-year DFS was 82% for dose-dense regimens and 75% for other groups (risk ratio, 0.74, P=0.01)
      • Three-year OS was 92% for dose-dense regimens and 90% in other groups (risk ratio, 0.69, P=0.013)
    • There was no difference in either DFS or OS:
      • Between the concurrent and sequential schedules
    • Severe neutropenia:
      • Was less common in patients who received the dose-dense regimens
    • As a result of this study:
      • Dose-dense and concurrent AC chemotherapy has become one of the standard components of breast cancer therapy
• References:
  • Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol.2003;21(8):1431-1439.
  • Orzano JA, Swain SM. Concepts and clinical trials of dose-dense chemotherapy for breast cancer. Clin Breast Cancer. 2005;6(5):402-411

• NSABP B-14:
  • Was a randomized, double-blind, placebo-controlled trial:
    • Comparing tamoxifen to placebo in women with node-negative ER positive invasive breast cancer
  • It demonstrated a statistically significant improvement in 10-year disease-free survival (DFS)with the use of 5 years of tamoxifen:
    • 69% vs. 57%, P<0.0001
  • Tamoxifen was also associated with a 37% reduction in contralateral breast cancers

• The results of B-14 raised questions about the benefit of administration of additional adjuvant hormonal therapy following completion of 5 years of tamoxifen:
  • More specifically, the administration of aromatase inhibitors after completion of tamoxifen therapy became of interest

• NSABP B-33:
  • Was developed to compare exemestane with placebo in recurrence-free postmenopausal women who completed 5 years of tamoxifen therapy
  • Accrual to this study was terminated prematurely when results of NCIC-CTG MA.17 showed:
    • A significant improvement with letrozole after 5 years of tamoxifen
    • With a median follow-up of 64 months:
      • The hazard ratios of letrozole after 5 years of tamoxifen compared to placebo after similar tamoxifen therapy were:
        • 0.52 (95% confidence interval [CI], 0.45 to 0.61; P<.001) for DFS
        • 0.51 (95% CI, 0.42 to 0.61; P<.001) for distant DFS
        • 0.61 (95% CI, 0.52 to 0.71; P<.001) for overall survival
  • The patients in NSABP B-33 were then unblinded and offered 5 years of exemestane:
    • The improvement in relapse-free survival observed in B-33 with exemestane was similar to that observed in the NCIC-CTG MA.17 trial with letrozole
  • To further examine the benefits of aromatase inhibitors as primary therapy or after 2 to 5 years of tamoxifen:
    • In women with early-stage, hormone receptor-positive breast cancer:
      • The MA.17 R trial analyzed prolonging duration of therapy to 10 years:
        • With DFS as the primary endpoint
    • The study randomized 1,918 women to placebo versus letrozole
    • After a median follow-up of 6.3 years:
      • DFS was 95% for the letrozole group and 91% for the placebo group
      • There was also an improvement in the annual incidence of contralateral breast cancer:
        • With the letrozole group at 0.21% versus 0.49% for the placebo group. 
      • These data support a new standard of care for this patient population, i.e., to improve DFS through 10-year treatment with aromatase inhibitors
• References:
  • Fisher B, Dignam J, Bryant J, Wolmark N. Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst. 2001;93(9):684-690.
  • Fisher B, Jeong JH, Dignam J, Anderson S, Mamounas E, Wickerham DL, et al. Findings from recent National Surgical Adjuvant Breast and Bowel Project studies in Stage I breast cancer. J Natl Cancer Inst Monogr. 2001;93(30):62-66.
  • Mamounas EP, Jeong JH, Wickerham DL, Smith RE, Ganz PA, Land SR, et al. Benefit from exemestane as extended adjuvant therapy after 5 years of adjuvant tamoxifen: intention-to-treat analysis of the National Surgical Adjuvant Breast and Bowel Project B-33 trial. J Clin Oncol. 2008;26(12):1965-1971.
  • Ingle JN, Tu D, Pater JL, Muss HB, Martino S, Robert NJ, et al. Intent-to-treat analysis of the placebo-controlled trial of letrozole for extended adjuvant therapy in early breast cancer: NCIC CTG MA.17. Ann Oncol. 2008;19(5):877-882.
  • Jin H, Tu D, Zhao N, Shepherd LE, Goss PE. Longer-term outcomes of letrozole versus placebo after 5 years of tamoxifen in the NCIC CTG MA.17 trial: analyses adjusting for treatment crossover. J Clin Oncol. 2012;30(7):718-721.
  • Lemieux J, Goss PE, Parulekar WR, Ingle JN, Pritchard KI, Robert NJ, et al. Patient-reported outcomes from MA.17R: a randomized trial of extending adjuvant letrozole for 5 years after completing an initial 5 years of aromatase inhibitor therapy alone or preceded by tamoxifen in postmenopausal women with early-stage breast cancer. J Clin Oncol. 2016;34(18 

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