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Version 2.2010 03/16/10 © 2010 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 NCCN. MS-41

Breast CancerGuidelines Index

Breast Cancer TOCStaging, Discussion, References

Practice Guidelinesin Oncology – v.2.2010NCCN ®

cancer or those with associated DCIS should consider tamoxifen forrisk reduction. Those with an associated invasive cancer should receiveadjuvant systemic therapy based on the stage and hormone receptorstatus as outlined in BINV-4 to BINV-9.

Phyllodes tumors of the breast (also known as phylloides tumors,cystosarcoma phyllodes)

Phyllodes tumors of the breast are rare tumors comprised of bothstromal and epithelial elements.372 Phyllodes tumors exist in benign,borderline, and malignant subtypes, although there is not uniformagreement on the criteria for assigning subtype or for predictingbiological behavior.373 Subtype of phyllodes tumor appears lessimportant for risk of recurrence than does the margin of tumor-freeresection achieved by surgical treatment. Diagnosis of phyllodestumors prior to excisional biopsy/lumpectomy is uncommon. Phyllodestumors occur in an older age distribution than fibroadenoma, a youngerage distribution than the invasive ductal and lobular cancers, and with amean age in the 40’s.374 Phyllodes tumors often enlarge rapidly and areusually painless. Phyllodes tumors often appear on ultrasound andmammography as fibroadenomas, and fine needle aspiration cytologyand even core needle biopsy are inadequate to reliably distinguishphyllodes tumors from fibroadenoma.374 Thus in the setting of a large orrapidly enlarging clinical fibroadenoma, excisional biopsy should beconsidered to pathologically exclude a phyllodes tumor. Patients withthe Li-Fraumeni Syndrome (germ line p53 mutation, see NCCNGenetic/Familial High Risk Assessment Guidelines) have an increasedrisk of phyllodes tumors.375 Local recurrences of phyllodes tumors arethe most common site of recurrence. Most distant recurrences occur inthe lung, and may be solid nodules or thin-walled cavities.

Treatment of phyllodes tumors (which includes benign, borderline andmalignant subtypes) is with local surgical excision with tumor freemargins of 1 cm or greater. Lumpectomy or partial mastectomy is the

preferred surgical therapy. Total mastectomy is necessary only ifnegative margins cannot be obtained by lumpectomy or partialmastectomy376 (see PHYLL-1). Since phyllodes tumors rarelymetastasize to the axillary lymph nodes, surgical axillary staging oraxillary lymph node dissection is not necessary unless the lymph nodesare pathologic on clinical examination.377 In those patients whoexperience a local recurrence, resection of the recurrence with widetumor-free surgical margins should be performed (see PHYLL-2). Somemembers of the Panel recommend local radiation therapy of theremaining breast or chest wall following resection of a local recurrence,but this recommendation is controversial (category 2B).378

While the epithelial component of most phyllodes tumors containsestrogen receptor (58%) and/or progesterone receptor (75%),379

endocrine therapy has no proven role in the treatment of phyllodestumors. Similarly, there is no evidence that adjuvant cytotoxicchemotherapy provides benefit in reduction of recurrences or death. Inthe rare patient who experiences a systemic recurrence (usually in thelung), treatment should be as recommended in the NCCN Soft TissueSarcoma Guidelines.

Breast cancer during pregnancyBreast cancer occurring concurrent with pregnancy is an infrequentclinical event. In a California registry study, there were 1.3 breastcancers diagnosed per 10,000 live births.380 Unfortunately, breastcancer during pregnancy is most often axillary lymph node-positive andwith larger primary tumor size. Histologically the tumors are poorlydifferentiated, more frequently estrogen and progesterone receptor-negative and approximately 30% are HER2-positive.381,382 Thediagnosis is often delayed because neither the patient nor the physiciansuspects malignancy.

Evaluation of the pregnant patient with suspected breast cancer shouldinclude a physical examination with particular attention to the breast





and regional lymph nodes. Mammogram of the breast with shieldingcan be done safely and the accuracy is reported to be greater than80%.383 Ultrasound of the breast and regional lymph nodes can beused to assess the extent of disease and also to guide biopsy.Ultrasound has been reported to be abnormal in up to 100% of breastcancers occurring during pregnancy.383 Biopsies for cytologic evaluationof a suspicious breast mass may be done with a fine needle aspiration(FNA) of the breast and suspicious lymph nodes. However, thepreferred technique is core needle biopsy. This provides tissue forhistologic confirmation of invasive disease as well as providingadequate tissue for hormone receptor and HER2 analyses.

Staging assessment of the pregnant patient with breast cancer may beguided by clinical disease stage. For clinically node-negative T1-T2tumors, a chest x-ray (with shielding), liver function and renal functionassessment and complete blood count with differential are appropriate.In patients who have clinically node-positive or T3 breast lesions, inaddition to the aforementioned, an ultrasound of the liver andconsideration of a screening MRI of the thoracic and lumbar spinewithout contrast may be employed. The documentation of the presenceof metastases may alter the treatment plan and influence the patient’sdecision regarding maintenance of the pregnancy. Assessment of thepregnancy should include a maternal fetal medicine consultation andreview of antecedent maternal risks such as hypertension, diabetes andcomplications with prior pregnancies. Documentation of fetal growthand development and fetal age by means of ultrasonographicassessment is appropriate. Estimation of the date of the delivery willhelp with systemic chemotherapy planning. In addition, maternal fetalmedicine consultation should include counseling regarding maintainingor terminating pregnancy. Counseling of the pregnant patient withbreast cancer should include a review of the treatment options whichinclude mastectomy or breast-conserving surgery as well as the use ofsystemic therapy. The most common surgical procedure has been

modified radical mastectomy. However, Kuerer et al. have shown thatbreast-conserving surgery is possible if radiation therapy can bedelayed to the postpartum period,384 and breast-conserving therapyduring pregnancy does not appear to have a negative impact onsurvival.384,385 When surgery is performed at 25 weeks gestation orlater, obstetrical and prenatal specialists must be on site andimmediately available in the event of precipitous delivery of a viablefetus.

Although there are a limited number of isolated case reports and smallretrospective studies evaluating use of sentinel lymph node biopsy inthe pregnant patients,386,387 the sensitivity and specificity of theprocedure has not been established in this setting. Thus, there areinsufficient data on which to base recommendations for its use in thepregnant woman. Decisions related to use of sentinel lymph nodebiopsy in pregnancy should be individualized. A recent review of therelative and absolute contraindications to sentinel node biopsyconcluded that sentinel node biopsy should not be offered to pregnantwomen under 30 weeks gestation.388 There are limited data with onlycase reports and estimations of fetal radiation dose regarding use ofradioactive tracer (eg, technectium 99m sulfur colloid).389-391 Isosulfanblue or methylene blue dye for sentinel node biopsy procedures isdiscouraged during pregnancy.

The indications for systemic chemotherapy are the same in thepregnant patient as in the non-pregnant breast cancer patient, althoughchemotherapy should not be administered at any point during the firsttrimester of pregnancy. The greatest experience in pregnancy has beenwith anthracycline and alkylating agent chemotherapy.392,393 Collecteddata of chemotherapy exposure in utero indicates that the first trimesterhas the greatest risk of fetal malformation.394,395 Fetal malformation risksin the second and third trimester are approximately 1.3%, not differentthan that of fetuses not exposed to chemotherapy during pregnancy. If

The majority of these case reports indicated oligo- or anhydramnios





systemic therapy is initiated, fetal monitoring prior to eachchemotherapy cycle is appropriate. Chemotherapy during pregnancyshould not be given after week 35 of pregnancy or within 3 weeks ofplanned delivery in order to avoid the potential for hematologiccomplications at the time of delivery. Recent data from a singleinstitution prospective study indicate that FAC chemotherapy (5-FU 500mg/m2 IV day 1 and 4, doxorubicin 50 mg/m2 by IV infusion over 72hours and cyclophosphamide 500 mg/m2 IV day 1) may be given withrelative safety during the second and third trimesters of pregnancy.393

Ondansetron, lorazepam and dexamethasone can be used as part ofthe pre-chemotherapy antiemetic regimen. As reported by Gwyn et al.,the median gestational age at delivery was 38 weeks, more than 50%of the patients had vaginal delivery and there have been no fetaldeaths. An update of this experience reported on 57 women treatedwith FAC in the adjuvant or neoadjuvant setting. There were 57 livebirths. A survey of parents/guardians reported on the health of 40children. There was 1 child with Down’s syndrome and 2 withcongenital abnormalities (club foot; congenital bilateral ureteral reflux).The children are reported to be healthy and progressing well inschool.393,396

Ondansetron, lorazepam and dexamethasone can be used as part ofthe pre-chemotherapy antiemetic regimen.

There are limited data on the use of taxanes during pregnancy and theiruse is not recommended during pregnancy.397-401 If a taxane isindicated clinically, it may be used in the post-delivery setting. Preferredchemotherapy choices are those doxorubicin-based regimens that havealready been evaluated in pregnant patients.

There are only case reports of trastuzumab use during pregnancy. 402-409

with administration of trastuzumab; fetal renal failure occurred in onecase. If trastuzumab is otherwise indicated, it should be administered in

the postpartum period; the Panel recommends against its use duringpregnancy.

A single case report of first trimester exposure to lapatinib duringtreatment for breast cancer reported an uncomplicated delivery of ahealthy female neonate.410

Endocrine therapy and radiation therapy are contraindicated duringpregnancy. Endocrine therapy and radiation therapy, if indicated,should thus not be initiated until the post-partum period.

Communication between the oncologist and maternal fetal medicinespecialist is essential at every visit and treatment decision point for thepatient (see PREG-1)

Inflammatory breast cancerInflammatory breast cancer (IBC) is a rare, aggressive form of breastcancer estimated to account for 1%-6% of breast cancer cases in theUnited States.411,412 IBC is a clinical diagnosis that requires erythemaand dermal edema (peau d’orange) of a third or more of the skin of thebreast with a palpable border to the erythema. IBC is classifiedaccording to the 6th edition of the AJCC Cancer Staging Manual asstage IIIB, stage IIIC, or stage IV breast cancer, depending on thedegree of nodal involvement and whether distant metastases arepresent. The primary tumor of IBC is classified as T4d by definition,even when no mass is specifically apparent in the breast. Onradiographic imaging, findings of skin thickening and, in some cases,an underlying mass is observed. Despite use of the term“inflammatory”, the characteristic clinical features of IBC are due toblockage of dermal lymphatics by tumor emboli. Although a biopsy isrequired to evaluate for the presence of cancer in breast tissue and thedermal lymphatics, a diagnosis of IBC is based of clinical findings, anddermal lymphatic involvement is neither required for, nor sufficient by





itself, to assign a diagnosis of IBC.5,413 The differential diagnosisincludes cellulitis of the breast and mastitis.

In the past, IBC has often been placed under the general heading oflocally advanced breast cancer. There is a growing body of evidencethat IBC patients, when compared with those with noninflammatoryforms of locally advanced breast cancer, are more likely to havedisease that is HER2-positive and hormone receptor-negative414,415, tohave a less favorable prognosis416,417 (ie, disease-free survival at 5years were 35% and 50% for inflammatory vs. non-inflammatory status[P=0.020]418 ), and to be younger at the time of disease presentation.419

The Panel acknowledges that studies focusing on geneticcharacterization of IBC are needed to more clearly define IBC as adisease entity and to optimize treatment.420,421 Nevertheless, currentevidence provides justification for a separate guideline for the work-upand treatment of patients diagnosed with IBC (see IBC-1).

Women with a clinical/pathologic diagnosis of IBC without distantmetastasis (stage T4d, N0-N3, M0) should undergo a thorough stagingevaluation. Recommendations include a complete history and physicalexamination involving a complete blood cell count and platelet count.Evaluations for the presence of distant metastasis include liver functiontesting, bone scan (category 2B), CT imaging of the chest, abdomenand pelvis (category 2B; category 2A for CT imaging of the chest whenpulmonary symptoms are present). Evaluation of the extent of localdisease is determined using diagnostic bilateral mammogram, with theaddition of ultrasound as necessary. A breast MRI scan is optional. Apathology review and pre-chemotherapy determinations of tumorhormone-receptor and HER2-receptor status should be performed.Genetic counseling is recommended if the patient is considered to be athigh risk of hereditary breast cancer as defined by the NCCNGenetic/Familial High-Risk Assessment: Breast and OvarianGuidelines. PET/CT scan is also included as an optional additional

study (category 2B). The consensus of the Panel is that PET/CT ismost helpful in situations where standard imaging results are equivocalor suspicious. However, there is limited evidence suggesting thatPET/CT may be a useful adjunct to standard imaging in the setting ofinflammatory breast cancer due to the increased risk of regional lymphnode involvement and distant spread of disease in this group ofpatients. 73,76,422,423 Nevertheless, equivocal or suspicious sitesidentified by PET/CT scanning or other imaging methods should bebiopsied for confirmation of stage IV disease whenever possible.

The treatment of patients with IBC should involve a combined modalityapproach.412 The benefit of preoperative chemotherapy followed bymastectomy over preoperative chemotherapy alone in patients with IBCwas shown in a retrospective analysis in which lower local recurrencerates and longer disease-specific survival were reported for thecombined modality approach.424 Results from a retrospective study ofpatients with IBC performed over a 20-year period at M.D. Andersondemonstrated that initial treatment with doxorubicin-basedchemotherapy followed by local therapy (ie, radiation therapy ormastectomy, or both) and additional postoperative chemotherapyresulted in a 15-year disease-free survival rate of 28%.425 Additionalsupport for the use of anthracycline-based preoperative chemotherapycomes from the only randomized trial of patients with IBC. In this study,5-year survival rates of 44% were observed whenepirubicin/cyclophosphamide-based regimens were administered asinitial therapy.426 A recent retrospective study has demonstrated thataddition of a taxane to an anthracycline-based regimen improved PFSand overall survival in patients with ER-negative IBC.427 A recentsystematic review found evidence for an association between theintensity of preoperative therapy and the likelihood of a pathologiccomplete response.428





It has been known for many years that primary surgical treatment ofpatients with IBC is associated with very poor outcomes.429 Use ofbreast-conserving surgery in patients with IBC has been associatedwith poor cosmesis, and limited data suggest that rates of localrecurrence may be higher when compared with mastectomy.

The Panel recommends preoperative chemotherapy with ananthracycline-based regimen with or without taxanes for the initialtreatment of patients with IBC (see IBC-1). Inclusion of trastuzumab inthe chemotherapy regimen is recommended for patients with HER2-positive disease. Patients with a clinical/pathologic diagnosis of IBCshould not be treated with pre-chemotherapy surgery. Patientsresponding to preoperative chemotherapy should undergo mastectomywith axillary lymph node dissection; breast-conserving therapy is notrecommended for patients with IBC. Any remaining plannedchemotherapy should be completed postmastectomy followedsequentially by endocrine therapy in patients with hormone receptor-positive disease. If the IBC is HER2 positive, completion of one year oftrastuzumab is recommended. Finally, post-mastectomy chest wall andregional node irradiation is recommended following the completion ofany planned chemotherapy (see IBC-1). Mastectomy is notrecommended for patients with IBC who do not respond to preoperativechemotherapy. Additional systemic chemotherapy and/or preoperativeradiation should be considered for these patients, and patientsresponding to this secondary therapy should undergo mastectomy andsubsequent treatment as described above. Patients with stage IV orrecurrent IBC should be treated according to the guideline forrecurrence/stage IV disease (BINV-15 to BINV-20).

Axillary breast cancerAxillary metastasis from an occult breast cancer representsapproximately 3-5% of breast cancers. Evidence to supportrecommendations on the management of these patients comes from a

limited number of retrospective studies involving small numbers ofpatients430-432 (see also references therein). Although treatment ofwomen with axillary metastases from an unknown primary tumor hastypically involved mastectomy and axillary nodal dissection, some ofthese patients have also been successfully treated with axillary nodaldissection followed by radiation therapy.431,432

There is some evidence to indicate that MRI of the breast can facilitatethe identification of occult breast cancer, and help select those patientsmost likely to benefit from mastectomy. For example, in a study of 40patients with biopsy-proven breast cancer in the axilla, and a negativeor indeterminate mammogram, MRI identified the primary breast lesionin 70% of the patients.432 In addition, of the 7 patients with a negativeMRI who subsequently underwent axillary lymph node dissection andradiation therapy to the whole breast, no evidence of local recurrencewas evident at a median follow-up of 19 months.

The NCCN Occult Primary Guidelines provide guidance on thediagnosis and initial work-up of patients with a suspicious axillary massin the absence of any signs of a primary tumor. (It is also worth notingthat a small subset of these patients may have a primary cancer in theaxillary tail of the breast.) These guidelines also providerecommendations for additional work-up, including chest andabdominal CT to evaluate for evidence of distant metastases forpatients diagnosed with adenocarcinoma (or carcinoma not otherwisespecified) of the axillary nodes without evidence of a primary breastlesion; in particular, breast MRI and ultrasound are recommended.Axillary ultrasound should also be performed.

Patients with MRI-positive disease should undergo further evaluationwith ultrasound or MRI-guided biopsy and receive treatment accordingto the clinical stage of the breast cancer. Treatment recommendationsfor those with MRI-negative disease are based on nodal status. Forpatients with T0,N1,M0 disease, options include either mastectomy plus





axillary nodal dissection or axillary nodal dissection plus whole breastirradiation with or without nodal irradiation (see BINV-H). Systemicchemotherapy, endocrine therapy, or trastuzumab is given according tothe recommendations for Stage II or III disease (BINV-4). Neoadjuvantchemotherapy, trastuzumab, and endocrine therapy should beconsidered for patients with T0, N2-N3,M0 disease followed by axillarynodal dissection and mastectomy as for patients with locally advanceddisease (BINV-14).

SummaryThe therapeutic options for patients with noninvasive or invasive breastcancer are complex and varied. In many situations, the patient andphysician have the responsibility to jointly explore and select the mostappropriate option from among the available alternatives.

With few exceptions, the evaluation, treatment, and follow-uprecommendations in these Guidelines are based on the results of pastand present clinical trials. However, there is not a single clinicalsituation in which the treatment of breast cancer has been optimizedwith respect to either maximizing cure or minimizing toxicity anddisfigurement. Therefore, patient/physician participation in prospectiveclinical trials allows patients to not only receive state-of-the-art cancertreatment but also to contribute to improving the treatment of futurepatients.

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