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breast cancer

Classification: 1) carcinoma, NOS (not otherwise specified) 2) ductal breast carcinoma a) intraductal (in situ) b) invasive with predominant intraductal component c) invasive, NOS d) comedo e) inflammatory f) medullary with lymphocytic infiltrate g) mucinous (colloid) h) papillary i) scirrhous j) tubular k) other 3) lobular breast carcinoma a) in situ b) invasive with predominant in situ component c) invasive 4) nipple a) Paget disease, NOS b) Paget disease with intraductal carcinoma c) Paget disease with invasive ductal carcinoma 5) other - undifferentiated carcinoma [48] 6) 4 molecular subtypes [63] a) luminal A (best prognosis) - despite best early survival, associated with a steady drop in survival over 20 years with little leveling off in later years [64] b) luminal B (2-fold higher mortality than luminal A) c) basal-like - genetic similarities with high-grade ovarian cancer [63] d) HER2-enriched (2-fold higher mortality than luminal A) Etiology: 1) chromosomal aberrations (see genetics) 2) see risk factors for breast cancer Epidemiology: - 10-12% of women will develop breast cancer - incidence is highest non-hispanic whites, 2nd in black women [4] - incidence of breast cancer increases with age - 95% of cases occur in women > 40 years of age - most common cause of cancer-related death in women age 35-54; 50% of breast cancer-related death occur in women < 50 years of age [78] - 3.5% will die of the disease - mortality rates are 15% higher in blacks despite a lower incidence of breast cancer [65] - incidence of metastatic breast cancer among women 25-39 years of age increased from 1.53/100,000 in 1976 to 2.90/100,000 in 2009 [66]; higher among blacks, non-Hispanic whites, & those with estrogen receptor-positive tumors [66] Pathology: 1) in general, patients with estrogen receptor positive tumors have a better prognosis 2) infiltrating ductal carcinoma is the most common histological type 3) lobular type is more frequently multifocal & bilateral 4) ductal carcinoma in situ is non-invasive (basement membrane is preserved) 5) sites of metastases (of those that metastasize) a) lymph nodes (60-80%) b) liver (40-60%) c) lung (66%) d) bone (62%) e) brain (23%); 1] ER(+): 0.7%; ER(-): 1.9% [46] 2] ER(-), PR(-), HER2(-): 9.6% (5-year incidence) [46] 3] 20% of ER(+). HER2(-) breast cancers with HER2(+) brain metastases [123] f) skin (20%) g) adrenal (20%) h) kidney (17%) 6) changes in ER/PR status in 40% of metastases [45] 7) changes in HER2 status in 8% of metastases [45] 8) metastases of breast cancer occurs predominantly during sleep [162] 9) tumor grade & hormone receptor status more important than tumor size in predicting prognosis [126] Genetics: - 70% of cases are sporadic - absolute lifetime risk for developing breast cancer for commonly mutated genes: - 50-70% for BRCA1 & BRCA2 (autosomal dominant with incomplete penetrance) - 30% for PALB2 - 25% for CHEK2 - 20% for ATM [154] - BRCA2 & PALB2 variants were associated with triple-negative disease [160] - BRAC1 associated with all subtypes with highest risk for triple-negative disease [160] - RAD51C, RAD51D, & BARD1 variants associated with triple-negative disease [160] - women with ATM & CHEK2 mutations more likely to develop ER-positive than ER-negative breast cancer [154] - CHEK2 variants associated with all subtypes except triple-negative disease [160] - BRCA genes: BRCA-1, BRCA-2; BRIP1, BARD1 - 10% incidence at age 47 within 2 years - ATM, CDH1, MLH1, MSH2, STK11 also included in CPT panels - HER2/NEU proto-oncogene - overexpression in 15-25% of cases - overexpression predicts more aggressive disease - BRMS1 is a breast carcinoma metastasis suppressor gene that maps to 11q13, a hotspot in breast cancer progression - fascin marks & mediates breast cancer metastasis to lungs - Li-Fraumeni syndrome - 17q23 region is commonly amplified - in ER(+)/HER2(-) postmenopausal, early-stage BC, amplifications on 11q13 & 8p11 associated with risk for distant recurrence [139] - methylation-mediated silencing may affect genes & proteins that act as positive mediators of cell death including: PYCARD - chromosomal deletion involving UHRF2 is found in multiple kinds of malignancies - n ER(+)/HER2(-) BC, PIK3CA mutations predictive of greater response to letrozole [139] - other implicated genes - ROBO1, LDOC1, POSTN, EMSY, ACRBP, BCAS1, BCAS2, BCAS3, BCAS4, RB1CC1, PPP1R13L, CITED4, PBOV1, TSP50, C2orf4, LYPD3, WFDC2, NANOGP8, ATAD2, ANKRD30A, JARID1B, SUV420H1, SH3PXD2A, CHRDL2, SULF1, KAT, CHPT1, ANLN, PRAF2, KIAA0100, TBRG1, ARID4B, SGOL1, CDCA7, CSAG2, TAK1L, FMR1NB, MIER1, BAGE1, PELP1, SBEM, LRP16, PHB, LRRC26, LETMD1, CXCL17, BANP, PVRL4, DPH1, SLC39A10, BCL9L, EPSTI1, AFAP1, LENG4, XRRA1, CRIPAK, GREB1, CCNDBP1, PPIAL4B, PPIAL4, PEG10, CCNG1, CDK1, ITIH5, PRKCDBP, MMP11, CLCA2, HEATR6, RUNDC3B, SLC5A8, c-MYC, VTCN1, GLI1, EED, MCTS1, ZNF202, CDH1, SLC22A18, CD167a, ADAM11, ADAMTS20, MMP17, S100L, TPM1, WISP1, HYOU1, SNCG, CDKN3, KTN1, BIRC5, RAD51, TFF1, BRCC3, KCNK9, MRE11A, NEK3, SIK1, NEK8, SCGB2A2, SCGB3A1, FAIM2, LIMD1 Clinical manifestations: 1) solitary or dominant breast mass 2) breast thickening or asymmetry a) skin edema and thickening b) lobular breast carcinoma may be felt as a fullness rather than as a distinct mass 3) nipple inversion 4) unilateral bloody discharge 5) axillary or supraclavicular mass Laboratory: 1) surveillance testing not indicated in the absence of specific symptoms 2) for diagnosed breast cancer a) liver function testing b) serum alkaline phosphatase c) complete blood count (CBC) 3) immunocytochemistry a) estrogen receptor + progesterone receptor in tissue b) HER2/neu in tissue - HER2 in breast cancer specimen 4) FISH or PCR/southern blot/northern blot/ISH for HER2/neu if histopathology confirms invasive breast cancer - HER2 copy number - HER2/CEP17 in tissue 5) nipple discharge fluid for cytology [4] 6) BRCA1 & BRCA2 genotyping - family history of breast cancer ovarian cancer or Ashkenazi Jewish heritage [4] - age < 45 years - family history of breast cancer or ovarian cancer - triple negative (ER-, PR-, HER2-) < 60 years [1] - USPSTF recommends against BRCA1 & BRCA2 genetic testing in women without family history of breast cancer [32] 7) breast cancer 21 mRNA expression analysis (multigene recurrence assay) - Oncotype DX for breast cancer [137, NICE] - assess need for chemotherapy in low-risk ER+ breast cancer - recurrence score < 26 & < 4 positive nodes can avoid adjuvant chemotherapy without negative impact on disease-free survival [159] - may become routine [137] - not useful for determining need for anti-estrogen therapy in DCIS [4] 8) loincs for pathology reports - adjacent structure invaded by breast cancer by microscopy - adjacent structure invaded by breast cancer gross observation - distance of carcinoma from surgical margin in breast cancer - surgical margin DCIS involvement in breast cancer - radial position in breast cancer specimen - estrogen receptor in breast cancer specimen - estrogen receptor Ag in breast cancer specimen - foci in breast cancer specimen - glandular differentiation in breast cancer specimen - growth pattern of DCIS in breast cancer specimen - LCIS in breast cancer specimen - mitotic rate in breast cancer specimen - breast cancer pathology panel - also see ductal carcinoma in siti (DCIS) & lobular carcinoma in situ (LCIS) 9) not routine a) breast cancer-related disorders genomic sequencing b) breast cancer gene duplication & deletion analysis c) DNA microarray analysis - prognosis for developing metastasis in axillary node-negative breast cancer [13] - multigene testing proposed for hereditary breast cancer & ovarian cancer [103] d) bone marrow aspirate for micrometastasis [33] e) autoantibodies: KIAA1671 f) prognostic markers: EBAG9 g) measures of metastatic burden - circulating cell-free DNA carrying tumor-specific mutations [67] - cancer antigen CA 15-3 [67] (not for early-stage breast cancer) [4] h) cell-sorting to isolate circulating breast cancer cells from peripheral blood, culture & genotyping [91] i) 70-gene signature expression profile j) most of the 100-plus genes commonly included in gene panels have no known link to breast cancer [97] 10) assessment of recurrence - breast cancer Ag 225 in tissue [125] 11) other markers - mammaglobin Ag in tissue 12) see ARUP consult [61] 13) higher serum estradiol in men is associated with excess risk for breast cancer [100] Special laboratory: 1) core-needle biopsy - may be stereotactically guided by mammography 2) open excisional biopsy 3) fine needle aspiration (FNA) not recommended [4] a) may allow cytologic diagnosis of breast cancer b) a negative FNA is not sufficient to rule out breast cancer c) most useful for differentiating solid mass from cyst Radiology: 1) mammography a) 10% of breast carcinoma is negative on mammography b) sensitivity of mammography may be much less in high-risk women [27] c) core or excisional biopsy if mammography is negative, but lump or mass is present d) mammography screening leads to 15-25% overdiagnosis of invasive breast cancer [57] e) followup annual mammography for women with breast cancer [4] 2) ultrasonography as indicated 3) MRI in high-risk women BRCA1/2 mutations or family history [27,31] 4) bone scan not routinely indicated 5) negative imaging does not rule out breast cancer [4] 6) imaging studies to rule out metastases for stage 1 & 2 - not recommended in asymptomatic women [4] - symptomatic women & prior recommendations - hormone receptor negative - HER2 positive (overexpression) - large size of primary neoplasm - high tumor grade - positive lymph nodes - lymphatic &/or vascular invasion [4] 7) CT or PET scan for stage 3 or metastatic disease - PET-CT staging approach detects more distant metastases than conventional staging [164] 8) surveillance imaging not routinely indicated, imaging sign/symptom driven [4] 9) dual energy X-ray absorptiometry (DEXA) to assess bone mineral density for women taking aromatase inibibitor Complications: - complications of therapy - cognitive impairment (brain fog) [81] - risk factors include breast cancer & breast cancer treatment, as well as patient-related vulnerabilities [158] - persistent cognitive impairment > 20 years after adjuvant chemotherapy [56] - most older women do not experience cancer-related cognitive decline within the 1st 2 years after diagnosis & treatment [145] - women with an apoE4 allele may be at high risk for cognitive decline [145] - cognitive impairment may occur with hormonal therapy alone [149] - tamoxifen & aromatase inhibitors associated with lower incidence of neurodegenerative disorders [150] - increased risk of myelodysplasia, acute myeloid leukemia. endometrial cancer & (rarely) soft tissue sarcoma [4] - long-term aromatase inhibitor therapy increases risk of osteoporosis & pathologic fractures [4,8] - 30-50% of all long-bone pathologic fractures - most commonly occurs in proximal femur - alopecia - scalp cooling system (DigniCap) FDA-approved Dec 2015 may reduce chemotherapy (taxane)-related alopecia - malignant pericardial effusion - breast cancer identified between screening mammograms more likely associated with other cancers both before & after breast cancer diagnosis [146] - interval breast cancer detected between screeninga associated with higher mortality than breast cancer detected during routine screening mammography [146] Differential diagnosis: 1) fibroadenoma a) hard, mobile breast nodule b) generally in young women c) tend to fluctuate with menstrual cycle & pregnant d) may regress with menopause 2) cysts a) most common during breast involution which begins at age 35 & continues through menopause b) ultrasound & core or excisional biopsy are useful for distinguishing cysts from solid tumors 3) mastitis a) generally secondary to gram positive organisms b) associated signs of infection may be present c) response to antibiotics distinguishes from breast cancer 4) 80% of non-palpable suspicious breast lesions detected by mammography will be found benign on biopsy Management: === staging/prognosis === 1) lymph node involvement & tumor size are most important prognostic indicators 2) sentinel lymph node biopsy has replaced axillary lymph node dissection for staging in clinically lymph node negative women with early-stage breast cancer 3) sentinal lymph node biopsy - has not been shown to improve survival in the absence of palpable nodes (GRS9) [14] - recommended in addition to breast-conserving surgery in a patient with asymptomatic ER+/PR+/HER2- invasive ductal carcinoma without palpable nodes (GRS11) [14] - recommended if clinically negative axillary lymph nodes (MKSAP19) [4] 4) positive sentinal axillary node a) axillary lymph node dissection indicated (MKSAP19) [4] b) the majority of woman with positive axillary node(s) will have recurrence, thus are candidates for adjuvant therapy to surgery c) breast-conserving surgery with whole-breast radiotherapy - axillary lymph node dissection not indicated [84] d) mastectomy - axillary lymph node dissection should be offered [84] 5) negative sentinal axillary node a) 5-10% chance of involvement of other axillary lymph nodes [4] b) 25-30% of women will experience disease recurrence c) 10% of women with tumors < 1 cm will have recurrence d) receptor status, tumor grade, DNA index & S-phase fraction also affect likelihood of recurrence e) axillary lymph node dissection not indicated [84] 6) sentinal lymph node biopsy not indicated in women with concurrent pregnancy, pure ductal carcinoma in situ (DCIS) undergoing lumpectomy, or locally advanced (T3/T4) tumors or inflammatory breast cancer [122] 7) gene expression profiling is gaining acceptance === treatment modalities === 1) surgery [47] a) breast-conserving therapy - standard of care for all patients with early disease a] tumors < 5 cm involving a single quadrant b] no skin or chest wall involvement c] clear surgical margins after resection d] absence of hereditary breast cancer syndrome [4,14,70] - age >80 not a contraindication [117] - consists of excision of primary tumor & radiation therapy [4] - positive resection margins warrant additional surgery - negative margins with no ink on tumor provide optimal outcomes, and routine re-excision is not indicated [82] - shaving off additional breast tissue during partial mastectomy is associated with lower rate of cancer in the adjacent tissue [98] - 12% with negative margins have cancer detected after cavity shaving [98] - neo-adjuvant chemotherapy with breast-conserving surgery [4] - breast-conserving therapy + radiation therapy associated with better survival than mastectomy with or without radiation therapy [156] b) mastectomy 1] indications a] invasive breast cancer (positive margins) with tumors involving the skin, chest wall or > 1 quadrant b] breast cancers > 5 cm c] inflammatory breast cancer d] BRCA1 mutation or BRCA1 mutation is indication for bilateral mastectomy (subsequent risk of ipsilateral & contralateral breast cancer) [4,111] e] most patients with positive axillary nodes 2] modified radical mastectomy a] removal of breast b] axillary dissection c] preservation of pectoral muscle d] with or without breast reconstruction 3] mastectomy is not indicated for patients with metastatic breast cancer unless required for local cancer control [4] 4] prophylactic mastectomy is not completely protective against development of breast cancer c) axillary node dissection of uncertain benefit 1] does not affect overall or disease-free 10-year survival in women with 1 or 2 positive sentinal lymph nodes [54,131] a] resection of sentinal nodes alone non-inferior [131] b] unnecessary in patients with sentinel node micrometastasis [143] 2] not indicated for carcinoma in-situ or metastatic breast cancer d) chronic pain common after breast cancer surgery; associated factors include younger age, adjuvant radiation therapy, & more-extensive axillary surgery [48] e) prophylactic bilateral oophorectomy in BRCA1-positive estrogen receptor-negative breast cancer within 2 years of diagnosis (RR for mortality = 0.38) [96] f) combination of COX2 inhibitor + beta blocker for 11 days beginning 5 days prior to surgery & continuing 5 days after day of surgery may inhibit metastases [129] - etodolac 400 mg PO BID - propranolol 20 mg PO BID, 80 mg PO BID on day of surgery g) 30-day & 1-year mortality & functional decline high in elderly nursing home residents after surgery for breast cancer [142] 2) radiation therapy - 40 Gy in 15 fractions [79] - chest wall radiadion therapy indicated after mastectomy if: - invasive tumor > 5 cm [4] - positive surgical margins - dermal or chest wall invasion - inflammatory breast cancer - 4 or more positive nodes - ref [4] would suggest standard of care after mastectomy - increases survival (MKSAP19) [4] - used with breast-conserving therapy - hypofractionated whole-breast irradiation regardless of chemotherapy history, age, or tumor stage [136] - justified even for tumors < 1 cm in size [15] - not indicated for lobular breast carcinoma - accelerated partial breast irradiation noninferior to whole breast irradiation for preventing local recurrence, but associated with worse cosmetic.outcomes [147] - axillary irradiation after axillary dissection is NOT indicated; results in unacceptable lymphedema - reduces risk of recurrence after lumpectomy even in patients who receive adjuvant tamoxifen - reduces risk of recurrence after breast conserving surgery [55] - longer interval from breast conserving surgery to radiotherapy increases incidence of local recurrence in elderly women [50] - adds little benefit to adjuvant tamoxifen for women > 70 years of age with estrogen receptor-positive stage 1 breast cancer [93] - may not benefit subgroups of women [99] - older women with node-negative estrogen receptor positive who receive 5 years of adjuvant endocrine therapy [163] - local recurrence in low-risk (age >60, T1 stage, grade 1 or 2 histopathology) luminal A subtype treated with tamoxifen without radiation after lumpectomy is 1.3% vs 5.0% at 10 years if radiation therapy is given [99] - radiation therapy has no effect on survival of these women [163] - brachytherapy associated with worse outcomes than whole breast irradiation [60] - noninvasive stereotactic delivery of radiation to part of the breast in conjunction with breast conserving treatment(GammaPod) FDA-approved Dec 2017 [135] - has not been shown to be as effective as whole breast radiation [135] 3) ovarian suppression indicated for premenopausal women with high-risk breast cancer [4] - bilateral oophorectomy or pelvic irradiation 4) pharmaceutical agents (chemotherapy) a) hormonal therapy (tamoxifen or aromatase inhibitor) - indicated for stage 1-3 ER/PR-positive breast cancer [4] - can reduce risk of recurrence in estrogen receptor-positive & progesterone receptor-positive tumors by 50% [4] - associated with increased overall survival [4] - not recommended for node-negative tumors < 0.5 cm in size - endocrine therapy alone adequate for hormone receptor positive, HER2 negative, axillary node negative breast cancer with mid-range genetic scores (11-25) based on genetic testing of tumor [137]; no benefit of chemotherapy [4] - endocrine therapy preferably with an aromatase inhibitor (tamoxifen for aromatase inhibitor intolerance) prolongs survival in estrogen-receptor positive early breast cancer in postmenopausal women [157] - metastatic breast cancer is not curable, but hormonal therapy can improve survival, alleviate symptoms, & improve quality of life for women with hormone receptor positive breast cancer - for hormonal agents other than tamoxifen or aromatase inhibitor see antineoplastic endocrine agent & estrogen antagonist b) tamoxifen recommended for 1] premenopausal women with estrogen receptor positive breast cancer; 10 years of therapy [4,88] a] node-positive women > 50 years of age; both estrogen receptor positive & negative patients allegedly receive benefit b] estrogen receptor positive tumors > 2 cm, or 1-2 cm with other poor prognostic indicators c] node-negative, receptor positive women > 60 years of age [25] d] recommendations for postmenopausal women preceding aromatase inhibitors e] women who become postmenopausal may switch to aromatase inhibitor for an aditional 5 years after 5 years of tamoxifen [4] 2] ovarian suppression with leuprolide + exemestane [89] a] useful for premenopausal women who require adjuvant chemotherapy b] 5 year disease-free survival in premenopausal women higher for leuprolide + exemestane (aromatase inhibitor) than for leuprolide + tamoxifen (91.1% vs. 87.3%) [89] c] no better than tamoxifen for low risk breast cancer not needing adjuvant chemotherapy [4] d] useful for premenopausal women with contraindication to tamoxifen [4] - ovarian ablation is alternative [4] c) aromatase inhibitors are superior to tamoxifen in post-menopausal women [4,19,52,101] 1] lower breast cancer recurrence in postmenopausal women relative to tamoxifen by 30% [101] 2] lower breast cancer mortality in postmenopausal women relative to tamoxifen [101] 3] post-menopausal women with hormone receptor-positive, HER2 negative breast cancer with <=3 positive lymph nodes may be treated without chemotherapy with aromatase inhibitor alone regardless of 21-gene recurrence score [151] 4] selection of aromatase inhibitor a] anastrozole (Arimidex) [6,10,28,41] b] letrozole (Femara) [35];intermittent letrozole (2.5 mg/day for 9 months, followed by 3-month break for years 1 to 4; then daily treatment in year 5) with similar outcomes to continuous daily treatment [133] c] PIK3CA mutations predictive of greater response to letrozole [139] d] exemestatine (Aromasin) 5] 5 years of therapy [4] - 5 years of aromatase inhibitor or 2 years of tamoxifen followed by 3 years of aromatase inhibitor improves survival in women with higher grade cancer [4] 6] extending duration of aromatase inhibitor therapy beyond 5 years enhances disease-free survival & possibly lowers breast cancer-related mortality [43] 7] 10 years of aromatase inhibitor therapy beneficial [116] - reduces recurrence vs 5 years but does not improve overall survival [4] 8] 2 years of aromatase inhibitor therapy after 5 years of tamoxifen reduces risk of breast cancer relapse [134] 9] Ca+2, vitamin D & bisphosphonate may be appropriate* 10] dual energy X-ray absorptiometry (DEXA) to assess bone mineral density for women taking aromatase inibibitor* [4] d) single-agent paclitaxel not recommended [90] e) adjuvant combination chemotherapy, adjunct to radiation, surgery 1] not indicated in ER/PR receptor positive patients with either bone or asymptomatic visceral metastases [4] 2] indicated for most other patients with invasive breast cancer [4] 3] adjuvant anthracycline-based chemotherapy for triple negative or HER2+ breast cancer > 0.5 cm or with positive axillary nodes [4] 4] see chemotherapy for breast cancer f) neoadjuvant chemotherapy may facilitate lumpectomy in tumors otherwise too large [4] 1] ER/PR receptor negative, HER2 positive & triple negative (ER/PR receptor negative, HER2 negative) respond to neoadjuvant chemotherapy [4] - anthracycline-base chemotherapy for early stage triple negative breast cancer (ER-, PR-, HER2-) [4] 2] neoadjuvant trastuzumab benefits ER/PR receptor negative, HER2 positive tumors & may facilitate lumpectomy in tumors otherwise too large [4] a] pertuzumab may be used with trastuzumab for HER2-positive tumors > 2 cm or sentinal node positive [4] b] combination of pertuzumab, trastuzumab & docetaxel c] echocardiogram to evalute LV function prior to & during trastuzumab therapy d] NICE rejects adjuvant pertuzumab in HER2(+) breast cancer; may not offer meaningful benefit [138] 3] neoadjuvant chemotherapy for triple negative tumors uses standard chemotherapy (see chemotherapy for breast cancer) [4] 4] reduces risk of recurrence (53%), 2nd primary cancer, & mortality (34%) 5] women with ER+, PR+, HER+ tumors benefit from paclitaxel, trastuzumab, breast irradiation & aromatase inhibitor or tamoxifen [4] 6] cardiotoxicity of trastuzumab [36] 5) endocrine therapy [7,16] a) surgical: ovariectomy, adrenalectomy - oviariectomy in premenopausal women with estrogen receptor-positive women & a history of deep vein thrombosis [4,69] b) pharmaceutical agents: - premenopausal women with estrogen receptor-positive breast cancer should receive tamoxifen for 10 years [4] - leuprolide + aromatase inhibitor over tamoxifen in premenopausal women at high risk [4] - postmenopausal women with estrogen receptor-positive breast cancer should receive an aromatase inhibitor for 10 years regardless of prior tamoxifen therapy [4] - LHRH agonists (goserelin), progestins - goserelin may reduce incidence of ovarian failure in premenopausal women undergoing cyclophosphamide- containing chemotherapy (8% vs 22% at 2 years) [95] - adding chemotherapy to endocrine therapy may not improve survival for patients with ER+ tumors < 8 mm in size [148] - for women with BRCA mutations, poly (ADP-ribose) polymerase (PARP) inhibitors (olaparib, talazoparib) improve progression-free survival relative to standard chemotherapy [4] 6) aspirin & perhaps other NSAIDs appear to lower mortality in women with breast cancer [49,153] === locally advanced (T4) & inflammatory breast cancer === 1) systemic chemotherapy given prior mastectomy to reduces size of the tumor & improves the results of mastectomy 2) Cancer & Aging Research Group-Breast Cancer (CARG-BC) score is validated to predict grade 3-5 chemotherapy toxicity in early-stage breast cancer [166] 3) radiation therapy is given after mastectomy [4] === suspected recurrent breast cancer or metastases === - biopsy lesion of 1st recurrence or metastases [4] - confirm malignancy - establish hormone receptor & HER2 status [4,72] - may be discordant with primary neoplasm [4] - ER & HER2 status discordant in up to 15% [4] - axillary lymph node biopsy insufficient to confirm metastatic cancer - biopsy pulmonary nodule rather than axillary lymph node [4] - bone biopsy cannot confirm HER2 status without soft tissue === established metastatic breast cancer & relapse === 1) hormonal therapy (first line) [92] - estrogen-receptor positive breast cancer metastases limited to bone - hormonal therapy 1st line [4,110] - letrozole + abemaciclib, palbociclib or ribociclib [4] - hormonal therapy + fulvestrant in postmenopausal women {NGC} - hormone receptor-positive metastatic breast cancer responds better to fulvestrant plus anastrozole, than to anastrozole alone or to both drugs given in sequence [62] - use of bevacizumab is controversial [92] - improves treatment response but not overall survival 2) combination chemotherapy a) avoid combination chemotherapy unless the patient's cancer burden needs to be reduced quickly [80] b) taxanes & anthracyclines with strongest evidence of efficacy [92] c) adjuvant capecitabine after taxane &/or anthracycline for residual tumor after surgery in triple-negative breast cancer (HER2-, ER-, PR-) [128] d) niraparib + pembrolizumab for triple-negative breast cancer (HER2-, ER-, PR-) [140] e) paclitaxel plus bevacizumab - bevacizumab not recommended [44] - single-agent paclitaxel not recommended [90] f) trastuzumab plus docetaxel (HER2 +) g) pertuzumab, trastuzumab & docetaxel (HER2 +) - see HER2-positive breast cancer h) everolimus plus exemestane not recommended for advanced HER2-negative, hormone-receptor-positivebreast cancer after endocrine therapy (NICE) 3) ado-trastuzumab emtansine (Kadcyla) FDA-approved for metastatic breast cancer unresponsive to trastuzumab plus chemotherapy 4) high dose chemotherapy with autologous bone marrow or stem cell transplantation [3]; not recommended [4] 5) adoptive cell transfer plus pembrolizumab may eliminate metastases [141] 6) bone metastasis a) aromatase inhibitor for ER+ breast cancer with metastases to bone b) bisphosphonates &/or radiation therapy for painful lytic bone lesions [4] c) surgery may be needed for spinal cord compression due to vertebral bone metastasis [4] d) monthly administration of IV bisphosphonate may reduce new bone metastases & bone fractures [4] 7) mastectomy not indicated unless required for local cancer control [4] 8) see brain metastases 9) metastatic breast cancer is treatable but not curable [4] 10) support groups may be helpful for some patients [12] === prognosis, fertility, follow-up, prevention === 1) prognosis - tumor size & axillary lymph node status most prognostic [4] - prognosis better with estrogen receptor positive tumors - adjuvant endocrine therapy lowers risk for contralateral breast cancer in breast cancer survivors [121] - prognosis worse with increasing age - prognosis worse after recent pregnancy [20] - pregnancy following breast cancer treatment does not increase risk for recurrence of breast cancer [4] - prognosis improved by exercise [30], as little as 3-5 hours walking weekly at 2-3 miles/hour - comorbidities partly explains racial differences in survival [34] - breast cancer stage affects prognosis - tumor size & lymph node involvement most important, independent of tumor biology [104] - see staging of breast cancer (5 year survival by initial staging) - 70% of symptomatic recurrences occur between scheduled exams [37] - prognosis for multicentric disease similar to unicentric disease [38] - invasive breast cancers may regress [43] - local tumor recurrence correlates with risk of distant metastases [51] - metastatic breast cancer is generally incurable, with median survival of 2 years [4] - mean survival of recurrent breast cancer is 2.5 years from the diagnosis of recurrence - prognosis is improved with a multidisciplinary team approach [59], but cost-effectiveness is unknown - functional limitations in activities of daily living (ADL) following initial treatment predicts poor prognosis [85] - impecunity, comorbidities, functional impairment & cognitive impairment predict poor prognosis [86] - 30-day & 1-year mortality & functional decline high in elderly nursing home residents after surgery for breast cancer [142] 2) fertility issues [132] - women with breast cancer who wish to have children should be referred to a fertility specialist to discuss embryo cryopreservation [4] - goserelin with chemotherapy in premenopausal women with hormone-receptor-negative breast cancer may attenuate premature ovarian failure rate (8% vs. 22%), see POEMS trial - many young women have fertility concerns, but few pursue fertility preservation strategies [83] 3) follow-up - see breast cancer survival - treated early-stage breast cancer (< 5 cm tumor, < 4 positive nodes) can be tranferred to primary care after 1 year with same outcome [37] - no routine laboratory testing or imaging (except mammography) recommended [4,71] - little benefit to extensive monitoring of metastatic breast cancer [119] - overnight fasting for > 13 hours associated with diminished recurrence of breast cancer [115] 4) prevention of breast cancer - see screening for breast cancer - see risk factors for breast cancer & management of high-risk women * osteoporosis therapy in estrogen-deprived patient * bisphosphates lower breast cancer recurrence & mortality in postmenopausal women [102] * 3-5 years of bisphosphonate treatment (current recommendations) - > 2 years of zoledronate does not improve prognosis [155] Notes: - only 40% of all high-risk women & 62% of tested high-risk women received genetic counseling [124]

Interactions

disease interactions

Related

Breast Cancer Detection Demonstration Project breast cancer survival (includes breast cancer prognosis) breast conservation therapy breast lump/mass breast/ovarian cancer genotyping Canadian support groups for patients with metastatic breast cancer study Cancer & Aging Research Group-Breast Cancer (CARG-BC) score chemotherapy for breast cancer familial breast-ovarian cancer Li-Fraumeni syndrome Prevention of Breast Cancer (includes chemoprophylaxis for breast cancer) risk factors for breast cancer & management of high-risk women screening for breast cancer staging of breast cancer

Useful

breast cancer metastasis-suppressor 1 (BRMS1) breast cancer susceptibility gene-1 [BRCA-1] breast cancer susceptibility gene-2 [BRCA-2] Fanconi anemia group J protein; protein FACJ; ATP-dependent RNA helicase BRIP1; BRCA1-associated C-terminal helicase 1; BRCA1-interacting protein C-terminal helicase 1; BRCA1-interacting protein 1 (BRIP1, BACH1, FANCJ) her2/neu proto-oncogene (erb-B2)

Specific

Breast Cancer - Male breast cancer in men; comparison of male vs female breast cancer breast cancer in the elderly ductal carcinoma in-situ (DCIS) ductal carcinoma, breast HER2-positive breast cancer inflammatory breast cancer; mastitis carcinomatosa lobular carcinoma, breast metastatic breast cancer secondary breast cancer triple negative breast cancer; (ER-, PR-, HER2-)

General

breast neoplasm; mammary gland neoplasm malignant neoplasm of bone, connective tissue, skin, & breast

Database Correlations

OMIM 114480

References

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