Breast Cancer Invasive 1

Page 1 of 14

NOTE: Consider clinical trials as treatment options for eligible patients.

This practice algorithm has been specifically developed for MD Anderson using a multidisciplinary approach and taking into consideration circumstances particular to MD Anderson, including the following: MD Anderson’s specific patient population; MD Anderson’s services and structure; and MD Anderson’s clinical information. Moreover, this algorithm is not intended to replace the independent medical or professional judgment of physicians or other health care providers. This algorithm should not be used to treat pregnant women.

Breast Cancer – Invasive

1

Unfavorable tumor to breast size

ratio for breast conservation 5?

● Pathology review2,3

● Bilateral diagnostic mammography ● History and Physical

● CBC, platelets, liver function tests (total

bilirubin, alkaline phosphatase, transaminases), creatinine

●Baseline ultrasound of breast and regional

nodal basins with FNA of suspicious nodes

●Clinical stage III (optional) or in patients

with clinical suspicion of distant metastasis body imaging4 _recommended

●Consider need for genetic counseling,

fertility preservation, and pregnancy testing

●Breast conservation therapy5 with sentinel6 lymph node surgery ● Total mastectomy with sentinel6 lymph node surgery with or

without reconstruction7

●Consider neoadjuvant chemotherapy for biologically aggressive

tumors when appropriate

INITIAL EVALUATION

CLINICAL STAGING

LOCAL TREATMENT

●Breast conservation therapy5 with axillary surgery ●Total mastectomy with axillary lymph node surgery

with or without reconstruction7 or

● Consider neoadjuvant chemotherapy (see page 2)

Copyright 2015 The University of Texas MD Anderson Cancer Center

No Yes No Positive nodes? Clinical Stage II

●Breast conservation therapy5 with sentinel6 lymph node surgery ●Total mastectomy with sentinel6 lymph node surgery

with or without reconstruction7

●Consider neoadjuvant chemotherapy

Clinical Stage I

Yes

Department of Clinical Effectiveness V13 Approved by Executive Committee of the Medical Staff 06/30/2015 1 _{There are special circumstances in which these guidelines do not apply. These include, but are not limited to:}

● Sarcoma of the breast ● Patients with lupus and scleroderma ● Special histologies (i.e., tubular, medullary, pure papillary, or colloid)

●Male breast cancer ● Lymphoma of the breast ● Patients with limited life expectancy ● Cancer during pregnancy

2

Pathology Review to include:

●Tumor size ● Nuclear grade ● HER2 ● ER, PR receptor status ● Vascular/lymphatic invasion ●Size of metastasis ● Lymph node status ● Histologic type ● Margin status ● Extracapsular extension (focal less than 2 mm or gross greater than 2 mm) 3 _{Consider approved biomarkers.}

4 _{Body imaging: CT abdomen and bone scan preferred for initial imaging. CT chest optional, PET-CT for inflammatory breast cancer.} 5 _{Candidates for breast conservation therapy:}

●unicentric disease ● tumor to breast size ratio allows for acceptable cosmetic result ● Negative margins ●resolution of any skin edema after systemic therapy

● no evidence of diffuse calcifications on mammogram ● No contraindication to radiotherapy

6 _{Surgeons with an established record of lymphatic mapping experience for breast cancer (a minimum of 20 cases with an identification rate of greater than 85% and a false negative rate of less than 5%) may consider} sentinel lymph node surgery as the initial and primary means of evaluating nodal status for selected patients who are clinically node negative.

7 _{For patients with stage II disease requiring post-mastectomy radiation, consider delayed reconstruction. For patients with stage III disease, delayed reconstruction is preferred}

See Page 2, Post-Surgery See Page 2, Post -Surgery See Page 3 Consider neoadjuvant chemotherapy or neoadjuvant

NOTE: Consider clinical trials as treatment options for eligible patients.

● Consider endocrine therapy if tumor is hormone receptor positive

● Anti-HER2 based therapy if HER2 positive3

● Consider adjuvant chemotherapy with weekly paclitaxel times 12 followed by FAC3

times 4 (other NCCN approved regimens acceptable) for adverse prognostic features5

● If giving chemotherapy, useanti-HER2 based therapy3 for HER2 positive disease

● Adjuvant endocrine therapy if tumor is hormone receptor positive4

● Consider multi-gene prognostic assays, see Appendix A

● Consider adjuvant chemotherapy when appropriate 3 (other NCCN approved

regimens acceptable)

● Anti-HER2 based therapy if HER2 positive3

● Adjuvant endocrine therapy if tumor is hormone receptor positive4

● Consider multi-gene prognostic assays, see Appendix A

Tumor less than or equal to 0.5 cm Tumor greater than 0.5 to 1 cm Tumor greater 1 cm See Page 4 For Radiotherapy Options Positive Nodes? Yes No

Department of Clinical Effectiveness V13 1 _{There are special circumstances in which these guidelines do not apply. These include, but are not limited to:}

● Sarcoma of the breast ● Patients with lupus and scleroderma ● Special histologies (i.e., tubular, medullary, pure papillary, or colloid) ●Male breast cancer ● Lymphoma of the breast ● Patients with limited life expectancy ● Cancer during pregnancy

2 _{Z0011 criteria: Clinical T1 or T2, N0, M0, lumpectomy and sentinel lymph node surgery, and tumor positive sentinel node (up to two nodes positive on sentinel node surgery) planned}

for whole breast irradiation and systemic therapy.

3 _{Cardiac evaluation at baseline, during and after treatment and as clinically indicated}

4 _{Endocrine therapy for all patients with ER positive and/or PR positive tumors (endocrine therapy is not indicated in patients with ER negative and PR negative tumors):} ●Premenopausal women: Tamoxifen 5 years

● Women with chemotherapy induced menopause: Tamoxifen until postmenopausal status biochemically confirmed, then at least 1 year to complete, aromatase inhibitors for 5 years. ● Postmenopausal (refer to NCCN guideline for definition) women: aromatase inhibitors for 5 years

5 _{Lymphovascular invasion (LVI), triple receptor negative, HER2 positive, High-grade 3.}

PATHOLOGICAL STAGING

ADJUVANT THERAPY FOLLOWING SURGERY AS LOCAL TREATMENT

Meets Z0011

criteria2? _{Completion Axillary Lymph} Node Dissection (ALND)

No further axillary surgery

No Yes

● Adjuvant chemotherapy with weekly taxane and anthracycline based regimen3

● Anti-HER2 based therapy regimen

● Adjuvant endocrine therapy if tumor is hormone receptor positive4

POST-SURGERY

Department of Clinical Effectiveness V13 Approved by Executive Committee of the Medical Staff 06/30/2015

Page 3 of 14

NOTE: Consider clinical trials as treatment options for eligible patients.

This practice algorithm has been specifically developed for MD Anderson using a multidisciplinary approach and taking into consideration circumstances particular to MD Anderson, including the following: MD Anderson’s specific patient population; MD Anderson’s services and structure; and MD Anderson’s clinical information. Moreover, this algorithm is not intended to replace the independent medical or professional judgment of physicians or other health care providers. This algorithm should not be used to treat pregnant women.

HER2 positive?

Anti-HER2 based therapy options from NCCN5

CLINICAL

STAGE/

PRESENTATION

● Assess tumor size

every 6 weeks and at completion of

systemic treatment with physical exam

● Imaging with mammogram and/or ultrasound at completion of systemic treatment ● Consider treatment ultrasound or other imaging at any point for clinical suspicion of disease progression Breast conservation therapy candidate4 _?

Breast Conserving Surgery4

● If clinically node negative

at diagnosis, proceed with sentinel node surgery6 followed by axillary node surgery if sentinel node is positive

● If clinically node positive,

confirmed by needle biopsy proceed with axillary node dissection

Total mastectomy with nodal treatment as determined by initial nodal status:

● If clinically node negative

at diagnosis, proceed with sentinel node biopsy6 followed by axillary node

surgery if sentinel node

positive, or

● If clinically node positive,

confirmed by needle biopsy proceed with axillary node dissection

● Consider reconstruction

and plastic surgery consult7

Chemotherapy options for HER2- negative breast cancer from NCCN

LOCAL TREATMENT

Copyright 2015 The University of Texas MD Anderson Cancer Center

Stage III2 Unfavorable breast to tumor ratio for breast conservation No Yes Yes No Recommend neoadjuvant systemic chemotherapy3 OR neoadjuvant endocrine therapy as clinically indicated

●If candidate for breast

conservation therapy4, place radio-opaque markers See Pathological Findings on Page 4

Breast Cancer – Invasive

1

1 _{There are special circumstances in which these guidelines do not apply. These include, but are not limited to:}

● Sarcoma of the breast ● Patients with lupus and scleroderma ● Special histologies (i.e., tubular, medullary, pure papillary, or colloid)

●Male breast cancer ● Lymphoma of the breast ● Patients with limited life expectancy ● Cancer during pregnancy 2 _{If tumor meets criteria for breast conservation therapy}5_{, then consider page 2 for local treatment first.}

3 _{For postmenopausal (refer to NCCN guideline for definition) patients with ER-positive disease, aromatase inhibitors may be an option.}

4 _{Candidates for breast conservation therapy:}

●unicentric disease ● tumor to breast size ratio allows for acceptable cosmetic result ● margins greater than or equal to 2 mm,

●resolution of any skin edema after systemic therapy ● no evidence of diffuse calcification on mammogram ● No contraindication to radiotherapy 5 _{Cardiac evaluation at baseline, during and after treatment and as clinically indicated}

6 _{Surgeons with an established record of lymphatic mapping experience for breast cancer (a minimum of 20 cases with an identification rate of greater than 85% and} a false negative rate of less than 5%)

may consider sentinel lymph node dissection as the initial and primary means of evaluating nodal status for selected patients who are clinically node negative.

NOTE: Consider clinical trials as treatment options for eligible patients.

From local treatment

● Whole breast radiotherapy2 for breast conservation

_{therapy with or without regional lymphatics.}

● Consider partial breast radiotherapy for tumors less

than or equal to 3 cm and negative lymph nodes.

● XRT consult for consideration ofchest wall

radiotherapy with or without regional lymphatics for patients with total mastectomy and tumor greater than 5 cm or any positive lymph nodes.

SURVEILLANCE

10

Stage I - II disease, with 0-3 involved

lymph node(s)

● Post mastectomy radiotherapy to chest wall and

regional lymphatics

● Whole breast radiotherapy2 with regional

lymphatics for breast conservation therapy

● Physical exam at least every 6 months

for 5 years, then annually after year 5

● If breast conservation therapy, mammogram

of treated breast at 6-12 months, then annually

● Annual gynecologic exam, if receiving

tamoxifen

● Assess bone health (See Breast Cancer

Survivorship: Bone Health Algorithm)

● Encourage age appropriate cancer and general

health guidelines

● Endocrine therapy

for hormone receptor positive tumors sequential after chemotherapy3 _and local therapy

● Trastuzumab to

complete one year if HER2-positive tumor

PATHOLOGICAL

FINDINGS

Stage III disease or 4 or more involved

lymph nodes

Department of Clinical Effectiveness V13

TREATMENT

1 _{There are special circumstances in which these guidelines do not apply. These include, but are not limited to:}

● Sarcoma of the breast ● Patients with lupus and scleroderma ● Special histologies (i.e., tubular, medullary, pure papillary, or colloid)

●Male breast cancer ● Lymphoma of the breast ● Patients with limited life expectancy ● Cancer during pregnancy

2 _{Radiotherapy for BCT and post-mastectomy radiation, are generally delivered at completion of chemotherapy. For early stage node negative patients, radiotherapy may be} delivered before or after chemotherapy.

3 _{Endocrine therapy for all patients with ER positive and/or PR positive tumors (endocrine therapy is not indicated in patients with ER negative and PR negative tumors):} ● Premenopausal women: Consider tamoxifen for 5-10 years or ovarian suppression + exemestane in high risk premenopausal women

● Women with chemotherapy induced menopause: Tamoxifen for 5 -10 years, consider switch to aromatase inhibitor if remains postmenopausal after 2-3 years or add aromatase inhibitor for 5 years after completion of 5 years of tamoxifen

Page 5 of 14

NOTE: Consider clinical trials as treatment options for eligible patients.

This practice algorithm has been specifically developed for MD Anderson using a multidisciplinary approach and taking into consideration circumstances particular to MD Anderson, including the following: MD Anderson’s specific patient population; MD Anderson’s services and structure; and MD Anderson’s clinical information. Moreover, this algorithm is not intended to replace the independent medical or professional judgment of physicians or other health care providers. This algorithm should not be used to treat pregnant women.

Progressive disease?

● Non-steroidal aromatase inhibitors with or

without fulvestrant (if no prior aromatase inhibitor)

● Tamoxifen (if no prior tamoxifen) ● Exemestane with or without everolimus ● Fulvestrant

● Other endocrine treatments:

● Estrogens ● Progestins ● Androgens

EVALUATION FOR METASTASIS

TREATMENT FOR METASTASIS

● ER positive and

bone or soft tissue metastasis only or

● Limited visceral disease

Disease response or

clinical benefit?3

Continue treatment until progressive disease, maximum benefit, or

unacceptable side effects

● Tamoxifen with or without ovarian ablation

● In premenopausal patient following ovarian

ablation use post-menopausal endocrine options

● Chemotherapy plus trastuzumab if

no prior trastuzumab ● If prior trastuzumab: ●Taxane ●Trastuzumab ●Pertuzumab ● T-DM-1(Ado-trastuzumab emtansine) ● Lapatanib ● Chemotherapy

● Endocrine therapy if hormone

receptor positive or

● Additional chemotherapy with or

without HER2 targeted therapy Failure to respond to 3

sequential regimens or Zubrod status greater than or equal to 3, discontinue chemotherapy

Continue current treatment until

progressive disease or unacceptable toxicity then consider alternate endocrine therapy Distant metastasis1,2 Biopsy to confirm metastatic disease: ● Bone Scan ● CT or MRI of abdomen ● Consider chest CT ● ER/PR ● HER2 ● Creatinine ● Consider CA15-3 when appropriate ●Consider PET/CT scan Palliative care

NOTE: All patients with bone metastases and life expectancy greater than 12 weeks should consider after dental evaluation: a bisphosphonate (creatinine clearance is 30 or greater) or denosumab.

Copyright 2015 The University of Texas MD Anderson Cancer Center

HER2 negative Pre-menopausal endocrine options Post-menopausal endocrine options No No Yes

Department of Clinical Effectiveness V13 Approved by Executive Committee of the Medical Staff 06/30/2015

Breast Cancer – Invasive

1

Yes

1 _{There are special circumstances in which these guidelines do not apply. These include, but are not limited to:}

●Sarcoma of the breast ● Patients with lupus and scleroderma ● Special histologies (i.e., tubular, medullary, pure papillary, or colloid)

●Male breast cancer ● Lymphoma of the breast ● Patients with limited life expectancy ● Cancer during pregnancy 2 _{See Appendix B for scenarios requiring individualized therapy.}

3_{Consider breast surgery for patients with responding metastatic disease who have an intact primary.}

ER = Estrogen Receptor FISH = Fluorescence In Situ Hybridization

HER2 = Human Epidermal Growth Factor Receptor 2 PR = Progesterone Receptor LHRH = Luteinizing Hormone-Releasing Hormone

● ER negative or

● ER positive and extensive

visceral disease or

● Symptomatic disease

HER2 positive by either Immunohistochemistry

3+ or FISH

Chemotherapy until progressive disease or maximum benefit can include:

●Anthracyclines if have not had lifetime limiting dose ●Gemcitabine ●Ixabepilone

●Taxanes ●Capecitabine ●Eribulin ●Vinorelbine

NOTE: Consider clinical trials as treatment options for eligible patients.

Previous breast radiotherapy?

EVALUATION FOR RECURRENCE

TREATMENT FOR RECURRENCE

Invasive histology? Total mastectomy with

lymph node surgery consider sentinel lymph node surgery if clinically node negative

● Surveillance and endocrine

therapy if hormone receptor positive

● Consider chemotherapy

● Wide local excision (WLE)

with margin assessment

● Consider neoadjuvant

systemic therapy prior to WLE

Consider systemic therapy

Biopsy to confirm recurrence with:

● Consider body imaging for invasive recurrence

● If intact breast, bilateral diagnostic mammogram

● Ultrasound of affected breast including regional nodal basins

● Consider preoperative systemic therapy ● Consider biomarkers1 (e.g. DCIS) No Yes Consider additional systemic therapy Ipsilateral breast/chest wall

recurrence or ipsilateral regional recurrence without distant metastasis

● Breast conservation therapy

with margin assessment, or

● Total mastectomy; lymph

node surgery; radiation therapy consult Endocrine therapy or HER2-directed therapy with or without chemotherapy Surveillance and endocrine therapy if estrogen receptor positive

Breast intact? Yes No Resectable? Yes No Resectable? No

Surgical resection with margin assessment

Radiotherapy to chest wall and regional lymphatics, if no previous radiation

Persistent disease?

Consider systemic therapy

Radiotherapy to chest wall and regional lymphatics (if not DCIS alone) Previous chest wall radiotherapy? No Yes Yes No No Yes

Department of Clinical Effectiveness V13 1 _{Refer to Appendix A for MD Anderson approved Biomarkers.}

Page 7 of 14

including the following: MD Anderson’s specific patient population; MD Anderson’s services and structure; and MD Anderson’s clinical information. Moreover, this algorithm is not intended to replace the independent medical or professional judgment of physicians or other health care providers. This algorithm should not be used to treat pregnant women.

Department of Clinical Effectiveness V13 Approved by Executive Committee of the Medical Staff 06/30/2015

Breast Cancer – Invasive

Inflammatory Breast Cancer

Operable?

●HER2 negative:

neoadjuant doxorubicin and taxane based chemotherapy1

●HER2 positive:

dual anti-HER2 therapy containing regimen with chemotherapy

●Consider clinical trial(s) No

Yes Stage III1

Stage IV1

(de novo)

●Modified radical mastectomy

●Radiotherapy to chest wall

and regional lymphatics, if no previous radiation2

● Adjuvant endocrine therapy

if tumor is hormone receptor positive3 HER2 positive HER2+ maintenance therapy Additional systemic therapy with or without radiotherapy ●Additional systemic therapy ● Symptom management (supportive care)

● Consider clinical trial(s)

●Single/multi-agent systemic therapy

● Symptom management (Supportive care) ● Clinical trials Adjuvant endocrine therapy ●HER2 ●Hormone receptors Hormone receptor positive

NOTE: Consider clinical trials as treatment options for eligible patients.

Copyright 2015 The University of Texas MD Anderson Cancer Center

Multidiciplinary evaluation of response Operable? No Yes Multidiciplinary evaluation of response 1_{Diagnostic Workup:}

●Medical history and physical

●Obtain photograph to establish baseline clinical appearance and follow up medical photography for a treatment response documentation.

●Imaging of breast with mammogram or tomosythesis, ultrasound, and MRI mammography ●Ultrasound of the axillary, supraclavicular, and internal mammary lymph nodes basins ●Baseline ultrasound of breast and regional nodal basins with FNA of suspicious nodes ●PET scan/CT scan- If PET/CT scan not possible: neck (if clinically indicated) in addition to chest/abdominal pelvic CT with bone scan.

●Obtain skin biopsy and ultrasound guided core biopsy of the tumor ( random biopsies of mass not present) 2_{Evaluate pathology response:}

●Minimal residual disease or partial complete response(PCR) less than 45 and negative margins -every day to 66 Gy; ●Significant residual disease or greater than 45 or close/+margins-twice a day 66Gy

3 _{Endocrine therapy for all patients with ER positive and/or PR positive tumors (endocrine therapy is not indicated in} patients with ER negative and PR negative tumors):

●Premenopausal women: tamoxifen 5 years

●Women with chemotherapy induced menopause: tamoxifen until postmenopausal status biochemically confirmed, then at least 1 year to complete, aromatase inhibitors for 5 years.

●Postmenopausal (refer to NCCN guideline for definition) women: aromatase inhibitors for 5 years

TREATMENT

Department of Clinical Effectiveness V13

Breast All invasive Cancer

types HER2/neu

●ER ●PR

●Ki-67 (MIB-1)labeling index ●HER2/neu

● MammaPrint2 ● Oncotype DX2

DISEASE CELL TYPE FISH IMMUNOHISTOCHEMISTRY MOLECULAR

BIOMARKER

1 _{Literature support for MD Anderson approved Biomarkers is available and can be found under Clinical Management Algorithms  “Biomarkers – MD Anderson Approved”} 2 _{Multi-gene prognostic assay}

Page 9 of 14

including the following: MD Anderson’s specific patient population; MD Anderson’s services and structure; and MD Anderson’s clinical information. Moreover, this algorithm is not intended to replace the independent medical or professional judgment of physicians or other health care providers. This algorithm should not be used to treat pregnant women.

Copyright 2015 The University of Texas MD Anderson Cancer Center

Department of Clinical Effectiveness V13 Approved by Executive Committee of the Medical Staff 06/30/2015

Breast Cancer – Invasive

1

APPENDIX B - Clinical Scenarios Requiring Individualized Therapy:

● Brain metastases ● Cord compression

● Ureteral obstruction ● Pericardial effusion

● Leptomeningeal disease ● Plexopathy/radiculopathy

● Impending pathologic fracture ● Biliary obstruction

● Choroid metastases ● Superior vena cava syndrome

● Pathologic fracture ● Stage IV NED

● Extensive local-regional disease ● Oligometastasis

● Pleural effusion ● Pregnancy

NOTE: Oligometastases – selected patients with isolated metastatic breast cancer may be considered for definitive treatment.

SUGGESTED READINGS

Albain KS, Barlow WE, Ravdin PM, et al. (2009). Breast Cancer Intergroup of North America. Adjuvant chemotherapy and timing of tamoxifen in postmenopausal patients with endocrine-responsive, node-positive breast cancer: a phase 3, open-label, randomised controlled trial. Lancet; 374(9707):2055-63.

Baselga J, Campone M, Piccart M, et al. (2012). Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med; 366(6): 520-9.

Baselga J, Cortes J, Kim SB, et al. (2012). CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med; 366(2):109-19.

Bear H, Anderson S, Smith R, et al. (2006). Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol; 24(13):2019-27.

Breast. In: Edge SB, Byrd SR, Compton CC, Fritz AG, Greene FL, Trotti A III, eds. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010:347-376.

Buchholz TA, Theriault RL, Niland JC, et al. (2006). The use of radiation as a component of breast conservation therapy in National Comprehensive Cancer Network Centers. J Clin Oncol; 24(3):361-9.

Buchholz TA. (2009). Radiation therapy for early-stage breast cancer after breast-conserving surgery. N Engl J Med; 360(1):63-70.

Burstein HJ, Prestrud AA, Seidenfeld J, et al. (2010). American Society of Clinical Oncology clinical practice guideline: Update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer.

J Clin Oncol; 28(23):3784-3796.

Buzdar A, Ibrahim N, Francis D, et al. (2005). Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: Results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol; 23(16):3676-85.

Caudle AS, Gonzalez-Angulo AM, Hunt KK, et al. (2010). Predictors of tumor progression during neoadjuvant chemotherapy in breast cancer. J Clin Oncol; 28(11):1821-8.

Caudle AS, Hunt KK, Kuerer HM, et al. (2011). Multidisciplinary considerations in the implementation of the findings from the American College of Surgeons Oncology Group (ACOSOG) Z0011 study: a practice-changing trial. Ann Surg Oncol; 18(9):2407-12.

Clarke M, Collins R, Darby S, et al. (2005). Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Lancet; 366(9503):2087-106.

Early Breast Cancer Trialists' Collaborative Group. (2005). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials.

Lancet; 365(9472):1687-1717.

EBCTCG (Early Breast Cancer Trialists’ Collaborative Group), McGale P, Taylor C, Correa C, et al. (2014). Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet; 383(9935):2127-35.

Fearmonti RM, Vicini FA, Pawlik TM, et al. (2007). Integrating partial breast irradiation into surgical practice and clinical trials. Surg Clin North Am; 87(2):485-98.

Fisher B, Bryant J, Wolmark N, et al. (1998). Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol; 16(8):2672-85.

Fisher B, Jeong JH, Anderson S, et al. (2002). Twenty-five-year follow-up of a randomized trial comparing radical mastectomy, total mastectomy, and total mastectomy followed by irradiation.

N Engl J Med; 347(8):567-75.

Floyd SR, Buchholz TA, Haffty BG, et al. (2006). Low local recurrence rate without postmastectomy radiation in node-negative breast cancer patients with tumors 5 cm and larger.

Int J Radiat Oncol Biol Phys; 66(2):358-64.

Foulkes WD, Smith IE, Reis-Filho JS. (2010). Triple-negative breast cancer. N Engl J Med; 363(20):1938-48.

Gennari A, Stockler M, Puntoni M, et al. (2011). Duration of chemotherapy for metastatic breast cancer: a systematic review and meta-analysis of randomized clinical trials. J Clin Oncol; 29(16):2144-9.

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including the following: MD Anderson’s specific patient population; MD Anderson’s services and structure; and MD Anderson’s clinical information. Moreover, this algorithm is not intended to replace the independent medical or professional judgment of physicians or other health care providers. This algorithm should not be used to treat pregnant women.

Breast Cancer – Invasive

SUGGESTED READINGS - Continued

Copyright 2015 The University of Texas MD Anderson Cancer Center

Gianni L, Eiermann W, Semiglazov V, et al. (2010). Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): A randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet; 375(9712):377-84.

Gianni L, Pienkowski T, Im YH, et al. (2012). Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol; 13(1):25-32.

Giordano SH, Kuo YF, Freeman JL, et al. (2005). Risk of cardiac death after adjuvant radiotherapy for breast cancer. J Natl Cancer Inst; 97(6):419-24.

Giuliano AE, Hunt KK, Ballman KV, et al. (2011). Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial.

JAMA; 305(6):569-75.

Giuliano AE, McCall L, Beitsch P, et al. (2010). Locoregional recurrence after sentinel lymph node dissection with or without axillary dissection in patients with sentinel lymph node metastases: the American College of Surgeons Oncology Group Z0011 randomized trial. Ann Surg; 252(3):426–33.

Huang EH, Strom EA, Valero V, et al. (2007). Locoregional treatment outcomes for breast cancer patients with ipsilateral supraclavicular metastases at diagnosis.

Int J Radiat Oncol Biol Phys;67(2):490-6.

Hunt KK, Yi M, Mittendorf EA, et al. (2009). Sentinel lymph node surgery after neoadjuvant chemotherapy is accurate and reduces the need for axillary dissection in breast cancer patients.

Ann Surg; 250(4):558-66.

Jeruss J, Mittendorf E, Tucker S, et al. (2008).Combined use of clinical and pathologic staging variables to define outcomes for breast cancer patients treated with neoadjuvant therapy.

J Clin Oncol; 26(2):246-52.

Jones SE, Savin MA, Holmes FA, et al. (2006). Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer.

J Clin Oncol; 24(34):5381-5387.

Kelly CM, Hortobagyi GN. (2010). Adjuvant chemotherapy in early-stage breast cancer: what, when, and for whom? Surg Oncol Clin N Am; 19(3):649-68.

Krag DN, Anderson SJ, Julian TB, et al. (2010).Sentinel-lymph-node resection compared with conventional axillary-lymph-node dissection in clinically node-negative patients with breast cancer: overall survival findings from the NSABP B-32 randomised phase 3 trial. Lancet Oncol; 11(10):927-33.

Krag DN, Anderson SJ, Julian TB, et al. (2007). Technical outcomes of sentinel-lymph-node resection and conventional axillary-lymph-node dissection in patients with clinically node-negative breast cancer: results from the NSABP B-32 randomised phase III trial. Lancet Oncol; 8(10):881-8.

Kuerer H, Sahin A, Hunt K, et al. (1999). Incidence and impact of documented eradication of breast cancer axillary lymph node metastases before surgery in patients treated with neoadjuvant chemotherapy. Ann Surg; 230(1):72-8.

Kuerer HM, Hunt KK, Newman L, et al. (2000). Neoadjuvant chemotherapy in women with invasive breast carcinoma: conceptual basis and fundamental surgical issues.

J Am Coll Surg; 190(3):350-63.

Kuerer HM, Newman LA, Smith TL, et al. (1999). Clinical course of breast cancer with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy. J Clin Oncol; 17(2):460-9.

Lucci A, McCall LM, Beitsch PD, et al. (2007). American College of Surgeons Oncology Group. Surgical complications associated with sentinel lymph node dissection (SLND) plus axillary lymph node dissection compared with SLND alone in the American College of Surgeons Oncology Group trial Z0011. J Clin Oncol; 25(24):3657–63.

Department of Clinical Effectiveness V13 Approved by Executive Committee of the Medical Staff 06/30/2015

Mehta RS, Barlow WE, Albain KS, et al. (2012). Combination anastrozole and fulvestrant in metastatic breast cancer. N Engl J Med; 367(5):435-44.

Mittendorf EA, Buchholz TA, Tucker SL, et al. (2013). Impact of chemotherapy sequencing on local-regional failure risk in breast cancer patients undergoing breast-conserving therapy.

Ann Surg; 257(2):173-9.

National Comprehensive Cancer Network (NCCN). Practice Guidelines in Oncology: Breast Cancer. Version 3.2014.

Paik S, Shak S, Tang G, et al. (2004). A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Eng J Med; 351:2817-26.

Paik S, Tang G, Shak S, et al. (2006). Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol; 24(23):3726-34.

Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. (2005). Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med; 353(16):1659-1672.

Pritchard KI, Shepherd LE, O’Malley FP, et al. (2006). HER2 and responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med; 354(20):2103-11.

Prudence A, Francis MD, Meredith, MR, et al (2015). Adjuvant ovarian suppression in premenopausal breast cancer. N England J Med; 372:436-446. PMID: 25495490 doi: 10.1056/NEJMoa1412379. Epub 2014 Dec 11.

Romond EH, Perez EA, Bryant J, et al. (2005). Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med; 353(16):1673-1684.

Smith BD, Arthur DW, Buchholz TA, et al. (2009). Accelerated partial breast irradiation consensus statement from the American Society for Radiation Oncology (ASTRO).

J Am Coll Surg; 209(2):269-77.

Smith BD, Haffty BG, Buchholz TA, et al. (2006). Effectiveness of radiation therapy in older women with ductal carcinoma in situ. J Natl Cancer Inst; 98(18):1302-10.

Smith BD, Haffty BG, Smith GL, et al. (2008). Use of postmastectomy radiotherapy in older women. Int J Radiat Oncol Biol Phys; 71(1):98-106.

Sparano JA, Wang M, Martino S, et al. (2008). Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med; 358(16):1663-71.

Symmans W, Peintinger F, Hatzis C, et al. (2007). Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol; 25(28):4414-22.

Veronesi U, Viale G, Paganelli G, et al. (2010). Sentinel lymph node biopsy in breast cancer: ten-year results of a randomized controlled study. Ann Surg; 251(4):595–600.

Vicini F, Beitsch P, Quiet C, et al. (2011). Five-year analysis of treatment efficacy and cosmesis by the American Society of Breast Surgeons MammoSite Breast Brachytherapy Registry Trial in patients treated with accelerated partial breast irradiation. Int J Radiat Oncol Biol Phys; 79(3):808-17.

Yamauchi H, Woodward WA, Valero V, et al. (2012). Inflammatory breast cancer: What we know and what we need to learn. Oncologist; 17(7):891-9.

SUGGESTED READINGS - Continued

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including the following: MD Anderson’s specific patient population; MD Anderson’s services and structure; and MD Anderson’s clinical information. Moreover, this algorithm is not intended to replace the independent medical or professional judgment of physicians or other health care providers. This algorithm should not be used to treat pregnant women.

Breast Cancer – Invasive

Burstein HJ, Kuter I, Campos SM, et al. (2001). Clinical activity of trastuzumab and vinorelbine in women with HER2-overexpressing metastatic breast cancer. J Clin Oncol,19,2722-30.

Cobleigh MA, Vogel CL, Tripathy D, et al. (1999). Multinational Study of the Efficacy and Safety of Humanized Anti-HER2 Monoclonal Antibody in Women Who Have HER2- Overexpressing Metastatic Breast Cancer That Has Progressed After Chemotherapy for Metastatic Disease. J Clin Oncol, 17,2639-48.

Esteva FJ, Valero V, Booser D, et al. (2002). Phase II Study of Weekly Docetaxel and Trastuzumab for Patients With HER2-Overexpressing Metastatic Breast Cancer. J Clin Oncol, 20,1800-1808. Geyer CE, Forster J, Lindquist D, et al. (2006). Lapatinib plus Capecitabine for HER2-Positive Advanced Breast Cancer. NEJM,355,2733-43.

Gradishar WJ, Tjulandin S, Davidson N, et al. (2005). Phase III Trial of Nanoparticle Albumin-Bound Paclitaxel Compared With Polyethylated Castor Oil-Based Paclitaxel in Women With Breast Cancer. J Clin Oncol 23:7794-7803 Leyland-Jones, Gelmon, Ayoub JB, et al. (2003). Pharmacokinetics, Safety, and Efficacy of Trastuzumab Administered Every Three Weeks in Combination with Paclitaxel. J Clin Oncol 21, 3965-3971.

O’Brien, M. E., Wigler, N., Inbar M, et al. (2004). Reduced Cardiotoxicity and Comparable Efficacy in a Phase lll Trial of Pegylated Liposomal Doxorubicin HC1 (CAELYX/Doxil) vs. Conventional Doxorubicin for First-Line Treatment of Metastatic Breast Cancer. Ann Oncol, 15(3), 440-9.

Perez E. (2004). Carboplatin in combination therapy for metastatic breast cancer. The Oncologist, 9,518-527.

Slamon DJ, Leyland-Jones B, Shak S, et al. (2001). Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med, 344,783-92.

SUGGESTED READINGS – Chemotherapy Regimens for Metastatic Breast Cancer and in Combination with Transtuzumab

Copyright 2015 The University of Texas MD Anderson Cancer Center

Department of Clinical Effectiveness V13 Approved by Executive Committee of the Medical Staff 06/30/2015

This practice consensus algorithm is based on majority expert opinion of the Breast Center Faculty at the University of Texas MD Anderson Cancer Center. It was developed using a multidisciplinary approach that included input from the following breast multidisciplinary team members.

DEVELOPMENT CREDITS

ŦCore Development Team

Sausan Abouharb, MD Beatriz Adrada, MD Catherine Akay, MD Constance Albarracin,MD Frederick Ames, MD Elsa Arribas, MD Banu K. Arun, MD Carlos Barcenas, MD Robert C. Bast, MD Gildy Babiera, MD Isabelle Bedrosian, MD Daniel J. Booser, MD Shon Black, MD Abenna Brewster, MD Powel Brown, MD Thomas Buchholz, MD Aman U. Buzdar, MD Abigail Caudle, MD

Mariana Chavez-Mac Gregor, MD

Department of Clinical Effectiveness V13

Hui Chen, MD Alejandro Contreras, MD Sarah DeSnyder, MD Mark Dryden, MD Mary Edgerton, MD Barry Feig, MD Bruno Fornage, MD Michael Gilcrease, MD Sharon Giordano, MD Tamara Haygood, MD Karen Hoffman, MD Gabriel N. Hortobagyi, MD Kelly K. Hunt, MD Ŧ Lei Huo, MD Rosa Hwang, MD Nuhad K. Ibrahim, MD Meghan Karuturi, MD Kimberly Koenig, MD Savitri Krishnamurthy, MD Henry M. Kuerer, MD, PhD Deanna Lane, MD Huong Le-Petross, MD Jennifer Litton, MD Ŧ Anthony Lucci, MD Funda Meric-Bermstam, MD Lavinia Middleton, MD Elizabeth Mittendorf, MD, PhD Stacy Moulder, MD James L. Murray,III, MD Rashmi Murthy, MD George Perkins, MD Erika Resetkova, MD Merrick I. Ross, MD Aysegul A. Sahin, MD Lumarie Santiago, MD Simona Shaitelman, MD Benjamin Smith, MD Nour Sneige, MD Tanya Moseley, MD Michael Stauder, MD Eric Strom, MD Fraser W. Symmans, MD Welela Tereffe, MD Ŧ Mediget Teshome, MD Alastair Thompson, MD Debasish Tripathy, MD Naoto T. Ueno, MD, PhD Vicente Valero, MD Ronald Walters, MD Gary Whitman, MD Wendy Woodward, MD Yun Wu, MD Wei Yang, MD Amy Zhang, MD