Breast Cancer module - 3: Stages 0 and I Breast cancer

Breast Cancer Module-3

Breast Cancer Module-3

This module focuses on the diagnosis and management of early-stage breast cancer, ie, stages 0 and I disease. This is an important area, since more noninvasive and small breast cancers are being diagnosed due to the increasing use of screening mammography. Treatment of these malignancies will continue to evolve as the results of clinical trials lead to further refinements in therapy.

STAGE 0 BREAST CANCER

Stage 0 breast cancer includes noninvasive breast cancerlobular carcinoma in situ ( !IS" and ductal carcinoma in situ (#!IS" as well as $aget%s disease of the nipple when there is no associated invasive disease.

L B!LAR CARCIN MA IN SIT!

!IS is nonpalpable, produces no consistent mammographic changes, and is often an incidental finding after breast biopsy performed for another reason. The biologic behavior of !IS continues to be an issue of debate. &ost clinicians agree that it is a mar'er for increased ris' for all types of breast cancer (both noninvasive and invasive". E"#dem#olog$ and et#olog$ The incidence of !IS has doubled over the past () years and is now (.* per +00,000 women. In the past, the pea' incidence of !IS was in women in their ,0s. -ver the past . decades, the pea' incidence has increased to the )0s. The incidence of !IS decreases in women who are in their /0s-*0s. It has been suggested that the increase in the age of pea' incidence of !IS is related to the use of hormone replacement therapy (01T". It is also possible that the use of 01T prevents the usual regression of !IS normally seen at the time of menopause. S#gns and s$m"toms !IS is nonpalpable and has no consistent features on breast imaging. &ost often, !IS is found in association with a completely separate mammographic abnormality or palpable mass. R#s% o& #n'as#'e cancer 2ppro3imately (04-()4 of women with !IS will develop invasive cancer within +) years after the diagnosis of !IS. &ore often, the invasive cancer is ductal in origin, and both breasts are at ris'. 2t this point, there are no reliable molecular mar'ers to determine which patients with !IS will progress to invasive cancer. 5ust as the incidence of !IS has increased, there has also been an associatedincrease in the incidence of cases of infiltrating lobular carcinoma in 3

Breast Cancer Module-3

postmenopausalwomen. The increase in invasive lobular carcinoma pea's inwomen in their 60s. (at)olog$ !IS appears to arise from the terminal duct-lobular apparatus, and the disease tends to be multifocal, multicentric, and bilateral. Subse7uently, other types of !IS have also been described and include pleomorphic !IS. This entity tends to be associated with infiltrating lobular carcinoma, and the cytologic features are similar to those of intermediate- or high-grade #!I S. $leomorphic !IS may be more aggressive, with a higher li'elihood of progression to invasion than classic !IS. Treatment o"t#ons The management of !IS is continuing to evolve since the disease appearsto be heterogeneous. $resently, treatment options include close follow-up, participation in a chemoprevention trial, tamo3ifen, or bilateral prophylactic total mastectomy with or without reconstruction. 2t present, the decision for a given treatment will depend upon the patient%s individual ris' profile for#!IS or invasive breast cancer after careful counseling. In the future, treatment decisions may be based upon an analysis of a series of molecular mar'ers, which can separate those patients with a low ris' for invasion from those who are at high ris' for disease progression.

*!CTAL CARCIN MA IN SIT!

#!IS is being encountered more fre7uently with the e3panded use of screening mammography. In some institutions, #!IS accounts for ()4-)04 of all breast cancers. E"#dem#olog$ #!IS, li'e invasive ductal carcinoma, occurs more fre7uently in women, although it accounts for appro3imately )4 of all male breast cancers. The average age at diagnosis of #!IS is ),-)/ years, which is appro3imately a decade later than the age at presentation for !IS. S#gns and s$m"toms The clinical signs and symptoms of #!IS include a mass, breast pain, or bloody nipple discharge. -n mammography, the disease most often appears as microcalcifications. 8ecause these microcalcifications are nonpalpable and are not always associated with a mass, #!IS is often discovered with mammography alone. 2ppro3imately )4 of patients who present with pathologic nipple

Breast Cancer Module-3

discharge will have underlying breast cancer, and many of them will have #!IS alone. R#s% o& #n'as#'e cancer The ris' of developing an invasive carcinoma following a biopsy-proven diagnosis of #!IS is between ()4 and )04. 9irtually all-invasive cancers that follow #!IS are ductal and ipsilateral and generally present in the same 7uadrant within +0 years of the diagnosis of #!IS. :or these reasons, #!IS is considered a more ominous lesion than !IS (which is considered a mar'er for ris'" and appears to be a more direct precursor of invasive cancer. (at)olog$ 2 variety of histologic patterns are seen with #!IS, including solid, cribriform, and papillary. Some researchers have divided #!IS into two subgroups; comedo and noncomedo types. 2s compared with the noncomedo subtypes, the comedo variant has a higher proliferative rate, overe3pression of 0<1-(= neu, and a higher incidence of local recurrence and microinvasion. #!IS is less li'ely to be bilateral and has appro3imately a .04 incidence of multicentricity.

Treatment of noninvasive breast carcinoma

*!CTAL CARCIN MA IN SIT! Breast-conserving surgery 8reast-conservation surgery, followed by radiation therapy to the intact breast, is now considered the standard treatment for patients with #!IS. Since the incidence of positive lymph nodes after a3illary lymph node dissection for #!IS is >+4-(4, a3illary dissection is not indicated in most instances. The most important factor in determining local control within the breast is margin status. 2 surgical margin of + mm has been associated with a ,.4 chance of having residual disease at the time of ree3cision. ?hen a surgical margin of +0 mm can be obtained, there is an e3tremely low rate of recurrence (,4". 2 +0-mm surgical margin may not be practical, however, when trying to provide a good cosmetic outcome. ?hen using breast-conserving therapy alone (without irradiation" a margin of at least +0 mm is re7uired, and the tumor should be small (@ + cm" and a noncomedo type. 2lthough a wide margin is always desirable, narrower margins are acceptable for #!IS when radiation therapy is used after lumpectomy.

Breast Cancer Module-3

Sent#nel node -#o"s$ &or *CIS The sentinel lymph node is the first node in the draining lymphatic basin that receives primary lymph flow. The techni7ue of sampling the first draining lymph node was initially described in the management of patients with melanoma to determine who would benefit from regional lymph node dissection and was performed using a vital blue dye. This same techni7ue has been used in patients with breast cancer, and sentinel lymph node biopsy represents a minimally invasive way to determine whether the a3illa is involved with disease. If the sentinel lymph node is negative, the patient may be spared lymph node dissection. The precise methods for identifying the sentinel lymph node (filtered vs unfiltered Tc-AAm sulfur colloid and=or blue dye" and assessing the node (hemato3ylin and eosin staining vs immunohistochemistry vs polymerase chain reaction B$!1C" are being studied. The location of the inDection is also being evaluated to determine whether there is an advantage to the inDection being administered either subdermally or intraparenchymally at the site of the primary tumor or in the periareolar location. 23illary lymph node dissection is not routinely recommended for patients with #!IS. 1ecently, however, investigators have used sentinel lymph node biopsy to determine whether individuals with #!IS may harbor occult nodal metastases. !urrent studies have identified metastatic disease to the a3illary nodes in up to +(4 of patients who have undergone sentinel lymph node biopsy. #espite this relatively high percentage of positive sentinel nodes, recurrence in the nodal basins is rare (about (4". 8ased on this and recent wor', there is no indication for routine sentinel lymph node biopsy in patients with #!IS. :actors associated with an increased ris' of a3illary metastasis with a diagnosis of #!IS are (+" e3tensive #!IS re7uiring mastectomy, ((" suspicion of microinvasion, (." #!IS associated with a palpable mass, and (," evidence of lymphovascular permeation or invasion seen on review of the slides. These factors li'ely are associated with a preoperatively nondiagnosed invasive component. 0owever, for patients diagnosed with #!IS who are scheduled for mastectomy, sentinel lymph node sampling, prior to mastectomy, is a reasonable practice. In the event that an occult invasive cancer within the mastectomy is found, a negative sentinel node would be reassuring and perhaps wouldma'e it possible to avoid follow-up a3illary dissection. Technique used in breast cancer In breast cancer, lymphatic mapping has been performed using a vital blue dye and=or lymphoscintigraphy. The primary tumor site is inDected with the blue dye or a radioactive tracer, usually technetiumlabeled sulfur colloid. ?hen a vital dye is used, the a3illary dissection is carefully carried out to identify the blue-stained afferent lymphatic vessels that lead to the .

Breast Cancer Module-3

sentinel node. ?hen the radioactive tracer is inDected peritumorally, a handheld gamma counter is used to locate the sentinel node. Ad/u'ant rad#at#on t)era"$ 1etrospective series of patients with #!IS, as well as subsets of patients with early invasive cancer, have been treated with conservative surgery alone, omitting radiation therapy to the intact breast. In addition, several prospective, randomiEed trials have attempted to address this issue of omission of breast irradiation for both invasive cancer and #!IS. It is clear from all of these series that omission of breast irradiation results in a significantly higher ipsilateral breast tumor recurrence rate but has not, as yet, had an impact on overall survival. Two large prospective randomiEed trials have demonstrated a significant reduction in local relapse with the use of postlumpectomy irradiation in treatment of #!IS. In the Fational Surgical 2dDuvant 8reast and 8owel $roDect (FS28$" 8 +6, local recurrence rates at * years were reduced from (64 to +(4 with postlumpectomy irradiation. Similar results were recently reported by a <uropean cooperative group study of +,0+0 women with #!IS randomly assigned to receive either )0 Gy of radiotherapy to the whole breast over ) wee's or no further treatment. ?ith a median follow-up of ,.() years, the ,-year local relapse-free rate was A+4 in the radiotherapy arm vs *,4 in the observation arm. 0aEard ratios with poste3cision radiotherapy were 0./( for all local relapses, 0./) for #!IS recurrences, and 0./0 for noninvasive recurrences. 8oth trials showed that radiotherapy reduces the ris' of both noninvasive and invasive recurrences. Identification of a subgroup of patients who did not benefit from postlumpectomy irradiation has not as yet been clearly defined. The 9an Fuys $rognostic Inde3 (9F$I", based on tumor siEe, grade, presence of necrosis, and width of the e3cision margin, is an algorithm commonly used to predict local recurrence after breast-conserving surgery for #!IS. In some series, 9F$I lac'ed discriminatory power for guiding further patient management. In studies performed by this group, it appears that the width of the e3cision margin is the most important predictor of local recurrence after breastconserving surgery for #!IS. -ne study demonstrated acceptable local control in patients with #!IS treated by e3cision alone, provided that wide negative margins were obtained. In this retrospective series of ,/A patients, radiation therapy did not lower the local recurrence rate in patients with wide (H +0 mm" negative margins but did produce a significant benefit in patients with close (I + mm" margins. The authors concluded that radiation therapy is unli'ely to benefit patients with wide negative margins and small tumors. These findings need to be confirmed in prospective, randomiEed trials. 0

Breast Cancer Module-3

2lthough there may be some patients in whom wide e3cision alone is appropriate therapy, the available literature has not consistently identified a specific subgroup of patients in whom radiation therapy should routinely be omitted. !learly, the omission of radiation therapy in subsets of patients remains a controversial issue worthy of further investigation. It is hoped that ongoing randomiEed studies will help resolve some of the controversy generated by selective, retrospective studies. Ad/u'ant tamo1#&en t)era"$ 2dDuvant therapy is not routinely employed in patients with #!IS. 0owever, the use of tamo3ifen for the prevention of secondary breast cancers in women at high ris' for breast cancer, which includes women previously diagnosedwith #!IS, has led some clinicians to consider the use of tamo3ifen inwomen diagnosed with #!IS. In an FS28$ trial (FS28$ 8-(,", +,*0, women with #!IS treated with lumpectomy and irradiation were randomly assigned to receive placebo or Two recent trials have tamo3ifen. 2t a median followup of 6, months, addressed the need for women in the tamo3ifen group had fewer breast postlumpectomy radiation cancer events than those in the placebo group therapy (1T" in older women (*.(4 vs +..,4J $ K .000A". Tamo3ifen with breast cancer. 8oth studies decreased the incidence of both ipsilateral and randomiEed patients, following contralateral events. The ris' of ipsilateral lumpectomy and adDuvant invasive cancers was reduced by tamo3ifen, hormonal therapy, to 1T or regardless of the presence or absence of observation. 2lthough both comedonecrosis or margin involvement. studies confirmed statistically significant improvements in local In a recent analysis of FS28$ 8-(,, it was found control with 1T, local relapse that e3clusively patients with hormone receptor rates were acceptable in positive disease derive the benefit from carefully selected patients. The tamo3ifen. 8ased on these results, tamo3ifen authors concluded that selected may be considered as adDuvant therapy in elderly patients may be treated patients with hormone receptor- positive #!IS. with hormonal therapy alone The role of tamo3ifen or other estrogen receptor (without 1T" following breastmodulators is li'ely to evolve rapidly over the conserving therapy (0ughes LS, ne3t decade, and additional data on the use of Schnaper 2, 8erry #, et al; F hormonal agents as adDuvant therapy for #!IS <ngl 5 &ed .)+;A6+-A66, (00,J are eagerly awaited. :yles 2?, &c!ready #1, &anchul 2, et al; F <ngl 5 &ed .)+;A/.-A60, (00,".

Breast Cancer Module-3

STAGE I BREAST CANCER

Stage I breast cancer ranges from microinvasive tumors (I 0.+ cm" to tumors I ( cm without evidence of spread to the regional lymph nodes. (at)olog$ o& #n'as#'e -reast cancer Ductal carcinoma. &ost cases of invasive carcinomas of the breast are ductal in origin. -f the different histologic subtypes of ductal carcinoma that have been described, tubular, medullary, mucinous (colloid", and papillary subtypes have been associated with a favorable outcome. Lobular carcinoma. 2ppro3imately )4-+04 of invasive breast cancers are lobular in origin. This histology has been associated with synchronous and metachronous contralateral primary tumors in as many as .04 of cases.

Treatment o& stage I -reast cancer

S!RGICAL AN* RA*IATI N TREATMENT &ultiple studies have demonstrated that patients with stage I breast cancer that is treated with either breast-conservation therapy (lumpectomy and radiation therapy" or modified radical mastectomy has similar disease-free and overall survival rates.

Breast-conser'at#on t)era"$ Extent of local surgery The optimal e3tent of local surgery has yet to be determined and, in the literature, has ranged from e3cisional biopsy to 7uadrantectomy. 2 consensus statement on breast-conserving therapy issued by the Fational !ancer Institute (F!I" recommended that the breast cancer be completely e3cised with negative surgical margins. 3

Breast Cancer Module-3

The e3tent of a3illary surgery also continues to evolve. In recent years, patients with early-stage breast cancer who have clinically node-negative disease have the option to undergo sentinel lymph node biopsy rather than a3illary node dissection. $resent standard of care for patients with a positive sentinel node is complete nodal dissection. 2 study is under way to determine whether patients with a positive sentinel node re7uire further a3illary surgery. Patient selection Specific guidelines must be followed when selecting patients for breast conservation. $atients may be considered unacceptable candidates for conservative surgery and radiation therapy either because the ris' of breast recurrence following the conservative approach is significant enough to warrant mastectomy or the li'elihood of an unacceptable cosmetic result is high. Some patients who are candidates for breast conservation can undergo breast &1I to identify sites of additional disease within the breast that may preclude breastconserving treatment, although this is not a standard for evaluation. !ontraindications to breast-conserving surgery are listed in Table +. Risk factors for ipsilateral recurrence. :or patients undergoing conservative surgery followed by radiation therapy to the intact breast, the ris' of ipsilateral 8reast tumor recurrence has been reported to range from 0.)4 to (.04 per year, ith long-term failure rates varying from 64 to (04. 1is' factors for ipsilateral breast tumor recurrence include, but are not limited to, young age (@ .)-,0 years", an e3tensive intraductal component, maDor lymphocytic stromal reaction, peritumoral invasion, presence of tumor necrosis, and positive resection margins. 2fter a wide e3cision has been performed, the specimen should be oriented and in'edJ the pathologist may then in' each margin a different color. If a positive surgical margin is Initial anecdotal reports have present, the color-coded system will guide the demonstrated higher complication ree3cision to obtain negative surgical margins with rates in patients with collagen the removal of the least amount of breast tissue vascular disease (!9#". In a possible. casecontrolled study of conservatively managed breast <arlier studies demonstrated that an e3tensive cancer patients, however, intraductal component was a ris' factor for local researchers at Nale relapse. 0owever, in subse7uent reports, when Oniversity found no adverse negative surgical margins are achieved, patients longterm se7uelae in patients with with an e3tensive intraductal component can be !9#, with the e3ception of safely treated with breast conservation. patients with scleroderma, who 2lthough it is desirable to achieve negative appear to have suboptimal results surgical margins, the available data do not with radiation therapy preclude the use of conservative treatment, (!hen 2,-bedian <, 0affty 8G; provided that ade7uate radiation doses (M /,000 !ancer 5 Sci 2m 6;,*0-,A+, cGy" to the tumor bed are employed. The role of (00+". the remaining ris' factors previously cited in

40

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predicting recurrence is unclear, and patients should not be denied breast conservation because of their presence. Cosmetic considerations include primary tumor siEe and location, overall breast siEe, total body weight, and a history of pree3isting collagen vascular disease. Tumor siEe and breast siEe are important in determining whether the patient will have an acceptable cosmetic outcome after surgical resection. $atients with large tumors with respect to breast siEe may consider neoadDuvant chemotherapy to reduce the siEe of the primary tumor and allow breast preservation. (See chapter ++ for discussion of neoadDuvant chemotherapy." -bese women with large, pendulous breasts may e3perience mar'ed fibrosis and retraction of the irradiated breast, ma'ing a good to e3cellent cosmetic outcome less li'ely. Techni7ues of brachytherapy may prove beneficial for these women. ?omen in this situation can undergo bilateral reduction mammoplasty after the wide e3cision of the primary tumor site has been completed. The partial mastectomy specimen should be evaluated by the pathologist to ensure ade7uate resection margins. 1adio-opa7ue clips can be left to mar' and identify the primary tumor site for the radiation oncologist. The followupmammograms will be more difficult to interpret due to scarring and radiotherapy effect. $atients with collagen vascular disease may develop mar'ed fibrosis and bone necrosis following adDuvant radiation therapy. &ost patients with active collagen vascular disease are not candidates for conservative therapyJ however, patients with minimal manifestations of the disease or those with rheumatoid arthritis may be considered for breast-preserving treatment. In some instances, it is necessary to e3cise s'in to obtain a negative surgical margin. This does not necessarily preclude the patient from having breastconserving therapy and does not mean the patient should have a poor cosmetic outcome. ?hen s'in must be removed to obtain a negative surgical margin, comple3 s'in closures, such as 9-N advancement flaps or P-plasties, can be utiliEed to enhance cosmesis. Patients with centrally located tumors Traditionally, patients who have centrally located tumors re7uiring e3cision of the nipple-areolar comple3 have not been offered the option of breast conservation. 0owever, the cosmetic result achieved after local tumor e3cision that includes the nipple-areolar comple3 may not differ significantly from that obtained following mastectomy and reconstruction. :urthermore, conservatively treated patients with subareolar lesions do not necessarily need to have the nipple-areolar comple3 sacrificed as long as negative surgical margins can be achieved. 0owever, if the comple3 is not removed, the remaining breast tissue and overlying s'in remain sensate. 1ecent studies also indicate that the incidence of local recurrence is not increased when primary tumors in this location are treated conservatively.

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Genetically predisposed breast cancer patients :or women harboring germline mutations in 81!2+ or 81!2(, there are limited data regarding long-term outcome. Studies, to date, have shown acceptable local control rates in the short term and increased but acceptable rates of acute, subacute, and chronic normal tissue reactions with lumpectomy followed by radiation therapy. ?omen with germline 81!2+ and 81!2( mutations, however, are at high ris' for second primary tumors in the contralateral breast. 2 study from Nale Oniversity demonstrated high rates of second primary tumors in the ipsilateral breast. This study suggests that if breast-conserving therapy is chosen, some prophylactic measures, such as selective estrogen receptor modulators or oophorectomy might be considered to reduce theris' of second primary tumors in the ipsilateral or contralateral breast. -ther studies also indicate a trend toward higher rates of late local relapses in 81!2 carriers. :urther studies are clearly warranted to assess the long-term ris's and benefits of breast-conserving strategies in women harboring mutations in 81!2+ and 81!2(. Role of axillary lymph node dissection The role of a3illary lymph node dissection in the management of breast cancer has been 7uestioned, particularly when a patient with a clinically negative a3illa is undergoing breastconservation therapy. In most instances, the breast surgery is performed with the patient under local anesthesia and sedation on an outpatient basis. ?hen a3illary lymph node dissection is added, the surgery is performed with the patient under general anesthesia. It has also been suggested that if the status of the nodes will not change therapy, the dissection is unnecessary and the a3illa can be treated with irradiation. -n the other hand, if a3illary lymph node staging is not performed, the patient will not be accurately staged and important prognostic information will be unavailable. $atients who may not be candidates for sentinel node biopsy are women who are pregnant or breast-feeding and women who have had prior irradiation. 2 prior e3cisional biopsy does not preclude the use of lymphatic mapping and sentinel node biopsy. It has recently been suggested that sentinel node biopsy accurately evaluates the a3illa, even in patients with tumors M ) cm and those who have been treated with neoadDuvant chemotherapy. -nce the sentinel node(s" have been identified, they can be sent to pathology for froEen section or touch-prep analysis. Sensitivity and specificity In breast cancer, lymphatic mapping has been performed using a vital blue dye and=or lymphoscintigraphy. Studies have suggested that the success rate for identifying the sentinel node can be increased when these techni7ues are used in combination. The ability to identify

42

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thesentinel node can reach as high as A64 when blue dye and Tc-AAm sulfur colloid are used together. ?hen blue dye is used alone, the success rate is *.4, and when Tc-AAm sulfur colloid is used alone, the success rate is A,4. 1ecent results in a multi-institution practice demonstrate that sentinel lymph node biopsy using dual-agent inDection provides optimal sensitivity. In the study, *0/ patients were enrolled by AA surgeons for sentinel lymph node biopsy by singleagent (blue dye alone or radioactive colloid alone" or dualagent inDection at the discretion of the surgeons. 2ll patients underwent complete level I=II dissection following the sentinel procedure. There were no significant differences in the identification of a sentinel node among patients who underwent single- compared with dual-agent inDection. 0owever, the false-negative rates were ++.*4 for single-agent vs ).*4 for dual-agent inDections ($ K .0)". The sensitivity and specificity of sentinel lymph node biopsy are high, and the li'elihood of a false-negative result is e3tremely low. :alse-negative rates vary between series, ranging from 04 to ++4. In one series, in +*4 of the cases where the froEen-section evaluation of the node was negative, the final pathologic evaluation revealed metastatic disease, and the patient ultimately re7uired lymph node dissection. This potential result can be distressing to patientsJ however, they should be informed of this possibility at the time of the sentinel lymph node biopsy. The decision to eliminate a3illary lymph node dissection when the sentinel node is negative is being evaluated in a clinical trial. There are, however, many surgeons who are well e3perienced with the techni7ue and thus have a low falsenegative rate. &any of these surgeons are comfortable eliminating a complete a3illary dissection in the face of a negative sentinel node biopsy. The decision to eliminate a3illary lymph node dissection in the face of a positive sentinel node is being e3amined by a large clinical trial. Mastectom$ o"t#ons $atients who are not candidates for breast conservation or who are not interested in breast conservation are offered mastectomy. :or patients who desire immediate reconstruction at the time of mastectomy, a s'in-sparing approach is recommended, provided it is oncologically safe. In most instances, the mastectomy can be performed through a circumareolar incision, where the nipple-areolar comple3 (F2!" is e3cised in continuity with the breast tissue. If a biopsy has been performed, this s'in should also be e3cised with the mastectomy specimen. There have been recent reports in the literature in which the F2! has been spared during the course of a s'in-sparing mastectomy. This concept awaits further study and is not considered standard of care. Rad#at#on t)era"$ a&ter -reast-conser'#ng surger$

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8ased on the results of a number of retrospective single-institution e3periences, as well as several prospective randomiEed clinical trials, breast-conserving surgery followed by radiation therapy to the intact breast is now considered a standard treatment for the maDority of patients with stage I or II invasive breast cancer. Radiation dose and protocol 1adiation therapy after breast-conservation surgery should employ careful treatment planning techni7ues that minimiEe treatment of the underlying heart and lungs. To achieve the optimal cosmetic result, efforts should be made to obtain a homogeneous dose distribution throughout the breast. #oses of +*0-(00 cGy=d to the intact breast, to a total dose of ,,)00-),000 cGy, are considered standard. 2dditional irradiation to the tumor bed is often administered. 2lthough the necessity of a boost to the tumor bed has been 7uestioned, at least two randomiEed clinical trials have demonstrated a small but statistically significant reduction in ipsilateral breast tumor relapses with the use of a radiation boost to the tumor bed following whole-breast irradiation of )0 Gy. In one of these trials, involving more than ),000 women randomiEed to receive either a +/-Gy boost to the tumor bed or not, a .4 absolute reduction in local relapse was seen with the use of the radiation boost (,..4 vs 6..4, $ @ .000+". This effect was particularly evident in patients younger than age )0. The boost is directed at the original tumor bed with either electron-beam irradiation or an interstitial implant, to bring the total dose to )0-// Gy. Regional nodal irradiation :or patients who undergo a3illary dissection and are found to have negative nodes, regional nodal irradiation is no longer routinely employed. :or patients with positive nodes, radiation therapy to the supraclavicular fossa and=or internal mammary chain may be considered on an individualiEed basis (see chapter +0". (art#al -reast #rrad#at#on There have been several recent reports demonstrating promising results with the use of partial breast irradiation, a potentially more convenient option for patients than the e3tended course of postoperartive radiotherapy. 2dditional options are now available that shorten the radiotherapy treatment time to +-) days (accelerated" and focus an increased dose of radiation on Dust the breast tissue around the e3cision cavity (partial breast". 4+ In a recent meta-analysis evaluating radiation therapy following breast-conserving surgery, a search of the literature identified +) trials with a pooled total of A,,(( patients available for analysis, who were randomiEed following breastconserving therapy to radiation therapy or observation. The relative ris' of ipsilateral breast tumor recurrence after surgery was ..00 (A)4 !I K (./) to ..,0". &ortality data were available for +. trials, with a pooled total of *,(0/ patients. The relative ris' of mortality was +.0*/ (A)4 !I K +.00. to +.+6)", corresponding to an estimated *./4 relative e3cess mortality if radiotherapy was omitted. The authors concluded that omission of radiotherapy is associated with a large increase in ris' of ipsilateral breast tumor recurrence and a small increase in the ris' of mortality (9inh-0ung 9, 9erschraegen ! ; 5 Fatl !ancer Inst (+;++)-+(+, (00,".

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!urrent accelerated partial breast irradiation (2$8I" approaches include interstitial brachytherapy, intracavitary (balloon" brachytherapy, and accelerated e3ternal beam (three-dimensional conformal" radiotherapy. Intraoperative radiotherapy (I-1T" is even shorter, with the entire treatment given as a single dose delivered immediately after surgery. <ach approach has benefits and limitations. $lanned randomiEed trials will shape how 2$8I is utiliEed in routine clinical practice. Some of the more important outcomes from these trials will be local to3icity, local and regional recurrence, and overall survival. If 2$8I is ultimately demonstrated to be as safe and effective as whole breast radiotherapy, breast conservation may become an even more appealing choice, and the overall impact of treatment may be further reduced for certain women with newly diagnosed breast cancer.

ME*ICAL TREATMENT
&edical management of local disease depends on clinical and pathologic staging. Systemic therapy is indicated only for invasive (infiltrating" breast cancers. In the past, systemic therapy was not offered to patients with stage I disease (tumors up to (.0 cm". 0owever, adDuvant chemotherapy and hormonal therapy have been shown to improve disease-free and overall survival in selected patients with node-negative disease. The se7uence of systemic therapy and definitive radiation therapy in women treated with breast-conserving surgery is a subDect of continued clinical research. The use of concomitant chemotherapy and irradiation is not recommended due to the radiomimetic effects of chemotherapy and the potential for increased locoregional to3icity. #elaying chemotherapy up to *-+0 wee's after surgery does not appear to have a negative impact on the development of metastasis or survival. Treatment reg#mens &ultiagent therapy with cyclophosphamide (!yto3an, Feosar", methotre3ate, and fluorouracil ()-:O, !&: regimen"J cyclophosphamide, methotre3ate, )-:O, and prednisone (!&:$"J se7uential methotre3ate and )-:O (&:"J and 2driamycin (do3orubicin" and cyclophosphamide (2!" has been used in patients with node-negative disease (Table (". 0ormonal therapy with tamo3ifen ((0 mg $- 7d for ) years" has been shown to be of value in women H )0 years of age with estrogen- and=or progesterone-receptorQpositive tumors. (See chapter +0 for further discussion about tamo3ifen and the 2T2! trial B2rimide3 and Tamo3ifen 2lone or in !ombinationC as well as for adDuvant chemotherapy regimens in node-positive breast cancer BTable +C."

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Ta3anes (ie, paclita3el and doceta3el BTa3otereC" are now routinely used in the adDuvant therapy for node-positive breast cancer. The role of ta3anes in nodenegative disease is still evolving. ode-negative tumors ! ".# cm The reduction in the odds of recurrence and death with adDuvant therapy is similar in estrogen-receptorQnegative and BnodeCnegative patients. Therefore, patients who have the lowest ris' of recurrence are 4.

Breast Cancer Module-3

least li'ely to benefit from systemic treatment when the attendant ris's of treatment are considered. Fone of the reported trials in nodenegative breast cancer included women with tumors @ +.0 cm, and because of the low ris' of recurrence (I +04" in this group, systemic adDuvant therapy is not used routinely. 1ecent results from the FS28$ in this group of patients are provocative in suggesting a potential benefit from systemic therapy. In this validation study, the li'elihood of distant recurrence in tamo3ifen-treated patients with node-negative, estrogen receptor-positive breast cancer was tested using a reverse transcriptase (1T"-$!1 assay of (+ prospectively selected genes (+/ cancer-related genes and ) reference genes" in paraffin-embedded tumor tissue. The levels of e3pression of the (+ genes were used in a prospectively defined algorithm to calculate a recurrence score and to determine a ris' group for each patient. The proportions of patients categoriEed as having a low, intermediate, or high ris' by the 1T-$!1 assay were )+4, ((4, and (64, respectively. The Laplan-&eier estimates of the rates of distant recurrence at +0 years in the low-, intermediate-, and high-ris' groups were /.*4, +,..4, and .0.)4, respectively. The rate in the low-ris' group was significantly lower than that in the high-ris' group ($ @ .00+". In a multivariate !o3 model, the recurrence score provided significant predictive power that was independent of age and tumor siEe ($ @ .00+". The recurrence score was also predictive of overall survival ($ @ .00+" and could be used as a continuous function to predict distant recurrence in individual patients. ode-negative tumors $ ".# cm The selection of a specific treatment program and the characteristics that predict ris' of recurrence and death in women with node-negative breast cancer re7uire further delineation and clarification in clinical trials. 2t present, women with tumors H +.0 cm who have poor histologic or nuclear differentiation, negative estrogen receptors, high S-phase percentage, or high Li-/6 can be considered appropriate candidates for adDuvant systemic therapy. 2n update of the FS28$ 8-(0 trial indicated a significant advantage in the estrogen-receptorQpositive, node-negative population when chemotherapy with !&: or se7uential &: is added to tamo3ifen in the adDuvant setting. $atients receiving !&: plus tamo3ifen appeared to derive the greatest benefit. 8enefits with respect to both disease-free and overall survival have been reported for patients given chemotherapy and tamo3ifen. !hemotherapy and ovarian function suppression are both effective adDuvant therapies for patients with early-stage breast cancer. The efficacy of their se7uential combination was investigated by the International 8reast !ancer Study Group (I8!SG" Trial 9III. This study randomiEed more than a thousand pre-and perimenopausal women with lymph node-negative breast cancer to receive either goserelin (Polade3" for (, months (n K .,/", si3 courses of

40

Breast Cancer Module-3

RclassicS !&: chemotherapy (n K ./0", or si3 courses of classic !&: followed by +* months of goserelin (!&: then goserelinJ n K .)6". The primary outcome was disease-free survival. In this study, patients with estrogen-receptorQnegative tumors achieved better )-year disease-free survival rates if they received !&: (*,4 and **4 for !&: and !&: then goserelin, respectively" than if they received goserelin alone (6.4". 0owever, for patients with estrogen-receptorQ positive disease, chemotherapy alone and goserelin alone provided similar outcomes (*+4 )-year disease-free survival rates for both treatment groups", whereas se7uential therapy provided a statistically nonsignificant improvement compared with either modality alone. 5ollo6-u" o& long-term sur'#'ors There is no consensus among oncologists as to the optimal follow-up routine for long-term breast cancer survivors. 8ased on F!!F guidelines from September (00,, patients with stage 0 breast cancer should undergo a medical history and physical e3amination every / months for ) years and then annually thereafterJ mammography should be performed every year. $atients with stage I breast cancer should undergo medical history and physical e3amination every , to / months for ) years and then annually thereafter. In stage I patients, mammography should be performed every / months in the ipsilateral breast after radiation therapy following breast-conservation surgery and then annually thereafter, including the contralateral breastJ if mastectomy was performed, mammography should be done annually in the contralateral breast. ?omen receiving tamo3ifen should undergo pelvic e3amination every +( months if the uterus is present. 2ll other follow-up evaluations are dictated by the development of symptoms.

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Breast Cancer Module-3

S!GGESTE* REA*ING 8artelin' 0, 0oriot 5!, $oortmans $, et al; 1ecurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. F <ngl 5 &ed .,);+.6*Q+.*6, (00+. !hung &0, Ne ?, Guiliano 2; 1ole of sentinel node dissection in the management of large (H ) cm" invasive breast cancers. 2nn Surg -ncol *;/**Q /A(, (00+. #erossis 2&, :ey 5, Neung 0, et al; 2 trend analysis of the relative value of blue dye and isotope localiEation in (,000 consecutive cases of sentinel node biopsy for breast cancer. 5 2m !oll Surg +A.;,6.Q,6*, (00+. :isher 8, 2nderson S, 8ryant 5, et al; Twenty-year follow-up of a randomiEed trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. F <ngl 5 &ed .,6;+(..Q+(,+, (00(. :isher 8, 2nderson S, Tan-!hiu <, et al; Tamo3ifen and chemotherapy for a3illary node-negative, estrogen receptor-negative breast cancer; :indings from the Fational Surgical 2dDuvant 8reast and 8owel $roDect 8-(.. 5 !lin -ncol +A;A.+QA,(, (00+. :isher 8, #ignam 5, Tan-!hiu <, et al; $rognosis and treatment of patients with breast tumors of + cm or less and negative a3illary lymph nodes. 5 Fatl !ancer Inst A.;++(Q +(0, (00+. Gibson G1, esni'os'i 8-2, Noo 5, et al; 2 comparison of in'-directed and traditional whole cavity ree3cision for breast lumpectomy specimens with positive margins. 2nn Surg -ncol *;/A.Q60,, (00+. Giuliano 2<, 0aigh $I, 8rennan &8, et al; $rospective observational study of sentinel lymphadenectomy without further a3illary dissection in patients with sentinel nodenegative breast cancer. 5 !lin -ncol +*;()).Q())A, (000. 0affty 8, ?ard 8, $athare $, et al; 1eappraisal of the role of a3illary lymph node dissection in the conservative treatment of breast cancer. 5 !lin -ncol +);/A+ 600, +AA6.

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Breast Cancer Module-3

0aigh $I, 0ansen F&, Ti L, et al; 8iopsy method and e3cision volume do not affectsuccess rate of subse7uent sentinel node dissection in breast cancer. 2nn Surg -ncol 6;(+Q(6, (000. 5ulien 5-$ for the <-1T! 8reast !ancer !ooperative Group; 1adiotherapy in breast conserving treatment for ductal carcinoma in situ; :irst results of the <uropean -rganiEation for 1esearch and Treatment of !ancer (<-1T!" randomised phase III trial. ancet .));)(*Q).., (000. Llauber-#e&ore F, Tan L, iberman , et al; Sentinel lymph node biopsy; Is it indicated in patients with high-ris' ductal carcinoma in situ and ductal carcinoma in situ with microinvasionU 2nn Surg -ncol 6;/./Q/,(, (000. &c&asters L&, Tuttle T&, !arlson #5, et al; Sentinel lymph node biopsy for breast cancer; 2 suitable alternative to routine a3illary dissection in multiinstitution practice when optimal techni7ue is used. 5 !lin -ncol +*;()/0Q()//, (000. $ai' S, Sha' S, Tang G, et al; 2 multigene assay to predict recurrence of tamo3ifen treated,node-negative breast cancer. F <ngl 5 &ed .)+;(*+6Q(*(/, (00,. $ierce 5, Strawderman &, Farod S2, et al; <ffect of radiotherapy following breastconserving treatment in women with breast cancer and germline 81!2+=( mutations. 5 !lin -ncol +*;../0Q../A, (000. Sa'orafas G0, Tsiotou 2G; #uctal carcinoma in situ (#!IS" of the breast; <volving perspectives. !ancer Treat 1ev (/;+0.Q+(), (000. 9oogd 2!, Fielsen &, $eterse 5 , et al; #ifferences in ris' factors for local and distant recurrence after breast-conserving therapy or mastectomy for stage I and II breast cancer; $ooled results of two large <uropean randomiEed trials. 5 !lin -ncol +A;+/**Q+/A6, (00+.

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Breast Cancer Module-3

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