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A Multidisciplinary Approach to the Management of Breast Cancer, Part 2: Therapeutic Considerations

New approaches to breast cancer treatment have enhanced clini- cal outcomes and patient care. These approaches include ad- vances in breast irradiation and hormonal and systemic adjuvant therapies. In addition to the identification of new drug
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   Mayo Clin Proc. • September 2007;82(9):1131-1140 • 1131 THERAPEUTIC CONSIDERATIONS OF BREAST CANCER For personal use. Mass reproduce only with permission from  Mayo Clinic Proceedings. For personal use. Mass reproduce only with permission from  Mayo Clinic Proceedings.   SYMPOSIUM ON SOLID TUMORS From the Breast Diagnostic Clinic, Division of General Internal Medicine(S.P.), Department of Surgery (J.C.B., A.C.D.), Department of Radiology(K.R.B.), Department of Oncology (G.K.D., M.P.G., J.N.I.), Department of Laboratory Medicine and Pathology (C.A.R.), and Department of RadiationOncology (P.J.S.), Mayo Clinic, Rochester, Minn; and Division of Hematology/ Oncology, Mayo Clinic, Jacksonville, Fla (E.A.P.).Dr Goetz is a consultant for F. Hoffman-La Roche Ltd and DNA Direct. DrPerez serves on an advisory board for Genentech, Inc, sanofi-aventis,GlaxoSmithKline, and Novartis and receives research support fromGlaxoSmithKline. Dr Ingle receives honoraria from AstraZeneca Pharmaceu-ticals LP, Novartis, and Pfizer Inc. Address correspondence to Sandhya Pruthi, MD, Division of General InternalMedicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (e-mail: Individual reprints of this article and a bound reprint of the entire Symposium on Solid Tumors will be available for purchase from ourWeb site © 2007 Mayo Foundation for Medical Education and Research A Multidisciplinary Approach to the Management of Breast Cancer, Part 2:Therapeutic Considerations S ANDHYA  P RUTHI , MD; J UDY  C. B OUGHEY , MD; K ATHLEEN  R. B RANDT , MD; A MY  C. D EGNIM , MD;G RACE  K. D Y , MD; M ATTHEW  P. G OETZ , MD; E DITH  A. P EREZ , MD; C AROL  A. R EYNOLDS , MD;P AULA  J. S CHOMBERG , MD; AND  J AMES  N. I NGLE , MD New approaches to breast cancer treatment have enhanced clini-cal outcomes and patient care. These approaches include ad-vances in breast irradiation and hormonal and systemic adjuvanttherapies. In addition to the identification of new drug targets andtargeted therapeutics (eg, trastuzumab), there is renewed reem-phasis in the development of biomarkers for the prediction ofresponse to therapy. One example is the pharmacogenetics oftamoxifen metabolism and the individualization of hormonaltherapy. The current treatment of breast cancer continues toevolve rapidly, with new scientific and clinical achievements con-stantly changing the standard of care and leading to substantialreductions in breast cancer mortality. The goal of this article is toprovide clinicians who care for women with breast cancer amultidisciplinary, state-of-the art approach to the treatment ofthese patients. Mayo Clin Proc  . 2007;82(9):1131-1140 AI = aromatase inhibitor; DCIS = ductal carcinoma in situ; CYP2D6 =cytochrome P450 2D6; DFS = disease-free survival; FDA = Food andDrug Administration; FEC = fluorouracil, epirubicin, and cyclophospha-mide; LHRH = luteinizing hormone-releasing hormone; NSABP = Na-tional Surgical Adjuvant Breast and Bowel Project; PBI = partial breastirradiation P art 1 of this contribution discussed the multidisci-plinary approach needed for the prevention and diag-nosis of breast cancer. This team of experts   includes medi-cal oncologists, breast radiologists, breast pathologists,surgical breast specialists, radiation oncologists, geneti-cists, and primary care physicians. 1  The current contribu-tion provides clinicians who care for women with breastcancer a multidisciplinary, state-of-the art approach to thetreatment of these patients. WHOLE BREAST IRRADIATION VSPARTIAL BREAST IRRADIATION: WHAT IS NEW? Breast-conserving surgery (lumpectomy) is consideredstandard treatment of early-stage breast cancer. Random-ized trials have shown that breast irradiation after suchsurgery reduces the risk of recurrence in the breast and thusimproves the likelihood of breast preservation. 2  To date, nosubset of patients has been identified in whom radiationcan be eliminated when local control and breast preserva-tion are end points. 3  Typically, the radiation schedule usedin the United States has been 45 to 50 Gy in 5 to 5 1  /  2  weeksto the entire breast sometimes followed by a tumor bedboost of an additional 10 to 15 Gy in 1 to 1 1  /  2  weeks. Localrecurrence after such an approach ranges from 6% to 14%,and survival is equivalent to the results of patients undergo-ing mastectomy. 2,4 However, some women who are candidates for a breast-conserving approach choose mastectomy instead becauseof issues related to the inconvenience of such a protractedtreatment regimen. 5  In the United States, only 43% of pa-tients with stage I and II disease undergo breast-conservingsurgery, and of these, 14% do not receive postoperativeradiotherapy. 6  To address this issue of inconvenience,many investigators have explored the use of shorter treat-ment schedules. Whelan et al 7  reported a Canadian ran-domized trial that compared 42.5 Gy in 16 fractions to 50Gy in 25 fractions. A total of 1234 women with lymphnode–negative invasive breast cancer were entered into thisstudy. With a median follow-up of 69 months, no differ-ence in local recurrence-free survival or overall survivalrates was detected between the study arms. The percentageof patients with excellent or good global cosmetic outcomeat 3 and 5 years was also comparable, thus suggesting thatthe more convenient shorter schedule is an acceptable alter-native to the standard 5-week regimen. This Canadianhypofractionated regimen has not been widely adopted inthe United States but is used for some patients.Traditionally, standard radiation after lumpectomy hastargeted the entire breast to treat clinically occult disease. 8 More recently, techniques for partial breast irradiation(PBI), which limits the radiation to the lumpectomy surgi-cal bed, have been introduced. These techniques are based   Mayo Clin Proc. • September 2007;82(9):1131-1140 • 1132 THERAPEUTIC CONSIDERATIONS OF BREAST CANCER For personal use. Mass reproduce only with permission from  Mayo Clinic Proceedings. For personal use. Mass reproduce only with permission from  Mayo Clinic Proceedings. on the assumption that in selected patients it may not benecessary to irradiate the entire breast. This approach issupported by the finding that most breast recurrences afterbreast conservation treatment with lumpectomy and wholebreast irradiation occur in or near the tumor bed. 9  Partialbreast irradiation offers the potential advantage of reducedtreatment-related toxic effects by limiting the volume of normal tissue such as heart and lung that is irradiated. Inaddition, PBI has the potential to significantly shorten thetreatment time since accelerating treatment is possiblewhen treating a more limited tissue volume. The mostcommon PBI treatment regimen delivers 34 Gy in 10 frac-tions given twice daily for 5 days to a volume that includesthe lumpectomy cavity with a margin of 1 to 2 cm. Mostdata from a number of single-institution studies that usePBI suggest promising local control and cosmesis in care-fully selected and properly treated patients. 10-12  In amatched-pair analysis, Vicini et al 10  demonstrated theequivalence of PBI to whole breast irradiation. Local recur-rence, failure in the breast beyond the tumor bed region,cosmesis, and survival were identical for the 2 treatmentapproaches, with a median follow-up of 5 years.In the United States, PBI initially was delivered withinterstitial brachytherapy at a low dose rate, but more re-cently this has been changed to a high dose rate. High ratesof local control and good cosmetic results have been re-ported. 13  However, interstitial brachytherapy is a relativelycomplex procedure that requires considerable technical ex-pertise. Thus, other methods of PBI have been introduced.One such method is an inflatable balloon-based interstitialcatheter (MammoSite, Proxima Therapeutics, Alpharetta,GA) that was approved by the Food and Drug Administra-tion (FDA) in 2002 and is now the most widely used formof PBI worldwide. 14  However, in some cases the lump-ectomy cavity size, shape, or location limits use of thisdevice. More recently, the use of a noninvasive tech-nique, 3-dimensional conformal external beam irradia-tion, has been explored. Early reports suggest promisingresults. 15,16  The Radiation Therapy Oncology Group con-ducted a phase 1/2 trial (0319) to evaluate the use of thistechnique. 17  Patients received 38.5 Gy in 3.85-Gy frac-tions delivered twice daily. In this preliminary analysis of the first 42 evaluable patients, accelerated PBI was shownto be technically feasible and reproducible in a multi-institutional trial. Single-fraction, large-dose intraopera-tive radiation with either photons or electrons at the timeof the lumpectomy is being evaluated in 2 clinical trials inEurope. 18,19 Regardless of the exact method, the key to effective PBIis the use of highly reproducible techniques with excellentquality assurance. 20  In addition, careful patient selection ismandatory. To that end, the American Brachytherapy Soci-ety 21  and the American Society of Breast Surgeons 22  havepublished similar guidelines for PBI. The AmericanBrachytherapy Society suggests the use of PBI in patientsolder than 45 years with unifocal, invasive ductal carci-noma that measures less than 3 cm with negative micro-scopic surgical margins and negative lymph nodes. Bothsocieties recommend enrollment in clinical trials if pos-sible and appropriate informed consent.The long-term efficacy of PBI compared with wholebreast irradiation needs to be confirmed in prospective,randomized trials. The National Surgical Adjuvant Breastand Bowel Project (NSABP) and the Radiation TherapyOncology Group are currently conducting such a phase 3randomized clinical trial (B39/R0413). This trial will ran-domize 3000 patients after lumpectomy for early-stagebreast cancer to either whole breast irradiation or PBI. Thetrial will allow use of any 1 of 3 PBI techniques: interstitialbrachytherapy, inflatable balloon-based interstitial cath-eter, or 3-dimensional conformal external beam irradiation.Thus, this trial will help to identify the most optimal meansof delivering PBI and the patient population most suitablefor its use. If proved effective, PBI may allow more womento choose breast conservation therapy. ADJUVANT CHEMOTHERAPY Adjuvant systemic chemotherapy plays an important rolein the management of patients with resected breast cancer,especially when the risk of recurrence despite local therapyis estimated to be greater than 10% at 10 years. 23  Clinicaltrials performed during the past 20 years that involve thou-sands of women have shown that adjuvant chemotherapysignificantly reduces the risk of recurrence and prolongsoverall survival. 24,25 The agents commonly used in the adjuvant setting in-clude anthracyclines, alkylating agents, taxanes, and anti-metabolites. Schedules of these agents include weekly andevery 2- or 3-week regimens administered during periodsthat extend from 2 months up to 6 months (duration of treatment varies by tumor stage). Historically, the use of more intense or longer duration chemotherapy schedulinghas been based on tumor stage. For example, women withearly-stage breast cancer have traditionally been treatedwith 4 cycles of anthracycline-based chemotherapy (eg, 4cycles of combination doxorubicin and cyclophospha-mide). In contrast, patients with more advanced-stagebreast cancer (eg, stage II or III) have been considered foradditional therapies (eg, taxanes) in which the total dura-tion may last 4 to 6 months. Some of the commonly usedregimens include 4 cycles of doxorubicin-cyclophospha-mide followed by 4 cycles of paclitaxel; the combinationdocetaxel, doxorubicin, and cyclophosphamide; the combi-   Mayo Clin Proc. • September 2007;82(9):1131-1140 • 1133 THERAPEUTIC CONSIDERATIONS OF BREAST CANCER For personal use. Mass reproduce only with permission from  Mayo Clinic Proceedings. For personal use. Mass reproduce only with permission from  Mayo Clinic Proceedings. nation fluorouracil, doxorubicin, and cyclophosphamide;or the combination cyclophosphamide, methotrexate, andfluorouracil. If radiation therapy is indicated, it is routinelyadministered after completion of chemotherapy. In general,systemic chemotherapy decreases the risk of recurrence byapproximately 30% to 50%, with greater absolute benefitin estrogen receptor–poor or absent breast cancer. 26 Because many patients do not benefit from chemo-therapy, current research is focused on identifying the bio-logical subsets of patients who benefit from adjuvant che-motherapy. Current approaches to the decision makinginclude integration of classic prognostic factors that shouldalways be considered, including age, performance status,and end-organ function (liver, renal, and cardiac). In termsof molecular markers in tumors, this in an evolving area of research that affects the selection of targeted agents, suchas selective estrogen receptor modulators and trastuzumab.Current trials are also evaluating gene profiles in tumortissue to determine the potential likelihood of benefit fromvarious chemotherapeutic agents. ADJUVANT ENDOCRINE THERAPY Appreciation has increased in the substantial value of adju-vant endocrine therapy for women with early-stage breastcancer whose tumors express the estrogen and/or proges-terone receptor. Until recently, tamoxifen had been thestandard of therapy in the adjuvant setting for postmeno-pausal women with early-stage breast cancer since its ap-proval by the FDA in 1986 for node-positive disease andin 1990 for node-negative disease. For premenopausalwomen, tamoxifen remains the only endocrine agent ap-proved by the FDA and remains an integral component of optimal therapy. The duration of tamoxifen therapy is cur-rently considered to be no longer than 5 years, primarilybased on a single large clinical trial that found 10 years of tamoxifen use to be inferior to 5 years. 25  The Early BreastCancer Trialists’ Collaborative Group (Oxford Overview),which considered all randomized trials, found that approxi-mately 5 years of tamoxifen use reduced the annual breastcancer death rate by 31%. 26 A substantial amount of endocrine therapy research hasbeen conducted in postmenopausal women during the pastdecade. Initially, in the advanced disease setting, a substan-tial body of evidence demonstrated the value of aromataseinhibitors (AIs), 27  and this stimulated multiple trials of theAIs vs tamoxifen in early-stage disease. Substantial datahave been generated that provide evidence for their use inthe management of postmenopausal patients in standardclinical practice. Three different AIs (anastrozole, exe-mestane, and letrozole) have been evaluated in 3 differentsettings: (1) initial therapy vs tamoxifen, (2) a switchingstrategy after 2 to 3 years of tamoxifen, and (3) extendedadjuvant therapy after 5 years of tamoxifen.In the initial therapy setting, 2 major trials have random-ized women to either tamoxifen or an AI for 5 years. Boththe Arimidex, Tamoxifen, Alone or in Combination   trial, 28 which examined anastrozole, and the Breast InternationalGroup trial, 29  which examined letrozole, showed an im-provement in disease-free survival (DFS), but to date noimprovement has been seen in overall survival. The reduc-tion in DFS events was 17% to 18% in both trials, with theabsolute reduction at 5 years being 2.8% to 2.9%. Bothtrials showed a difference in toxicity profile betweentamoxifen and the AI, with tamoxifen being associated withmore thromboembolic and gynecologic events. The AIswere also associated with more fractures and arthralgias.Clearly, attention must be paid to bone health, specificallybone mineral density, in women who receive AIs. 30 In patients who have already received approximately 2years of tamoxifen therapy, 3 trials have examined thevalue of switching to an AI vs continuing tamoxifentherapy for the full 5 years. 31-33  The largest of these trials, 31 the Intergroup Exemestane Study, has shown a significantimprovement in DFS and, when estrogen receptor–nega-tive patients who would not be expected to benefit wereexcluded, the survival advantage was statistically signifi-cant ( P =.05). Again, the toxicity patterns were similar tothose aforementioned, with more fractures and fewerthromboembolic events in patients who switched to the AI.Women who have received 5 years of tamoxifen shouldbe considered in terms of residual risk of recurrence of thebreast cancer. Ravdin and Davis 34  used the Oxford Over-view data to estimate residual risk of relapse in patientswho completed 5 years of tamoxifen therapy, and theyfound that the average annual risk of relapse from years 6through 10 was 2.0% for patients with node-negative dis-ease and 4.4% for women with node-positive disease. Twotrials have evaluated the use of AIs in such patients vs nofurther treatment. 35,36  The larger of these trials is the Na-tional Cancer Institute of Canada Clinical Trials GroupMA.17. 35  This trial showed a significant advantage forletrozole in DFS for all patients regardless of whether theyhad lymph node metastasis and a survival advantage thatwas statistically significant for patients with node-positivedisease. The second trial, from the Austrian Breast andColorectal Cancer Study Group, 36  found a similar advan-tage for anastrozole in improving DFS.On the basis of the evidence presented, AIs are clearly apositive addition to the clinician’s armamentarium for ad- juvant therapy for postmenopausal women with early-stagebreast cancer. Direct cross-setting comparisons of the find-ings in the initial treatment setting and switching setting asaforementioned are confounded by the fact that the popula-   Mayo Clin Proc. • September 2007;82(9):1131-1140 • 1134 THERAPEUTIC CONSIDERATIONS OF BREAST CANCER For personal use. Mass reproduce only with permission from  Mayo Clinic Proceedings. For personal use. Mass reproduce only with permission from  Mayo Clinic Proceedings. tions are substantially different in tumor characteristics,particularly sensitivity to hormonal therapy. The AmericanSociety of Clinical Oncology Aromatase Inhibitor Tech-nology Assessment Panel concluded that the optimal adju-vant therapy for a postmenopausal woman with hormonereceptor–positive breast cancer includes an AI as initialtherapy or after treatment with tamoxifen. 37  Currently, it isnot possible to unequivocally state whether it is better tostart with an AI or use a switching strategy in which an AIis given after approximately 2 years of tamoxifen. A rea-sonable strategy is to present the pros and cons of eachapproach to the patient. If a woman would rather start ther-apy with tamoxifen, emerging data related to cytochromeP450 2D6 (CYP2D6) indicate a diminished value of tamox-ifen with decreased CYP2D6 metabolism, as a result of either genetic variation or the coadministration of potentCYP2D6 inhibitors. 38  The subsequent section entitled “Ta-moxifen Pharmacogenetics” discusses this in more detail.Multiple questions remain in addition to the optimaltreatment strategy, including the optimal duration of AItreatment, the long-term adverse effects of AIs, the predic-tive value of molecular markers such as progesterone re-ceptor, and whether a particular AI is “best.” These ques-tions are being addressed by ongoing clinical research. Formany postmenopausal women with early-stage breast can-cer, AIs have clearly become established as valuable.Minimal data are available that relate to adjuvant endo-crine therapy for premenopausal women. The OxfordOverview 26  indicates that the proportional risk reductionswith tamoxifen are similar for younger (<50 years) andolder women, and this effect is present irrespective of thepresence or absence of chemotherapy. The role of ovarianfunction suppression in addition to tamoxifen or AIs isunknown, and these questions are the subject of ongoingglobal clinical trials. 39 A DJUVANT  E NDOCRINE  T HERAPY   AND  D UCTAL  C ARCINOMA  I N  S ITU The use of adjuvant hormonal therapy, specifically tamox-ifen, is becoming more standard in the clinical manage-ment of patients with ductal carcinoma in situ (DCIS) in thesetting of radiotherapy. The NSABP B-24 trial randomized1804 women with DCIS to receive tamoxifen or placeboafter excision and radiotherapy. 40  An overall benefit wasseen in the prevention of breast cancer events in patientswith estrogen receptor–positive tumors who receivedtamoxifen. 41  Similarly, the United Kingdom/Australia andNew Zealand DCIS trial found that tamoxifen decreasedthe overall rate of recurrence of DCIS but did not reducethe incidence of invasive cancer. 42  Currently, it is unclearwhether tamoxifen has any value in the setting of patientsdiagnosed as having DCIS who undergo wide excisionalone, but this remains to be defined. In addition, clinicaltrials are currently testing newer drugs (AIs) that may havethe potential to further reduce local recurrence. A DJUVANT  E NDOCRINE  T HERAPY   AND  M ETASTATIC  D ISEASE Endocrine therapy is the treatment of choice for womenwith estrogen receptor– and/or progesterone receptor–posi-tive breast cancer, except when clinical reasons exist tomove directly to chemotherapy, such as a rapid tempo of disease progression or the presence of a visceral crisis, suchas lymphangitic pulmonary metastasis. For postmeno-pausal women, numerous endocrine agents are available,including the selective estrogen receptor modulator tamox-ifen; the third-generation AIs (anastrozole, exemestane,and letrozole); the estrogen receptor down-regulator ful-vestrant; the progestins (megestrol acetate and medroxy-progesterone acetate); the androgen fluoxymesterone; andthe estrogens. 43  In premenopausal women, data are avail-able for tamoxifen and the luteinizing hormone-releasinghormone (LHRH) analogues both alone and in combina-tion and an AI in combination with an LHRH analogue.Endocrine therapies are generally administered sequen-tially until endocrine resistance is established or clinicalreasons exist to proceed to cytotoxic chemotherapy, withthe challenge being the most appropriate sequence of endo-crine therapy administration.For postmenopausal women, the introduction of the AIsas an alternative to tamoxifen or after tamoxifen for adju-vant therapy for those with resected hormone receptor–positive breast cancer has added a level of complexity todetermining which endocrine agent to use in the metastaticdisease setting. Several categories of patients can be identi-fied that will guide treatment selection: (1) tamoxifen sen-sitive (no prior AI), (2) tamoxifen resistant (no prior AI),and (3) AI resistant (with or without prior tamoxifen).Well-conducted phase 3 trials provide evidence for choos-ing first-line therapy for advanced disease in categories 1and 2. For tamoxifen-sensitive patients, defined as no priortamoxifen or at least 1 year of not taking adjuvanttamoxifen before disease recurrence, one can choose eithernonsteroidal AI anastrozole or letrozole. 27  For tamoxifen-resistant patients, the choices are the nonsteroidal AIs, thesteroidal AI exemestane, or the estrogen receptor down-regulator fulvestrant. Fewer data are available in category 3(AI resistant) on which to base the choice of endocrinetherapy. There are no published phase 3 (comparative)trials of agents in patients who have experienced diseaseprogression while taking an AI. Efficacy data are availablefor exemestane, fulvestrant, and high-dose estrogens, andretrospective data are available for tamoxifen. For the pa-tient resistant to a nonsteroidal AI, one can choose eitherexemestane or fulvestrant based on the 2006 29th AnnualSan Antonio Breast Cancer Symposium presentation of the   Mayo Clin Proc. • September 2007;82(9):1131-1140 • 1135 THERAPEUTIC CONSIDERATIONS OF BREAST CANCER For personal use. Mass reproduce only with permission from  Mayo Clinic Proceedings. For personal use. Mass reproduce only with permission from  Mayo Clinic Proceedings. Evaluation of Faslodex vs Exemestane Clinical Trial study, 44 which showed similar results for the 2 drugs, thus reservinghigh-dose estrogen, progestins, and androgens for later con-sideration. Additional clinical trials are needed to determinean optimal sequencing strategy and the role of the newertargeted therapies in combination with endocrine therapy.For premenopausal women with metastatic breast can-cer, both tamoxifen and ovarian function suppression,whether by surgery, radiation, or LHRH analogues, haveestablished efficacy. Data from a randomized clinical trial 45 showed that the combination of tamoxifen and an LHRHanalogue, so-called total endocrine blockade, produced sig-nificantly better results, including better overall survival,than either agent alone. A small study has shown that afterdisease progression occurs in a patient taking an LHRHanalogue plus tamoxifen, switching from tamoxifen to theAI anastrozole produces clinical benefit, defined as anobjective response or disease stability for at least 6 monthsin 75% of patients. 46  Data on the other endocrine agents forpremenopausal women rendered biochemically postmeno-pausal are needed. NEOADJUVANT OR PREOPERATIVE SYSTEMICCHEMOTHERAPY Chemotherapy in the preoperative setting was initially usedfor patients with inflammatory breast cancer and otherinoperable breast cancers. Its use has expanded to patientswith operable but locally advanced breast cancer, for whichsurgical resection may have been challenging in the past.With the use of chemotherapy before surgery, approxi-mately a quarter of these patients have been shown to beable to undergo breast conservation. 47  Additionally, now itsuse has expanded to patients with early-stage disease. Thehallmark study that evaluated neoadjuvant chemotherapy isthe NSABP B-18 trial, which enrolled patients with oper-able breast cancer (stage I and II) and stratified them byage, clinical tumor size, and clinical nodal status. Patientswere randomized to undergo either surgery first followedby 4 cycles of doxorubicin-cyclophosphamide chemother-apy and tamoxifen (if appropriate) or 4 cycles of doxorubi-cin-cyclophosphamide chemotherapy up front followed byoperation and tamoxifen (if appropriate). 48,49  This studyshowed that the DFS and overall survival were similar inboth groups. The local recurrence rate was also similarbetween the 2 groups: 7.6% in patients receiving postop-erative chemotherapy and 10.7% in those receiving preop-erative chemotherapy. The lumpectomy rate was increasedfrom 60% to 68% with the use of neoadjuvant chemo-therapy. 48,49  As a result, breast-conserving therapy becamepossible in 20% of the 40% of patients who were notinitially eligible for breast conservation.The criteria for breast conservation surgery afterneoadjuvant chemotherapy include a solitary residual tu-mor smaller than 5 cm, absence of skin or chest wallfixation, absence of a contraindication to breast radiation,and the patient’s desire for breast conservation surgery.Exclusion criteria include diffuse calcifications, inability toobtain negative margins, multicentric disease, residual skinchanges, or significant residual volume of disease afterchemotherapy.The response to chemotherapy is documented for clini-cal response, which is classified as complete response (noresidual disease clinically), partial response (>50% tumorreduction), minor response (<50% tumor reduction), nochange, or disease progression. Studies have shown thatapproximately 30% of patients will have a complete re-sponse, 44% a partial response, 17% stable disease, 3% nochange, and 2% disease progression. 49 The clinical response after neoadjuvant chemotherapyhas been shown to predict DFS and overall survival. 50 Therefore, therapies are being evaluated in clinical trials todetermine which therapies can provide the highest clinicalresponse rates.Responses to chemotherapy before surgery are not uni-form. Patients who have a complete response will haveabsolutely no evidence of residual disease; however, pa-tients with a partial response may have either a smallresidual nidus of tumor in the center of the srcinal tumorlocation or in some cases residual scattered cells that coverthe srcinal volume of the initial index tumor. 51  Neoadju-vant chemotherapy has no impact on the reexcision ratesfor negative margins and has been shown to reduce thevolume of breast tissue resected in patients with operablebreast tumors. 52  A smaller volume of tissue resected resultsin improved cosmesis after breast conservation surgery.Pathological evaluation after surgery will reveal whetherthere has been a true pathological complete response, de-fined as no residual invasive breast cancer in the breastor axilla, or will report on the extent of residual diseasein the breast and axilla. Patient treatment is based on clini-cal stage before receiving neoadjuvant chemotherapy,not on the pathological stage at the time of resection.Pathological complete response indicates improved patientsurvival.As advances are made with therapy for breast cancer,pathological complete response rates have increased. Arecent study that evaluated trastuzumab (Herceptin, Genen-tech, Inc, South San Francisco, CA) in the neoadjuvantsetting for patients with HER2/neu-positive operable breastcancer at the M.D. Anderson Cancer Center found a 65%pathological complete response rate in patients receivingneoadjuvant trastuzumab along with paclitaxel and fluoro-uracil, epirubicin, and cyclophosphamide (FEC) chemo-
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