Author: Rodrigo Arrangoiz MS, MD, FACS, FSSO

• The EORTC 1081 study:
  • Was a large multicenter clinical trial:
    • Designed to demonstrate the safety of breast conservation therapy (BCT) compared to modified radical mastectomy (MRM):
      • In patients with:
        • Tumors 5 cm or smaller and
        • Axillary node-negative disease
        • Axillary node-positive disease
  • This study was open for accrual:
    • Between 1980 and 1986:
    • In 8 centers in the UK, Netherlands, Belgium, and South Africa
  • Four hundred and forty eight patients (448) were randomized to BCT and 420 to MRM
  • Patients who received BCT:
    • Were treated with lumpectomy and complete axillary clearance:
      • Followed by breast radiotherapy and tumor bed boost
  • The primary endpoint:
    • Was time to distant metastasis
  • Compared to BCT:
    • MRM resulted in better local control:
      • But did not affect overall survival or time to distant metastasis
  • At the 20-year follow-up:
    • No significant difference was noted for long-term OS:
      • 44.5% MRM group vs 39.1% BCT group or time to distant metastasis
  • BCT was noted to have:
    • A higher LRR at 10 years of:
      • 20% versus 12% for MRM
    • Additionally, factors associated with increased LRR included:
      • Larger tumor size
      • Lymph node metastasis
      • Receptor type
• Interpretation of results from EORTC 10801 trial:
  • Found BCT to be a justifiable form of treatment for patients with small breast cancers:
    • Given that long-term follow-up showed similar OS compared to mastectomy
  • This study contributed to earlier bodies of evidence:
    • Found in the NSABP B-06 and Milan I:
      • Study which evaluated the safety and effectiveness of BCT for women with small breast tumors
  • One of the main differences between the studies was that:
    • The EORTC 10801 trial:
      • Generally had patients with larger tumors (80% had T2 tumors) and 41% had lymph node metastasis
  • Although tumor size > 2 cm and positive lymph node status:
    • Were found to increase risk for distant metastasis and death:
      • This was found to be independent of surgical intervention
  • Thus, the EORTC 10801 trial:
    • Provided valuable data that BCT can safely be performed for patients with larger tumors and positive lymph nodes

REFERENCES

1. Black DM, Hunt KK, Mittendorf EA. Long-term outcomes reporting the safety of breast conserving therapy compared to mastectomy: 20-year results of EORTC 10801. Gland Surgery. 2013;2:120-123
2. Liliere S, Werutsky G, Fentiman IS, et al. Breast conserving therapy versus mastectomy for stage I-II breast cancer: 20 year follow-up of the EORTC 10801 phase 3 randomized trial. Lancet Oncol. 2012;13:412-419.

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• Was designed to investigate the risk of ipsilateral breast events (IBEs):
  • In patients with DCIS:
    • Treated with local excision without radiation
• The ECOG and North Central Cancer Treatment Group conducted a prospective trial:
  • From 1997 to 2002
  • Known as the E5194 study
• Patients were stratified into two groups based on grade:
  • Low- and intermediate-grade DCIS measuring 2.5 cm or smaller
  • High-grade DCIS measuring 1 cm or smaller
• Margin widths:
  • Of 3 mm or wider were required along with no residual calcifications on postoperative mammograms
• Results:
  • The low- and intermediate-grade DCIS group:
    • With 565 eligible patients:
      • Had a 5-year IBE rate of 6.1%
  • The high-grade group:
    • With 105 eligible patients:
      • Had a 5-year IBE rate of 15.3%
• These results suggested:
  • That in patients with high-grade lesions:
    • Excision alone without radiation:
      • Is inadequate treatment
• However:
  • E5194 suggested that patients with low- and intermediate-grade lesions:
    • May be considered for omission of radiation:
      • Given the acceptably low rate of IBEs
• To further answer the question:
  • Of when radiation should be considered for treatment of DCIS patients:
    • Solin et al. used samples from the E5194 study to establish the DCIS score:
      • This assay utilized quantitative RT PCR from tumor specimens for 327 patients with DCIS:
        • Treated with surgical excision without radiation:
          • From the E5194 study
      • The DCIS score from 0 to 100:
        • Low less than 39
        • Intermediate 39 to 54
        • High ≥ 55
      • The DCIS score was then designed to predict:
        • The recurrence of:
          • IBE
          • DCIS
          • Invasive cancer
      • The DCIS score correlated with 10-year IBE risk of:
        • 10.6% in the low-risk group
        • 26.7% in the intermediate-risk group
        • 25.9% in the high-risk group
• Current literature reports:
  • A 50% decrease in local recurrence with radiotherapy after surgical excision of DCIS:
    • However, there are no clear criteria to determine which patients will have the maximum benefit
• The DCIS score can be used to stratify patients:
  • Into low- and high-risk groups:
    • Based on more than clinical or pathologic features and can aid in decision making about adjuvant treatments in patients with DCIS
• To study the effect of the DCIS score on recommendations for radiotherapy following excision:
  • The treatment plans for 127 patients with DCIS were evaluated before and after knowledge of the DCIS score by the surgeon and radiation oncologist
  • The DCIS scores varied within the study population:
    • With 66% with a low-risk score, 20% with an intermediate-risk score, and 14% with a high-risk score
  • Based on clinical and pathologic factors:
    • Radiotherapy was recommended:
      • In 71.7% of the patients
  • After the DCIS score was determined:
    • There was an overall change in 26.4% of the recommendations
  • With the additional information of the DCIS score:
    • Radiotherapy was recommended:
      • For 68.1% of the patients
• The clinical utility of the DCIS score is evident in these results:
  • Giving oncologists more objective information when deciding if the benefit of radiotherapy outweighs the risk in patients with DCIS

REFERENCES

1. Hughes LL, Wang M, Page DL, et al. Local excision alone without irradiation for ductal carcinoma in situ of the breast: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009;27:5319-5324.
2. Manders JB, Kuerer HM, Smith B, et al. Clinical utility of the 12-gene DCIS score assay: impact on radiotherapy recommendations for patients with ductal carcinoma in situ. Ann Surg Oncol. 2016 [Epub ahead of print].
3. Solin LJ, Gray R, Baehner FL, et al. A multigene expression assay to predict local recurrence risk for ductal carcinoma in situ of the breast. J Nat Can Inst. 2013;105:701-710.

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• The MINDACT is a randomized, controlled, prospective, phase III, clinical trial:
  • Evaluating the use of a 70-gene signature test (MammaPrint):
    • To aid in directing chemotherapy treatment of women with early-stage breast cancer
  • The goal of this study:
    • Was to reduce the overtreatment of early-stage breast cancer and
    • To determine if genomic risk (as defined by the 70-gene signature test):
      • Can be utilized to predict recurrence and possibly avoid chemotherapy:
        • In patients with a low genomic risk
• Patients were designated as:
  • High or low risk for recurrence:
    • Based on two categories:
      • Clinical / pathologic high-risk features:
        • Positive lymph nodes
        • High-grade tumors
        • T2 tumors
        • Premenopausal diagnosis
    • Genomic risk:
      • As defined by the 70-gene signature test
• Women who were:
  • Low risk in both categories:
    • Were not given chemotherapy
• While women who were:
  • High risk in both categories:
    • Were given chemotherapy in addition to endocrine therapy
• The patients who were deemed discordant between the two categories:
  • Were randomized to use either:
    • Clinical / pathologic or
    • Genomic risk
      • To determine chemotherapy recommendations
• Patients who had a:
  • Low genomic risk:
    • Had a 94.7% 5-year distant-metastasis-free survival without chemotherapy:
      • Even in the presence of high-risk clinical / pathologic factors
• The authors concluded that:
  • Selected patients with low genomic risk may be spared chemotherapy:
    • However, in an accompanying editorial:
      • Critics of this trial have noted the survival advantage of 1.5% for high-risk patients:
        • Who received chemotherapy, and that the study was underpowered to accurately analyze differences between these groups
      • They noted that small differences in survival may be more significant to certain patients:
        • Thus:
          • tThe decision to forgo standard treatment based on genomic assays:
            • Is a very personalized decision
• Similar results were reported with the 21-gene recurrence score assay (Oncotype DX):
  • With regard to benefit of adjuvant chemotherapy based on genomic risk stratification for women with estrogen receptor-positive, lymph node-negative breast cancer:
    • Patients with a high recurrence score via the 21-gene recurrence score assay:
      • Had a significant benefit from chemotherapy:
        • With a decrease in 10-year distant recurrence rates
    • While patients with a low score:
      • Showed minimal benefit
• While they differ in the individual genes used to determine their output score:
  • Both of these genomic assays support the concept of directing adjuvant therapy for breast cancer based on the biology and genetics of the tumor itself rather than only the clinical and/or pathologic factors

REFERENCES

1. Cardoso F, van’t Veer LJ, Bogaerts J, et al; MINDACT Investigators. 70-gene signature as an aid to treatment decisions in early-stage breast cancer. N Engl J Med. 2016;375:717-791.
2. Hudis CA, Dickler M. Editorial: increasing precision in adjuvant therapy for breast cancer. N Engl J Med. 2016;375:790-791.
3. Paik S, Tang G, Shak S, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol. 2006;24:3726-3734.

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• Milan I study:
  • Was a prospective randomized trial:
    • Conducted by the Milan Cancer Institute:
      • From 1973 to 1980
• Milan I played a critical role:
  • In the establishment of breast conserving therapy (BCT):
    • As a preferred mode of treatment:
      • For women with small breast cancers:
        • ≤ 2 cm
• For this study:
  • 701 women with tumors ≤ 2 cm were enrolled and randomized to:
    • Radical mastectomy (n = 349) versus
    • BCT (quadrantectomy and axillary node dissection) followed by radiotherapy (n = 352)
• Results from Milan I:
  • Were concurrent with those from:
    • The NSABP B-06 trial
  • Showing no appreciable differences:
    • In long-term survival between the groups:
      • Despite a higher cumulative incidence of recurrence at 20 years in patients treated with BCT
  • Ipsilateral breast tumor recurrence rates after 20 years follow-up were:
    • 8.8% for the BCT group compared to a 2.3% rate of local recurrence for the radical mastectomy group:
      • P<0.001
  • Additionally, there were no significant differences between the two groups:
    • In the rates of:
      • Contralateral breast cancer
      • Distant metastases
      • Secondary primary cancers
• Overall, Milan I concluded:
  • That long-term survival was the same for women who underwent radical mastectomy as those who received BCT:
    • Thus providing more evidence to support breast-conserving surgery as treatment for women with small cancers

REFERENCES

1. Julian TB, Venditti CA, Duggal S. Landmark clinical trials influencing surgical management of non-invasive and invasive breast cancer. The Breast Journal. 2015:21;60-66.
2. Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med. 2002;347:1227-1232.

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• In 2000, two landmark trials combined results:
  • That compared adjuvant chemotherapy with or without concurrent trastuzumab therapy:
    • In women with surgically removed HER2-positive breast cancer
• The NSABP B-31 trial:
  • Compared doxorubicin and cyclophosphamide followed by paclitaxel every 3 weeks (group 1) with the same regimen plus 52 weeks of trastuzumab given concurrently with paclitaxel (group 2)
• The NCCTG N9831 trial:
  • Conducted a similar study that compared three regimens:
    • Group A :
      • Doxorubicin and cyclophosphamide followed by weekly paclitaxel
    • Group B:
      • The same regimen in group A:
        • Followed by 52 weeks of trastuzumab given after paclitaxel
    • Group C:
      • The same regimen in group A:
        • Followed by 52 weeks of trastuzumab:
          • Initiated concurrently with paclitaxel
• The studies were combined to include:
  • A joint analysis comparing:
    • Groups 1 and group A (the control group) with groups 2 and group C (the trastuzumab group)
    • Group B was excluded
• Results by 2005 reported:
  • 394 events:
    • Recurrence
    • Second primary cancer
    • Death before recurrence
  • Of these events:
    • 133 were from the trastuzumab group
    • 261 were in the control group:
      • Hazard ratio, 0.48; P<0.0001
  • At 3 years:
    • The absolute difference in DFS between the trastuzumab group and the control group:
      • Was 12%
    • Trastuzumab therapy:
      • Was associated with a 33% reduction in the risk of death (P=0.015)
  • The interim analyses of these trials favored trastuzumab:
    • So strongly that the trials were stopped early and patients in the other arms were offered trastuzumab
  • Long-term analysis of these studies was reported in 2014:
    • At a median follow-up time of 8.4 years:
      • The addition of trastuzumab to chemotherapy:
        • Led to a 37% improvement in OS and
        • An increase in 10-year survival rate:
          • From 75.2% to 84%
      • Outcomes in DFS showed:
        • An improvement of 40% and
        • An increase in the 10-year DFS rate from 62.2% to 73.7%
• This study showed that all subgroups of HER2-positive patients (small and large tumors, hormone receptor-positive and -negative, low and high number of positive nodes, young and old patients):
  • Benefited from the addition of the targeted anti-HER2 agent:
    • Making trastuzumab an integral drug in the treatment of HER2-positive breast cancer

REFERENCES

1. Perez EA, Romond EH, Suman VJ, et al. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol. 2014;32:3744-3752.
2. Romond E, Perez E, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353:1673-1684.

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• Recognizing that bevacizumab, capecitabine, and gemcitabine:
  • Have been shown to improve outcomes:
    • When added to taxanes:
      • In patients with metastatic breast cancer
• The NSABP B-40 trial:
  • Was designed to determine whether adding capecitabine or gemcitabine to docetaxel, followed by the anthracycline doxorubicin and cyclophosphamide (AC):
    • Would improve the outcomes in patients with operable, HER2-negative breast cancer
  • It was also designed to determine the effect of adding bevacizumab to these neoadjuvant chemotherapy regimens
• Patients were divided into three groups:
  • Docetaxel followed by AC
  • Docetaxel and capecitabine followed by AC
  • Docetaxel plus gemcitabine followed by AC
    • Each of these three groups was then randomized to receive bevacizumab with the first six cycles of chemotherapy or not:
      • For a total of six treatment arms
• The addition of capecitabine or gemcitabine to docetaxel therapy, compared to docetaxel alone:
  • Did not significantly increase the rate of pCR:
    • 29.7% and 31.8%, respectively, vs 32.7%:
      • P=0.69
  • Both drugs were associated with increased toxic side effects such:
    • As hand-foot syndrome, mucositis, and neutropenia
• However, the addition of bevacizumab:
  • Significantly increased the rate of pCR in the breast:
    • From 28.2% to 34.5%:
      • P=0.02
  • This effect was more pronounced:
    • In the hormone receptor-positive subset of patients:
      • 15.1% pCR without bevacizumab vs 23.2% with bevacizumab)
  • However, the addition of bevacizumab also increased rates of:
    • Hypertension, left ventricular systolic dysfunction, the hand-foot syndrome, and mucositis

REFERENCES

1. Bear HD, Tang G, Rastogi P, et al. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med. 2012;366:310-320.
2. NSABP Clinical Trials Overview. Protocol B-40. A Randomized Phase III Trial of Neoadjuvant Therapy in Patients with Palpable and Operable Breast Cancer Evaluating the Effect on Pathologic Complete Response (pCR) of Adding Capecitabine or Gemcitabine to Docetaxel when Administered Before AC with or without Bevacizumab and Correlative Science Studies Attempting to Identify Predictors of High Likelihood for pCR with Each of the Regimens. http://www.nsabp.pitt.edu/B-40.asp. Accessed December 18, 2016.

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• The ATAC trial:
  • 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 9366 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:
    • 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
    • Lung cancers
  • Decreased incidence of:
    • Endometrial
    • Melanoma
    • 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

1. Cuzick J, Sestak I, Baum 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;11:1135-1141.
2. Howell A, Cuzick J, Baum M, 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;365:60-62.

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• 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:
      • It was 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, a total of 2005 patients were randomly assigned to receive 1 of the following 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:
    • DFS and 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

1. Citron ML, Berry DA, Cirrincione C, 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;21:1431-1439.

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• SENTINA:
  • Was a four arm, prospective, multicenter cohort study of 1737 patients
  • To evaluate the role of SNB in patients who had undergone NAC for invasive breast cancer
  • Clinical node status was determined by palpation and ultrasound in all patients
  • Ultrasound guided fine-needle aspiration or core biopsy:
    • Was recommended but not mandatory
  • Patients with clinically node-negative (cN-) disease:
    • Underwent SNB before NAC:
      • If the sentinel node SN was positive:
        • A second SNB and axillary lymph node dissection (ALND) was performed after NAC
  • Women who were clinically node positive (cN+) underwent NAC, and those who converted to being cN-:
    • Also had SNB and axillary lymph node dissection
  • When SNB was done before NAC:
    • No difference in the detection rate was found:
      • Between the combined (radiocolloid and blue dye) and single agent (radiocolloid alone) detection techniques:
        • 99.5% vs 98.8%
    • However:
      • When SNB was done after NAC:
        • The addition of blue dye:
          • Increased the detection rate and
          • The number of nodes retrieved
      • Dual tracer detection rate:
        • Was 76% after chemotherapy in patients who also had SNB prior to chemotherapy
        • 88% in those who converted from cN+ to cN- with NAC and had only one SNB
• For patients who were confirmed node positive by SNB biopsy prior to NAC:
  • The FNR of repeat SNB after NAC was 51.6%
• For patients who converted from cN+ to cN- with NAC:
  • FNR of SNB after NAC was 14.2%:
    • However, in the cN+ to cN- group:
      • The FNR was below 10%, for patients who had:
        • Three or more lymph nodes removed and if both blue dye and radiocolloid were used:
          • In these cases, the FNR was 8.6%

REFERENCES

1. Kuehn T, Bauerfeind I, Fehm T, et al. Sentinel-lymph-node biopsy in patients with breast cancer before and after neoadjuvant chemotherapy (SENTINA): a prospective, multicentre cohort study. Lancet Oncol. 2013;14:609-618.

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