NCCN Clinical Practice Guidelines in Oncology. Breast Cancer V Continue.

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1 Clinical in Oncology V Continue

2 Robert W. Carlson, MD/Chair Stanford Comprehensive Cancer Center D. Craig Allred, MD Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine Benjamin O. Anderson, MD Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance Harold J. Burstein, MD, PhD Dana-Farber/Brigham and Women's Cancer Center W. Bradford Carter, MD H. Lee Moffitt Cancer Center & Research Institute Stephen B. Edge, MD Roswell Park Cancer Institute John K. Erban, MD Massachusetts General Hospital Cancer Center William B. Farrar, MD Arthur G. James Cancer Hospital & Richard J. Solove Research Institute at The Ohio State University Sharon Hermes Giordano, MD MPH The University of Texas M.D. Anderson Cancer Center Guidelines Panel Disclosures Panel Members Lori J. Goldstein, MD Fox Chase Cancer Center William J. Gradishar, MD Robert H. Lurie Comprehensive Cancer Center of Northwestern University Daniel F. Hayes, MD University of Michigan Comprehensive Cancer Center Clifford A. Hudis, MD Memorial Sloan-Kettering Cancer Center Mohammad Jahanzeb, MD St. Jude Children s Research Hospital/ University of Tennessee Cancer Institute Britt-Marie Ljung, MD UCSF Helen Diller Family Comprehensive Cancer Center P. Kelly Marcom, MD Duke Comprehensive Cancer Center Ingrid A. Mayer, MD Vanderbilt-Ingram Cancer Center Beryl McCormick, MD Memorial Sloan-Kettering Cancer Center Continue Lisle M. Nabell, MD University of Alabama at Birmingham Comprehensive Cancer Center Lori J. Pierce, MD University of Michigan Comprehensive Cancer Center Elizabeth C. Reed, MD UNMC Eppley Cancer Center at The Nebraska Medical Center Mary Lou Smith, JD, MBA Consultant George Somlo, MD City of Hope Neal S. Topham, MD Ÿ Fox Chase Cancer Center John H. Ward, MD Huntsman Cancer Institute at the University of Utah Eric P. Winer, MD Dana-Farber/Brigham and Women's Cancer Center Massachusetts General Hospital Cancer Center Antonio C. Wolff, MD The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University Medical Oncology Hematology/Oncology Surgical Oncology Pathology Ÿ Reconstructive Surgery Version /23/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. Radiation Oncology Bone Marrow Transplantation Patient Advocacy * Writing Committee Member

3 Table of Contents Panel Members Summary of Guidelines Updates Noninvasive Lobular Carcinoma In Situ (LCIS-1) Ductal Carcinoma In Situ (DCIS-1) Invasive Clinical Stage, Workup (BINV-1) Locoregional Treatment of Clinical Stage l, lla, or llb Disease or T3,N1,M0 (BINV-2) Systemic Adjuvant Treatment (BINV-4) Preoperative Chemotherapy Guideline Clinical Stage lla, llb, Workup (BINV-10) Primary Treatment, Adjuvant Treatment (BINV-11) Clinical Stage llla, lllb, lllc, and Stage IV, Workup (BINV-13) Preoperative Chemotherapy, Locoregional Treatment, Adjuvant Treatment (BINV-14) Surveillance/Follow-Up, Recurrence Workup or Initial Workup for Stage lv Disease (BINV-15) Treatment of Recurrence/Stage IV Disease (BINV-16) Principles of HER2 Testing (BINV-A) Principles of Dedicated Breast MRI Testing (BINV-B) Invasive (continued) For help using these Surgical Axillary Staging - Stage l, lla, documents, please click here and llb (BINV-C) Axillary Lymph Node Staging (BINV-D) Print the Guideline Margin Status in Infiltrating Carcinoma (BINV-E) Special Considerations to Breast- Staging This discussion is being Conserving Therapy Requiring Radiation updated to correspond Discussion Therapy (BINV-F) with the newly updated Principles of Breast Reconstruction References algorithm. Following Mastectomy (BINV-G) Principles of Radiation Therapy (BINV-H) Adjuvant Endocrine Therapy (BINV-I) Clinical Trials: The believes that the best management Adjuvant Chemotherapy (BINV-J) for any cancer patient is in a clinical Definition of Menopause (BINV-K) trial. Participation in clinical trials is Subsequent Endocrine Therapy (BINV-L) especially encouraged. Preferred Chemotherapy Regimens for To find clinical trials online at Recurrent or Metastatic member institutions, click here: (BINV-M) nccn.org/clinical_trials/physician.html Special Considerations Phyllodes Tumor (PHYLL-1) Categories of Evidence and Consensus: All recommendations Paget s Disease (PAGET-1) are Category 2A unless otherwise During Pregnancy (PREG-1) specified. Inflammatory (IBC-1) See Categories of Evidence and Consensus These guidelines are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult these guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment. The National Comprehensive Cancer Network makes no representations nor warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way. These guidelines are copyrighted by National Comprehensive Cancer Network. All rights reserved. These guidelines and the illustrations herein may not be reproduced in any form without the express written permission of Version /23/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of.

4 Update Summary Summary of changes in the version of the Guidelines from the version include: DCIS-1 Footnote f has been modified. Complete axillary lymph node dissection should not be performed in the absence of evidence of invasive cancer or proven metastatic disease women with apparent pure DCIS. However, a small proportion of patients with apparent pure DCIS will be found to have invasive cancer at the time of their definitive surgical procedure. Therefore, the performance of a sentinel lymph node procedure may be considered if the patient with apparent pure DCIS is to be treated with mastectomy or with excision in an anatomic location compromising the performance of a future sentinel lymph node procedure. DCIS-2 Surveillance/Follow-up: Changed the recommendation for Mammogram to every 12 mo (and 6-12 mo postradiation therapy if breast conserved [category 2B]) to be consistent with the follow-up for invasive disease BINV-15. BINV-1 Moved the recommendation Genetic counseling if patient is high risk for hereditary breast cancer from optional additional studies to general work-up. Also added this recommendation to all of the work up sections. Clarified recommendations for additional studies. BINV-2 Removed radiation therapy may be given concurrent with CMF (category 2B) following lumpectomy with surgical axillary staging. Added a footnote i : Except as outlined in the Genetics/Familial High-Risk Assessment: Breast and Ovarian Guidelines and the Risk Reduction Guidelines, prophylactic mastectomy of a breast contralateral to a known unilateral breast cancer is discouraged. When considered, the small benefits from contralateral prophylactic mastectomy for women with unilateral breast cancer must be balanced with the risk of recurrent disease from the known ipsilateral breast cancer, psychological and social issues of bilateral mastectomy, and the risks of contralateral mastectomy. The use of a prophylactic mastectomy contralateral to a breast treated with breast conserving therapy is very strongly discouraged. BINV-5 Replace well differentiated with Grade 1 and moderate/poorly differentiated with Grade 2-3 BINV-10 Added Genetic counseling if the patient is high risk for hereditary breast cancer to the workup section. (Change applies to BINV-13,-15, and IBC-1). BINV-13 Added PET/CT scan as an additional study to Bone scan and CT scan to the optional workup as a category 2B. Added a footnote: FDG PET/CT is most helpful in situations where standard staging studies are equivocal or suspicious, especially in the setting of locally advanced or metastatic disease. FDG PET/CT may also be helpful in identifying unsuspected regional nodal disease and/or distant metastases in LABC when used in addition to standard staging studies. PET/CT is not recommended for newly diagnosed stage l or ll breast cancer. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Continued on next page Version /23/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. UPDATES

5 Update Summary Summary of changes in the version of the Guidelines from the version include: BINV-16 Footnote ff is new to the page. In women with a local breast recurrence after breast conserving surgery who had a prior sentinel lymph node biopsy, a repeat SNB may be technically possible. The accuracy of repeat SNB is unproven, and the prognostic significance of repeat SNB after mastectomy is unknown and its use discouraged. BINV-C Full axillary lymph node dissection has been removed as an option for women with clinically negative axilla. BINV-G The third bullet under Principles of Breast Reconstruction Following Surgery has been modified to include: Post-mastectomy radiation as outlined in these guidelines should be applied in cases treated by skin sparing mastectomy. The nipple-areolar complex is sacrificed with skin sparing mastectomy for cancer therapy. Current data are inadequate to support the use of nipple-areolar complex sparing procedures for breast cancer therapy outside the confines of a prospective clinical trial. BINV-I Footnote 2 was changed to: Some serotonin reuptake inhibitors decrease the formation of endoxifen, an active metabolite of tamoxifen. However, citalopram and venlafaxine appear to have minimal impact on tamoxifen metabolism. The clinical impact of these observations is not known. At this time, based on current data the Panel discourages CYP 2D6 testing. BINV-J Removed AC followed by paclitaxel every 3 weeks from other adjuvant regimens. Added new adjuvant chemotherapy regimen and reference: FEC (fluorouracil/epirubicin/cyclophosphamide followed by weekly paclitaxel. Martin M, Rodriguez-Lescure A, et al: Randomized phase 3 trial of fluorouracil, Epirubicin, and cyclophosphamide alone or followed by paclitaxel for early breast cancer. J Natl Cancer Inst 2008; 100: PREG-1 Footnote c has been modified. There are insufficient safety data to recommend the general use of taxanes during pregnancy. The use of blue dye and trastuzumab are contraindicated during pregnancy. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version /23/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. UPDATES

6 Lobular Carcinoma in Situ DIAGNOSIS WORKUP PRIMARY TREATMENT RISK REDUCTION SURVEILLANCE/FOLLOW-UP Lobular carcinoma in situ (LCIS) Stage 0 Tis, N0, M0 a History and physical Diagnostic bilateral mammogram Pathology review b Observationc Counseling regarding risk reduction with tamoxifen for premenopausal women, d or with tamoxifen or raloxifene for postmenopausal women (category 1, see also Risk Reduction Guidelines) or In special circumstances, bilateral mastectomy (see also Risk Reduction Guidelines) ± reconstructione may be considered for risk reduction Interval history and physical exam every 6-12 mo Mammogram every 12 mo, unless postbilateral mastectomy If treated with tamoxifen, monitor per Breast Cancer Risk Reduction Guidelines asee Screening and Diagnosis Guidelines. bthe panel endorses the College of American Pathology Protocol for pathology reporting for all invasive and non-invasive carcinomas of the breast. csome variants of LCIS ("pleomorphic LCIS") may have a siml i ar biological behavior to that of DCIS. Clinicians may consider complete excision for pleomorphic LCIS but outcome data regarding the efficacy of surgical excision to negative margins and/or radiotherapy are lacking. dsome serotonin reuptake inhibitors decrease the formation of endoxifen, an active metabolite of tamoxifen. However, citalopram and venlafaxine appear to have minimal impact on tamoxifen metabolism. The clinical impact of these observations is not known. esee Principles of Breast Reconstruction Following Surgery (BINV-G). Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version /23/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. LCIS-1

7 Ductal Carcinoma in Situ DIAGNOSIS WORKUP PRIMARY TREATMENT Ductal carcinoma in situ (DCIS) Stage 0 Tis, N0, M0 a History and physical exam Diagnostic bilateral mammogram Pathology reviewb Determination of tumor estrogen receptor (ER) status Genetic counseling if patient is high risk for hereditary breast cancerc d,e Lumpectomy without lymph node surgery f + whole breast radiation therapy (category 1) g,h,i,j,k or Total mastectomy with or without sentinel node biopsy f,i ± reconstructionl or Lumpectomyd,e without lymph node surgeryf without radiation therapy (category 2B) h,j,k See Postsurgical Treatment (DCIS-2) asee Screening and Diagnosis Guidelines. bthe panel endorses the College of American Pathology Protocol for pathology reporting for all invasive and non-invasive carcinomas of the breast. csee Genetic/Familial High-Risk Assessment: Breast and Ovarian Guidelines. dre-resection(s) may be performed in an effort to obtain negative margins in patients desiring breast conserving therapy. Patients not amenable to margin-free lumpectomy should have total mastectomy. esee Margin Status in DCIS (DCIS-A). f Complete axillary lymph node dissection should not be performed in the absence of evidence of invasive cancer or proven metastatic disease in women with apparent pure DCIS. However, a small proportion of patients with apparent pure DCIS will be found to have invasive cancer at the time of their definitive surgical procedure. Therefore, the performance of a sentinel lymph node procedure may be considered if the patient with apparent pure DCIS is to be treated with mastectomy or with excision in an anatomic location compromising the performance of a future sentinel lymph node procedure. gsee Principles of Radiation Therapy (BINV-H). hcomplete resection should be documented by analysis of margins and specimen radiography. Post-excision mammography should also be performed whenever uncertainty about adequacy of excision remains. ipatients found to have invasive disease at total mastectomy or re-excision should be managed as stage l or stage ll disease, including lymph node staging. jsee Special Considerations Breast-Conserving Therapy (BINV-F). kwhole breast radiation therapy following lumpectomy reduces recurrence rates in DCIS by about 50%. Approximately half of the recurrences are invasive and half DCIS. A number of factors determine that local recurrence risk, include size, tumor grade, margin status and patient age. Some patients may be treated by excision alone, if the patient and physician view the individual risks as "low". All data evaluating the three local treatments show no differences in patient survival. lsee Principles of Breast Reconstruction Following Surgery (BINV-G). Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version /23/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. DCIS-1

8 Ductal Carcinoma in Situ DCIS POSTSURGICAL TREATMENT SURVEILLANCE/FOLLOW-UP Risk reduction therapy for ipsilateral breast following breast conserving surgery: Consider tamoxifenm for 5 years for: Patients treated with breast-conserving therapy (lumpectomy) and radiation therapy (category 1), n especially for those with ER-positive DCIS. The benefit of tamoxifen for ER-negative DCIS is uncertain Patients treated with excision alonen Risk reduction therapy for contralateral breast: Counseling regarding consideration of tamoxifen for risk reduction (category 2B). m See also Risk Reduction Guidelines Interval history and physical exam every 6-12 mo for 5 y, then annually Mammogram every 12 mo (and 6-12 mo postradiation therapy if breast conserved [category 2B]) If treated with tamoxifen, monitor per Breast Cancer Risk Reduction Guidelines m Some serotonin reuptake inhibitors decrease the formation of endoxifen, an active metabolite of tamoxifen. However, citalopram and venlafaxine appear to have minimal impact on tamoxifen metabolism. The clinical impact of these observations is not known. n Available data suggest tamoxifen provides risk reduction in the ipsilateral breast treated with breast conservation and in the contralateral breast in patients with mastectomy or breast conservation with ER-positive primary tumors. Since a survival advantage has not been demonstrated, individual consideration of risks and benefits is important ( See also Risk Reduction Guidelines). Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version /23/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. DCIS-2

9 Ductal Carcinoma in Situ MARGIN STATUS IN DCIS Substantial controversy exists regarding the definition of a negative pathologic margin in DCIS. Controversy arises out of the heterogeneity of the disease, difficulties in distinguishing the spectrum of hyperplastic conditions, anatomic considerations of the location of the margin, and inadequate prospective data on prognostic factors in DCIS. Margins greater than 10 mm are widely accepted as negative (but may be excessive and may lead to a less optimal cosmetic outcome). Margins less than 1 mm are considered inadequate. With pathologic margins between 1-10 mm, wider margins are generally associated with lower local recurrence rates. However, close surgical margins (< 1 mm) at the fibroglandular boundary of the breast (chest wall or skin) do not mandate surgical re-excision but can be an indication for higher boost dose radiation to the involved lumpectomy site. (category 2B) Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version /23/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. DCIS-A

10 Invasive CLINICAL STAGE WORKUP Stage I T1, N0, M0 or Stage IIA T0, N1, M0 T1, N1, M0 T2, N0, M0 or Stage IIB T2, N1, M0 T3, N0, M0 or T3, N1, M0 General workup including: History and physical exam CBC, platelets Liver function tests and alkaline phosphatase Diagnostic bilateral mammogram, ultrasound as necessary Pathology reviewa Determination of tumor estrogen/progesterone receptor (ER/PR) status and HER2 statusb Genetic counseling if patient is high risk for hereditary breast cancerc Optional studies for breast imaging: Breast MRId If clinical stage llla (T3, N1, M0) consider: Bone scan (category 2B) Abdominal ± pelvis CT or US or MRI Chest imaging Additional studies as directed by symptoms: e Bone scan indicated if localized bone pain or elevated alkaline phosphatase Abdominal ± pelvis CT or US or MRI if elevated alkaline phosphatase, abnormal liver function tests, abdominal symptoms, abnormal physical examination of the abdomen or pelvis Chest imaging (if pulmonary symptoms are present) See Locoregional Treatment (BINV-2) a The panel endorses the College of American Pathology Protocol for pathology reporting for all invasive and non-invasive carcinomas of the breast. bsee Principles of HER2 Testing (BINV-A). csee Genetics/Familial High-Risk Assessment: Breast and Ovarian Guidelines. dsee Principles of Dedicated Breast MRI Testing (BINV-B). ethe use of PET or PET/CT scanning is not indicated in the staging of clinical stage I, II, or operable III breast cancer. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version /23/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. BINV-1

11 LOCOREGIONAL TREATMENT OF CLINICAL STAGE I, IIA, OR IIB DISEASE OR T3, N1, M0 4 positive axillary nodes k Invasive Radiation therapy to whole breast with or without boost (by photons, brachytherapy, or electron beam) to tumor bed (category 1), infraclavicular region and supraclavicular area. Consider radiation therapy to internal mammary nodes m (category 3). Radiation therapy should follow chemotherapy when chemotherapy indicated. l Lumpectomy with surgical axillary staging (category 1) f,g,h or 1-3 positive axillary nodes Negative axillary nodes Radiation therapy to whole breast with or without boost (by photons, brachytherapy, or electron beam) to tumor bed (category 1) following chemotherapy when chemotherapy indicated. Strongly consider radiation therapy to infraclavicular region and supraclavicular area (category 2B). Consider radiation therapy to internal mammary nodes m (category 3). Radiation therapy should follow chemotherapy when chemotherapy indicated. Radiation therapy to whole breast with or without boost (by photons, brachytherapy, or electron beam) to tumor bed. Radiation therapy should follow chemotherapy when chemotherapy indicated. n l l See BINV-4 Total mastectomy with surgical axillary staging f,g,i (category 1) ± reconstructionj or If T2 or T3 and fulfills criteria for breast conserving therapy except for size h See Locoregional Treatment (BINV-3) Consider Preoperative Chemotherapy Guideline (BINV-10) j fsee Surgical Axillary Staging (BINV-C). See Principles of Reconstruction Following Surgery (BINV-G). k gsee Axillary Lymph Node Staging (BINV-D) and Consideration may be given to additional staging including bone scan and Margin Status in Infiltrating Carcinoma (BINV-E). abdominal CT/US/MRI; chest CT (category 2B). l hsee Special Considerations to Breast-Conserving Therapy (BINV-F). See Principles of Radiation Therapy (BINV-H). i m Except as outlined in the Genetics/Familial High-Risk Assessment: Breast Radiation therapy should be given to the internal mammary lymph nodes if they are and Ovarian Guidelines and the Risk Reduction Guidelines, clinically or pathologically positive, otherwise the treatment to the internal mammary prophylactic mastectomy of a breast contralateral to a known unilateral breast nodes is at the discretion of the treating radiation oncologist. CT treatment planning cancer is discouraged. When considered, the small benefits from contralateral should be utilized in all cases where radiation therapy is delivered to the internal prophylactic mastectomy for women with unilateral breast cancer must be mammary lymph nodes. n balanced with the risk of recurrent disease from the known ipsilateral breast Breast irradiation may be omitted in those 70 y of age or older with estrogenreceptor positive, clinically node negative, T1 tumors who receive adjuvant cancer, psychological and social issues of bilateral mastectomy, and the risks of contralateral mastectomy. The use of a prophylactic mastectomy contralateral to a endocrine therapy (category 1). breast treated with breast conserving therapy is very strongly discouraged. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version /23/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. BINV-2

12 Invasive LOCOREGIONAL TREATMENT OF CLINICAL STAGE I, IIA, OR IIB DISEASE OR T3, N1, M0 4 positive axillary nodes k Postchemotherapy radiation therapy to chest wall (category 1) + supraclavicular area. l Consider radiation therapy to internal mammary nodes (category 3) l,m 1-3 positive axillary nodes Strongly consider postchemotherapy radiation therapy to chest wall + supraclavicular area; l if radiation therapy is given, consider internal mammary node radiation therapy l,m (category 3). Total mastectomy with surgical axillary staging f,g (category 1) ± reconstructionj Negative axillary nodes and tumor > 5 cm or margins positive Postchemotherapy radiation therapy to chest wall. l See BINV-4 Negative axillary nodes and tumor 5 cm and close margins (< 1 mm) Consider radiation therapy to chest wall ± supraclavicular nodes. Consider radiation therapy to internal mammary nodes (category 3) l Negative axillary nodes and tumor 5 cm and margins 1 mm No radiation therapy fsee Surgical Axillary Staging (BINV-C). gsee Axillary Lymph Node Staging (BINV-D) and Margin Status in Infiltrating Carcinoma (BINV-E). jsee Principles of Reconstruction Following Surgery (BINV-G). k Consideration may be given to additional staging including bone scan; abdominal CT/US/MRI; chest CT (category 2B). lsee Principles of Radiation Therapy (BINV-H). mradiation therapy should be given to the internal mammary lymph nodes that are clinically or pathologically positive, otherwise the treatment to the internal mammary nodes is at the discretion of the treating radiation oncologist. CT treatment planning should be utilized in all cases where radiation therapy is delivered to the internal mammary lymph nodes. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version /23/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. BINV-3

13 Invasive HISTOLOGY HORMONE HER2 STATUS SYSTEMIC ADJUVANT TREATMENT RECEPTOR STATUS HER2 positive b See Systemic Adjuvant Treatment - Hormone Receptor Positive - HER2 Positive Disease (BINV-5) o Ductal Lobular Mixed Metaplastic ER-positive and/or PR positive ER-negative and PR-negative HER2 negative b HER2 positive b HER2 negative b See Systemic Adjuvant Treatment - Hormone Receptor Positive - HER2 Negative Disease (BINV-6) See Systemic Adjuvant Treatment - Hormone Receptor Negative - HER2 Positive Disease (BINV-7) See Systemic Adjuvant Treatment - Hormone Receptor Negative - HER2 Negative Disease (BINV-8) ER-positive and/or PR positive Tubular Colloid See Systemic Adjuvant Treatment - Favorable Histologies (BINV-9) ER-negative and PR-negative b See Principles of HER2 Testing (BINV-A). o This includes medullary and micropapillary subtypes. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version /23/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. BINV-4

14 Invasive SYSTEMIC ADJUVANT TREATMENT - HORMONE RECEPTOR POSITIVE - HER2 POSITIVE DISEASE b Histology: p Ductal Lobular Mixed Metaplastic pt1, pt2, or pt3; and pn0 or pn1mi ( 2 mm axillary node metastasis) Tumor 0.5 cm or Microinvasive or Tumor cm, grade 1 Tumor cm, grade 2 or 3, unfavorable featuresq Tumor > 1 cm Node positive (one or more metastases > 2 mm to one or more ipsilateral axillary lymph nodes) b See Principles of HER2 Testing (BINV-A). p Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. pn0 pn1mi No adjuvant therapy r Consider adjuvant endocrine therapy s Adjuvant endocrine therapy ± adjuvant chemotherapy (category 1) s,t,u ± trastuzumab (category 3) v Adjuvant endocrine therapy + adjuvant chemotherapy + trastuzumab (category 1) s,t,u Adjuvant endocrine therapy + adjuvant chemotherapy + trastuzumab (category 1) s,t,u See Follow-Up (BINV-15) See Adjuvant Endocrine Therapy (BINV-I) and Adjuvant Chemotherapy (BINV-J) Mixed lobular and ductal carcinoma as well as metaplastic carcinoma should be graded based on the ductal component and treated based on this grading. The metaplastic or mixed component does not alter prognosis. q Unfavorable features: angiolymphatic invasion, high nuclear grade, or high histologic grade. rif ER-positive consider endocrine therapy for risk reduction and to diminish the small risk of disease recurrence. s Evidence supports that the magnitude of benefit from surgical or radiation ovarian ablation in premenopausal women with hormone-receptor-positive breast cancer is similar to that achieved with CMF alone. Early evidence suggests similar benefits from ovarian suppression (ie, LHRH agonist) as from ovarian ablation. The combination of ovarian ablation/suppression plus endocrine therapy may be superior to suppression alone. The benefit of ovarian ablation/suppression in premenopausal women who have received adjuvant chemotherapy is uncertain. tchemotherapy and endocrine therapy used as adjuvant therapy should be given sequentially with endocrine therapy following chemotherapy. The benefits of chemotherapy and of endocrine therapy are additive. However, the absolute benefit from chemotherapy may be small. The decision to add chemotherapy to endocrine therapy should be individualized, especially in those with a favorable prognosis and in women age 60 y where the incremental benefit of chemotherapy may be smaller. Available data suggest sequential or concurrent endocrine therapy with radiation therapy is acceptable. u There are insufficient data to make chemotherapy recommendations for those over 70 y old. Treatment should be individualized with consideration of comorbid conditions. vthe prognosis of patients with T1a and T1b tumors that are node negative is generally favorable even when HER2 is amplified or over-expressed. This is a population of breast cancer patients that was not studied in the available randomized trials. The decision for use of trastuzumab therapy in this cohort of patients must balance the known toxicities of trastuzumab, such as cardiac toxicity, and the uncertain, absolute benefits that may exist with trastuzumab therapy. Version /23/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. BINV-5

15 Invasive SYSTEMIC ADJUVANT TREATMENT - HORMONE RECEPTOR POSITIVE - HER2 NEGATIVE DISEASE b Histology: p Ductal Lobular Mixed Metaplastic pt1, pt2, or pt3; and pn0 or pn1mi ( 2 mm axillary node metastasis) Tumor 0.5 cm or Microinvasive or Tumor cm, grade 1, no unfavorable features Node positive (one or more metastases > 2 mm to one or more ipsilateral axillary lymph nodes) b See Principles of HER2 Testing (BINV-A). p Tumor cm, grade 2 or 3 or unfavorable featuresq Tumor > 1 cm Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. q pn0 pn1mi Consider 21-gene RT-PCR assay (category 2B) No adjuvant therapy r Adjuvant endocrine therapy + adjuvant chemotherapy (category 1) Consider adjuvant endocrine therapy s Not done Low recurrence score (< 18) Intermediate recurrence score (18-30) High recurrence score ( 31) Adjuvant endocrine therapy ± adjuvant chemotherapy (category 1) s Adjuvant endocrine therapy (category 2B) s Adjuvant endocrine therapy ± adjuvant chemotherapy (category 2B) s,t,u Adjuvant endocrine therapy + adjuvant chemotherapy (category 2B) s,t,u See Adjuvant Endocrine Therapy (BINV-I) and Adjuvant Chemotherapy (BINV-J) Mixed lobular and ductal carcinoma as well as metaplastic carcinoma should be graded based on the ductal component and treated based on this grading. The metaplastic or mixed component does not alter prognosis. q Unfavorable features: angiolymphatic invasion, high nuclear grade, or high histologic grade. rif ER-positive consider endocrine therapy for risk reduction and to diminish the small risk of disease recurrence. s Evidence supports that the magnitude of benefit from surgical or radiation ovarian ablation in premenopausal women with hormone-receptor-positive breast cancer is similar to that achieved with CMF alone. Early evidence suggests similar benefits from ovarian suppression (ie, LHRH agonist) as from ovarian ablation. The combination of ovarian ablation/suppression plus endocrine therapy may be superior to suppression alone. The benefit of ovarian ablation/suppression in premenopausal women who have received adjuvant chemotherapy is uncertain. tchemotherapy and endocrine therapy used as adjuvant therapy should be given sequentially with endocrine therapy following chemotherapy. The benefits of chemotherapy and of endocrine therapy are additive. However, the absolute benefit from chemotherapy may be small. The decision to add chemotherapy to endocrine therapy should be individualized, especially in those with a favorable prognosis and in women age 60 y where the incremental benefit of chemotherapy may be smaller. Available data suggest sequential or concurrent endocrine therapy with radiation therapy is acceptable. u There are insufficient data to make chemotherapy recommendations for those over 70 y old. Treatment should be individualized with consideration of comorbid conditions. Version /23/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. BINV-6

16 Invasive SYSTEMIC ADJUVANT TREATMENT - HORMONE RECEPTOR NEGATIVE - HER2 POSITIVE DISEASE b pt1, pt2, or pt3; and pn0 or pn1mi ( 2 mm axillary node metastasis) Tumor 0.5 cm or Microinvasive Tumor cm pn0 pn1mi No adjuvant therapy Consider chemotherapy ± trastuzumab (category 3) u,v Consider chemotherapy (category 1) ± trastuzumab (category 3) u,v Histology: p Ductal Lobular Mixed Metaplastic Tumor > 1 cm Adjuvant chemotherapy (category 1) u + trastuzumab (category 1) Node positive (one or more metastases > 2 mm to one or more ipsilateral axillary lymph nodes) Adjuvant chemotherapy u + trastuzumab (category 1) See Follow-Up (BINV-15) See Adjuvant Chemotherapy (BINV-J) b See Principles of HER2 Testing (BINV-A). pmixed lobular and ductal carcinoma as well as metaplastic carcinoma should be graded based on the ductal component and treated based on this grading. The metaplastic or mixed component does not alter prognosis. u There are insufficient data to make chemotherapy recommendations for those over 70 y old. Treatment should be individualized with consideration of comorbid conditions. vthe prognosis of patients with T1a and T1b tumors that are node negative is generally favorable even when HER2 is amplified or over-expressed. This is a population of breast cancer patients that was not studied in the available randomized trials. The decision for use of trastuzumab therapy in this cohort of patients must balance the known toxicities of trastuzumab, such as cardiac toxicity, and the uncertain, absolute benefits that may exist with of trastuzumab therapy. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version /23/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. BINV-7

17 Invasive SYSTEMIC ADJUVANT TREATMENT - HORMONE RECEPTOR NEGATIVE - HER2 NEGATIVE DISEASE b Tumor 0.5 cm or Microinvasive pn0 pn1mi No adjuvant therapy Consider chemotherapy u pt1, pt2, or pt3; and pn0 or pn1mi ( 2 mm axillary node metastasis) Tumor cm Consider chemotherapy (category 1) u Histology: p Ductal Lobular Mixed Metaplastic Tumor > 1 cm Adjuvant chemotherapy (category 1) u Node positive (one or more metastases > 2 mm to one or more ipsilateral axillary lymph nodes) Adjuvant chemotherapy (category 1) u See Follow-Up (BINV-15) See Adjuvant Chemotherapy (BINV-J) b See Principles of HER2 Testing (BINV-A). pmixed lobular and ductal carcinoma as well as metaplastic carcinoma should be graded based on the ductal component and treated based on this grading. The metaplastic or mixed component does not alter prognosis. u There are insufficient data to make chemotherapy recommendations for those over 70 y old. Treatment should be individualized with consideration of comorbid conditions. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version /23/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. BINV-8

18 Invasive SYSTEMIC ADJUVANT TREATMENT - FAVORABLE HISTOLOGIES Histology: Tubular Colloid ER-positive and/or PR-positive ER-negative and PR-negative pt1, pt2, or pt3; and pn0 or pn1mi ( 2 mm axillary node metastasis) < 1 cm cm 3 cm Node positive (one or more metastasis > 2 mm to one or more ipsilateral axillary lymph nodes) Repeat determination of tumor estrogen/progesterone receptor (ER/PR) status ER-positive and/or PR-positive ER-negative and PR-negative No adjuvant therapy r Consider adjuvant endocrine therapy s,u Adjuvant endocrine therapy s,u Adjuvant endocrine therapy ± adjuvant chemotherapy s,u Follow appropriate pathway above Treat as usual breast cancer histology (See BINV-7 and BINV-8) See Adjuvant Endocrine Therapy (BINV-I) and Adjuvant Chemotherapy (BINV-J) r If ER-positive consider endocrine therapy for risk reduction and to diminish the small risk of disease recurrence. s Evidence supports that the magnitude of benefit from surgical or radiation ovarian ablation in premenopausal women with hormone-receptor-positive breast cancer is similar to that achieved with CMF alone. Early evidence suggests similar benefits from ovarian suppression (ie, LHRH agonist or antagonist) as from ovarian ablation. The combination of ovarian ablation/suppression plus endocrine therapy may be superior to suppression alone. The benefit of ovarian ablation/suppression in premenopausal women who have received adjuvant chemotherapy is uncertain. uthere are insufficient data to make chemotherapy recommendations for those over 70 y old. Treatment should be individualized with consideration of comorbid conditions. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version /23/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. BINV-9

19 Invasive Preoperative Chemotherapy Guideline CLINICAL STAGE WORKUP Stage IIA T2, N0, M0 Stage IIB T2, N1, M0 T3, N0, M0 Stage llla T3, N1, M0 and Fulfills criteria for breast conserving surgery except for tumor size General workup including: History and physical CBC, platelets Liver function tests and alkaline phosphatase Diagnostic bilateral mammogram, ultrasound as necessary Pathology reviewa Determination of tumor ER/PR status and HER2 statusb Genetic counseling if patient is high risk for hereditary breast cancere Optional additional studies for breast imaging: Breast MRIc If clinical stage llla (T3, N1, M0) consider: Bone scan (category 2B) Abdominal ± pelvis CT or US or MRI Chest imaging Additional studies as directed by symptoms: d Bone scan indicated if localized bone pain or elevated alkaline phosphatase Abdominal ± pelvis CT or US or MRI if elevated alkaline phosphatase, abnormal liver function tests, abdominal symptoms, abnormal physical examination of the abdomen or pelvis Chest imaging (if pulmonary symptoms are present) See Primary Treatment (BINV-11) a b c The panel endorses the College of American Pathology Protocol for pathology reporting for all invasive and non-invasive carcinomas of the breast. See Principles of HER2 Testing (BINV-A). See Principles of Dedicated Breast MRI Testing (BINV-B). d The use of PET or PET/CT scanning is not indicated in the staging of clinical stage I, II, or operable III breast cancer. esee Genetics/Familial High-Risk Assessment: Breast and Ovarian Guidelines. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version /23/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. BINV-10

20 Invasive Preoperative Chemotherapy Guideline Desires breast preservation Core biopsy of breast tumor, localization of tumor bed for future surgical management Clinically negative axillary lymph node(s), consider sentinel lymph node procedure d Clinically positive axillary lymph node(s), consider core biopsy or FNA; or consider sentinel lymph node procedure if FNA or core biopsy negative PRIMARY TREATMENT Preoperative chemotherapyw,x (endocrine therapy alone may be considered for receptor positive disease in postmenopausal patients) y No response after 3-4 cycles or Progressive disease w Partial response, lumpectomy not possible Partial response, lumpectomy possible or Complete response Consider alternative chemotherapy No response after 3-4 cycles or Progressive disease w Partial response, lumpectomy not possible Complete response or partial response, lumpectomy possible See Lumpectomy Pathway (BINV-12) See Mastectomy Pathway (BINV-12) Does not desire See Stage I and II (BINV-3) breast preservation dsee Surgical Axillary Staging (BINV-C). w Anumber of combination and single agent chemotherapy regimens have activity in the preoperative setting. In general, those chemotherapy regimens recommended in the adjuvant setting ( See BINV-J) may be considered in the preoperative setting. If treated with endocrine therapy, an aromatase inhibitor is preferred for postmenopausal women. xpatients with HER2-positive tumors should be treated with preoperative chemotherapy incorporating trastuzumab for at least 9 weeks of preoperative therapy (See BINV-J). ydefinition of Menopause (See BINV-K). Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version /23/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. BINV-11

21 Invasive Preoperative Chemotherapy Guideline LOCAL TREATMENT Mastectomy and surgical axillary staging z ± reconstruction. If sentinel lymph node biopsy performed prechemotherapy and negative findings, may omit axillary lymph node staging Lumpectomy with surgical axillary staging. z If sentinel lymph node biopsy performed prechemotherapy and negative findings, may omit axillary lymph node staging Consider additional chemotherapy in the context of a clinical trial Consider additional chemotherapy in the context of a clinical trial ADJUVANT TREATMENT Adjuvant radiation therapy post-mastectomy is based on prechemotherapy tumor characteristics as per BINV-3l and Endocrine therapy if ER-positive and/or PRpositive (category 1) t Complete up to one year of trastuzumab therapy if HER2-positive (category 1). May be administered concurrent with radiation therapyl and with endocrine therapy if indicated. If capecitabine administered as a radiation sensitizer, trastuzumab may be given concurrent with the capecitabine. See Adjuvant Endocrine Therapy (BINV-I) Adjuvant radiation therapy post-lumpectomy based on prechemotherapy tumor characteristics as per BINV-2l and Endocrine therapy if ER-positive and/or PRpositive (category 1) t Complete up to one year of trastuzumab therapy if HER2-positive (category 1). May be administered concurrent with radiation therapyl and with endocrine therapy if indicated. If capecitabine administered as a radiation sensitizer, trastuzumab may be given concurrent with the capecitabine. See Adjuvant Endocrine Therapy (BINV-I) Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. See Surveillance/ Follow-up (BINV-15) lsee Principles of Radiation Therapy (BINV-H). t Chemotherapy and endocrine therapy used as adjuvant therapy should be given sequentially with endocrine therapy following chemotherapy. The benefits of chemotherapy and of endocrine therapy are additive. However, the absolute benefit from chemotherapy may be small. The decision to add chemotherapy to endocrine therapy should be individualized, especially in those with a favorable prognosis and in women age 60 y where the incremental benefit of chemotherapy may be smaller. Available data suggest sequential or concurrent endocrine therapy with radiation therapy is acceptable. zaxillary staging may include sentinel node biopsy (category 3) or level l/ll dissection. Version /23/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. BINV-12

22 Invasive LOCALLY ADVANCED INVASIVE BREAST CANCER (NON-INFLAMMATORY) CLINICAL STAGE WORKUP Stage IIIA T0, N2, M0 T1, N2, M0 T2, N2, M0 T3, N2, M0 (Stage IIIA patients with T3, N1, M0 disease, see BINV-1) Stage IIIB T4, N0, M0 T4, N1, M0 T4, N2, M0 Stage lllc Any T, N3, M0 Stage IV Any T, any N, M1 History and physical exam CBC, platelets Liver function tests and alkaline phosphatase Chest imaging Diagnostic bilateral mammogram, ultrasound as necessary Pathology review Prechemotherapy determination of tumor ER/PR status and HER2 statusb Genetic counseling if patient is high risk for hereditary breast cancere Optional additional studies or as directed by symptoms or other abnormal staging studies: aa Breast MRIc Bone scan (category 2B) Abdominal ± pelvic CT or US or MRI (category 2B) PET/CT scan (category 2B) See Initial Workup for Stage IV Disease (BINV-15) See Preoperative Chemotherapy and Locoregional Treatment (BINV-14) bsee Principles of HER2 Testing (BINV-A). csee Principles of Dedicated Breast MRI Testing (BINV-B). esee Genetics/Familial High-Risk Assessment: Breast and Ovarian Guidelines. aafdg PET/CT is most helpful in situations where standard staging studies are equivocal or suspicious, especially in the setting of locally advanced or metastatic disease. FDG PET/CT may also be helpful in identifying unsuspected regional nodal disease and/or distant metastases in LABC when used in addition to standard staging studies. PET/CT is not recommended for newly diagnosed stage l or ll breast cancer. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version /23/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. BINV-13