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E. Lim et 03204205206207208209210211212213214 hemotherapy in Different BreastCCancer SubtypesThe EBCTCG overview reported a benefitin terms of 5-year recurrence-free survival withadjuvant sequential chemoendocrine therapyEndocrine therapy forms the basis of adjuvant over endocrine therapy alone with hazard ratiostherapy in patients with HR-positive breast can- of 0.64 and 0.85 in patients with ER-positivecer, and the addition of chemotherapy benefits a tumors aged 50 and 50 years, respectivelysubset of these patients. In patients with HER2/ [27]. The larger impact of chemotherapy inneu-positive tumors, HER2-directed therapy younger patients may be partially explained byalone has not been tested in large adjuvant trials, the endocrine effect of chemotherapy on ovarand the addition of chemotherapy to HER2- ian function [6]. Similar long-term DFS benefitsdirected therapy is considered to be the current with the addition of chemotherapy to adjuvantstandard of care in the United States. Finally, for endocrine therapy were also noted in the phaseTNBC, there are no targeted therapies recom- III randomized NSABP B-20 and Southwestmended for use outside of a clinical trial in the Oncology Group (SWOG) 8814 trials [26, 28].adjuvant setting, again with combination chemo- The identification of predictors of chemosensitivtherapy recognized as the standard of care.ity in HR-positive tumors has been identified asa key challenge.There is evidence suggesting an inverse rela Chemotherapy in Hormonetionship between HR expression and chemotherReceptor- Positive Breast Cancerapy benefit in luminal breast cancers. In a studyof postmenopausal women with ER-positive andWhile adjuvant endocrine therapy is the standard node-positive cancers from the Internationalof care in patients with tumors that express HRs, Breast Cancer Study Group (IBCSG) Trials VIIthe indication for adjuvant chemotherapy in and 12-93, the addition of adjuvant chemotherpatients with HR-positive disease is undergoing apy to endocrine therapy improved the DFS (hazreevaluation. Adjuvant chemotherapy is typically ard ratio 0.81, p 0.02, median follow-up ofgiven in sequence with, and prior to, endocrine 13 years) [29]. Nonparametric subpopulationtherapy, as there have been conflicting outcomes treatment effect pattern plot (STEPP) analyseswith concurrent therapy [22–24]. On average, demonstrated that this benefit was limited to thepatients with HR-positive breast cancers derive patients whose tumors had low to intermediateless benefit from chemotherapy compared to levels of estrogen expression. The level of ERHR-negative tumors [25]. However, there still appears to predict the response to both endocrineappears to be a subset of patients with HR-positive and chemotherapies in opposite directions, buttumors that are chemosensitive. The basis for the these factors may not entirely overlap. It is likelyaddition of chemotherapy to adjuvant endocrine that there are other biological factors that interacttherapy is usually guided by the clinician’s esti- with the ER-signaling pathway to determine chemation of prognosis and assessment of the endo- mosensitivity. The assumption that chemosensicrine- and chemosensitivity of the tumor. Patients tivity is inversely related to endocrine sensitivityfor whom systemic chemotherapy should be in ER-positive breast cancer is therefore notstrongly considered include patients with grade 2 clearly defined. Tumors that are endocrine sensior 3 disease, those with high-risk features based tive may also be chemosensitive; conversely,upon the gene signature (such as Oncotype DX endocrine resistant tumors with poor prognosticand MammaPrint), and patients with a higher dis- factors may not always be chemosensitive.ease burden. That said, not every patient withOne biomarker that has been examined in chenode-positive disease has to be treated with che- mosensitive ER-positive tumors is Ki67, a markermotherapy, and multigene signatures are particu- of cellular proliferation. In an analysis of 1,521larly useful in guiding the clinicians in regards to premenopausal and postmenopausal patientsthe decision to recommend chemotherapy [26].with ER-positive tumors from the IBCSG 247248249250251252253254255256257258259260261262

23 Adjuvant Chemotherapy in Breast and IX trials, respectively, a high Ki67 index wasfound to be associated with poorer DFS, but didnot predict an OS benefit with the addition ofchemotherapy to endocrine therapy [30]. Theadjuvant chemotherapy used in these trials wasCMF and did not include anthracyclines and taxanes. In contrast, a high Ki67 index was predictive of both outcome and benefit to adjuvanttaxane chemotherapy in ER-positive breast cancers in subset analyses of the PACS 01 and BreastCancer International Research Group (BCIRG)001 trials [31, 32]. An important caveat of thesefindings is that these were unplanned subset analyses. At this point, Ki67 should not be used as abasis of recommendation for adjuvant chemotherapy outside of a clinical trial setting, at leastin part because the test is not always reliable.A major advancement in the identification ofbiomarkers of chemosensitivity in HR-positivebreast cancers has been the development of multigene prognostic signatures. These are typicallyderived from high-throughput analyses of tumorspecimens for gene expression patterns andsubsequently validated in patient cohorts fromclinical trials. These assays have the potentialto identify subsets of patients that would benefit from the addition of adjuvant chemotherapyto endocrine therapy. The 21-gene assay, calledthe Oncotype DX (Genomic Health, RedwoodCity, CA, USA), provides a recurrence score(RS) that predicts for risk of 10-year distantrecurrence. The RS is derived from a complexalgorithm calculated on the gene expressionsof a preselected list of 16 genes of biologicalinterest, including genes involved in estrogensignaling, cell proliferation, and HER2/neu signaling and 5 reference genes for normalizationpurposes [28]. The utility of the RS as a predictor of distant recurrence risk at 10 years wasinitially assessed in the NSABP B-14 trial, inwhich patients with ER-positive, node-negativebreast cancer were randomized to receive eithertamoxifen or placebo. The RS was shown tomore accurately predict for distant recurrencethan conventional clinicopathologic characteristics in the tamoxifen- treated patients [33].The utility of the RS to accurately predict10-year distance recurrences was demonstratedin a retrospective analysis of the NSABP B-20trial, in which patients with ER-positive, node- negative breast cancer were randomized to eithertamoxifen or tamoxifen plus chemotherapy.Patients with a low or intermediate RS (defined as 18, and 18 and 31, respectively) were foundnot to benefit from chemotherapy, while thosewith a high RS (defined as 31) derived a significant benefit from chemotherapy [28]. The absolute difference in the 10-year distant recurrencerates with the addition of chemotherapy in theseRS groups was an increase of 1.1 % and 1.8 %and a reduction of 28.6 %, respectively. Similarresults were obtained in a retrospective analysisof the SWOG 8814 trial, in which postmenopausal patients with ER-positive, node- positivebreast cancer were randomized to receive eithertamoxifen or tamoxifen plus anthracycline- basedchemotherapy [26]. One of the primary strengthsof this assay is that RNA may be extracted fromarchived formalin-fixed, paraffin- embedded tissue, which is the primary mode of preserving tissue in most pathology departments.Another multigene signature with prognosticutility is the FDA-approved 70-gene MammaPrintsignature (Agendia, Amsterdam, Netherlands).Unlike the Oncotype RS assay where genes arepreselected, MammaPrint was developed usingan unsupervised hierarchical clustering approachwhereby the high-risk gene signature predicted apoor clinical outcome in tumors of all subtypes[34]. A retrospective analysis of pooled patientcohorts with ER-positive, node-negative breastcancer demonstrated that the 70-gene score hadprognostic value and predicted improved survivaloutcomes with the addition of chemotherapy toendocrine therapy only in the subgroup of70-gene high-risk patients [35].While both the Oncotype and MammaPrintassays were tested retrospectively, the OncotypeRS was evaluated retrospectively in a prospectively assembled clinical trial. For this reason,there is far greater confidence, at this time,that the Oncotype assay can reliably predictwhich patients will benefit from chemotherapy,and even more importantly, which ones willnot. In addition, unlike the Oncotype assay,MammaPrint is performed on 55356357358

E. Lim et 91392393394395396397398399400401402403404405406t issue that may limit its feasibility for routineuse. Both of these multigene signatures are currently undergoing prospective validation in largeongoing studies (Oncotype RS, TAILORx andRxPONDER trials; MammaPrint, MINDACTtrial), which include over 100,000 patients collectively to definitively address their predictivevalue for chemosensitivity in ER-positive breastcancer [36, 37].In considering the benefits of adjuvant chemotherapy in patients with HR-positive tumors, it isimportant to consider common relapse patterns.Patients with HR-positive tumors are at a continued risk of relapse for many years after initialbreast cancer diagnosis [38]. More than half of allrecurrences among women treated with adjuvanttamoxifen therapy occur between 6 and 15 yearsafter diagnosis, and the greatest benefit with theaddition of chemotherapy in DFS was seen primarily within the first 5 years from diagnosis [27].The limited benefit from chemotherapy in preventing late relapses is also reflected in the DFSpatterns of patients with poor prognosis multigene signatures with both the Oncotype RS andMammaPrint assays [28, 39]. Late recurrencesand deaths remain a formidable clinical challengein HR-positive breast cancer, and chemotherapyis unlikely to be the answer to this problem.The summary recommendations for adjuvantchemotherapy in hormone receptor-positivebreast cancer are as follows: Adjuvant chemotherapy should be stronglyconsidered in the setting of node-positive disease, high-grade tumors, and high-risk genemultigene signatures. In regard to the utility of the Oncotype DXRecurrence Score:–– The use of Oncotype for node-positive disease is discouraged in poorer prognosisdisease, for example, 4 positive nodes, orin the setting of high- grade disease, as chemotherapy should routinely be given inthese settings.–– The use of chemotherapy is stronglyencouraged in patients with Oncotype RS 31.–– In node-positive patients, particularlythose with one to three positive nodes,c onsideration can be given to omittingchemotherapy if the Oncotype RS is low( 18) and there are no other unfavorablefeatures.–– Recommendations for patients withintermediate- risk multigene signatures(i.e., Oncotype RS 18-31) are an area ofcontroversy and active research, and prospective trials in this population are currently underway [36, 37].407408409410411412413414415416 hemotherapy in HER2-PositiveCBreast Cancer417The advent of HER2-directed therapy has revolutionized the management of HER2/neu-positive,early-stage breast cancer. Based on the resultsof five randomized clinical trials, 12 months ofadjuvant trastuzumab is now an integral part ofsystemic therapy for these patients [40–42]. Inall studies, trastuzumab was added to a chemotherapy backbone, and there is currently no datato support the use of adjuvant trastuzumab monotherapy. Evidence-based chemotherapy backbones in this context include AC T (NSABPB-31, NCCTG N9831), AC docetaxel (BCIRG006) and docetaxel carboplatin (BCIRG 006).Given the increased cardiotoxicity risk uponadministering trastuzumab concurrently withan anthracycline in the metastatic setting [43],trastuzumab is omitted during the period ofanthracycline chemotherapy.There remains controversy about the treatmentof small HER2/neu-positive cancers. There arelimited data on outcomes for patients with small,stage I HER2/neu-positive breast cancers becausethe seminal adjuvant trastuzumab trials excludedpatients with these tumors. Current guidelinesfrom St. Gallen and the European Society forMedical Oncology (ESMO) do not recommend adjuvant trastuzumab and chemotherapyfor node-negative HER2/neu-positive tumorsthat are 1 cm [44]. In contrast, the NationalComprehensive Cancer Network (NCCN) treatment guidelines have factored in the indirectevidence obtained from retrospective and subsetanalyses of trials and recommend 447448449450451

23 Adjuvant Chemotherapy in Breast Cancer Preoperative Chemotherapy(Neoadjuvant)489Most early systemic chemotherapy trials foroperable breast cancer were conducted in theadjuvant setting, with the use of preoperative(neoadjuvant) chemotherapy limited primarily toinflammatory and locally advanced breast cancer.The original rationale for neoadjuvant chemotherapy (NAC) was to render locally advancedtumors operable by shrinking the diameter ofthese tumors, thereby reducing the extent of surgery required in operable breast cancer. Studiescomparing the adjuvant and NAC approacheshave found the survival to be equivalent whenusing identical systemic agents (Table 23.2).These trials also demonstrated that patients whoachieved a pathological complete response (pCR)following NAC had improved clinical outcomescompared to patients who did not.The NAC and adjuvant chemotherapy regimens used clinically are identical. The NACapproach is now increasingly used in smaller,operable TNBC and HER2/neu-positive tumors,although less commonly with HR-positive tumorsas they are inherently less chemosensitive [4, 50].There has also been a trend by many clinicians toevaluate novel therapies in the preoperative setting. A NAC allows for the study of the biological impact of systemic therapy on pre- andposttreatment tissue and therefore represents afertile setting for tissue-intensive correlativeresearch. The goal of biomarker discovery inNAC clinical trials is to identify surrogate endpoints of clinical outcomes, such as predictivebiomarkers of therapeutic response or resistance.The US Food and Drug Administration (FDA) is491488be given to the use of trastuzumab- based therapyin T1bN0 tumors, in particular, in the hormonereceptor-negative subset [45].However, there is a wide variation in clinicalpractice in this subgroup. Recently, interest hasdeveloped in using less intensive, and thereforepotentially less toxic, partner chemotherapieswith adjuvant trastuzumab for low-risk HER2- positive tumors. In a phase II study in womenwith HER2/neu-positive metastatic breast cancer,weekly paclitaxel and trastuzumab resulted in a67–81 % response rate, and a 6 % incidence ofgrade 3 or 4 neutropenia [46]. The Dana-FarberCancer Institute led a multicenter, phase II, nonrandomized study of weekly paclitaxel plustrastuzumab for 12 weeks, followed by maintenance trastuzumab for a further 9 months inpatients with node-negative, HER2/neu-positivetumors that are 3 cm (information available atClinicalTrials.gov; identifier NCT00542451).This trial has completed accrual of 410 patients,of whom approximately 50 % had tumors 1 cm.If the 3-year DFS is 95 %, the regimen will bedeemed worthy of further investigation. It isexpected that the preliminary results will beavailable in late 2013.The adjuvant therapy of HER2/neu-positivebreast cancer will be discussed in detail in a separate chapter. The summary recommendationsfor systemic adjuvant chemotherapy inHER2/neu-positive breast cancer are as follows: Systemic adjuvant chemotherapy should begiven in combination with trastuzumab, especially in tumors 0.5 cm. Trastuzumab is omitted during the period ofanthracycline chemotherapy but can be givenconcurrently with taxanes.t2.1Table 23.2 Seminal trials comparing neoadjuvant chemotherapy to adjuvant chemotherapy for early-stage breast 83484485486487490Neoadjuvant vs. adjuvant therapyt2.2t2.3t2.4t2.5t2.6t2.7t2.8TrialNSBAP B-18EORTC 10902ECTOpCR rateChemotherapy(%)AC 4133.7FEC60 4AP 4 CMF 3 20pCR vs. non-pCRhazard ratioOS: 0.32†OS: 0.91RFS: 0.43†BCS rates68 % vs. 60 %*35 % vs. 22 %65 % vs. 34 %*DFS HR0.931.121.21OS HR0.991.091.10Reference[47][48][49]BCS breast cancer survival, DFS disease-free survival, OS overall survival, pCR pathological complete responsep 3524

E. Lim et 0541542543544545546547548549550551552considering the possibility of using pCR in theNAC setting as a surrogate end point for clinicalbenefit and as an indication for accelerated drugapproval [51].Practically, NAC should be managed onlyin a multidisciplinary team setting, with initialassessments made by the breast surgeon andmedical and radiation oncologists. Evaluationof treatment response to NAC could potentiallyallow the treating team to tailor individual treatment based upon tumor response, particularly ifthere is the suggestion of disease progression.There have been two trials in which patients wererandomized mid-treatment to non-cross-resistantchemotherapy regimens according to their mid- treatment response [52, 53]. In both trials, deviating from the initial course of therapy in clinicalnonresponders did not increase either the clinicalor pathological response rates or improve survival. For operable breast cancer, in the event ofdisease progression mid-NAC, we would recommend an immediate reevaluation by the breastsurgeon in order to assess the feasibility of surgical resection with mastectomy. Decisions aboutadditional chemotherapy can be deferred until theadjuvant setting. For patients with non- resectabledisease, radiation or alternative i nvestigationalapproaches should be considered [54].553 Special Clinical Scenarios554I nflammatory and Locally AdvancedBreast flammatory breast cancer (IBC) represents aunique biological entity characterized by distinctclinical and histopathological features, aggressivebehavior, and an exceptionally poor prognosis(median survival with current therapy 4 years)[55]. The current standard of care for management of stage 3B IBC is a multimodality approachconsisting of NAC followed by surgery and radiotherapy. Achieving a pCR to NAC is the singlemost important prognostic factor in IBC [56, 57].Given the relative rarity of IBC, there havebeen no specific randomized trials examining theoptimal NAC regimen, and moreover patientswith IBC have historically been excluded fromNAC systemic therapy studies due to their poorprognosis. Single-arm studies and retrospectivecase series show that anthracycline-based regimens are effective (clinical response rates around70 %) [56] and that their efficacy is enhanced bythe subsequent addition of a taxane as evidencedby increased clinical and pCR rates [58, 59]. Assuch, regimens included in the “Anthracycline andTaxane” section of Table 23.1 are recommended.Although outside the scope of this chapter, itis noteworthy that approximately 40 % of IBCare HER2/neu positive, and evidence from randomized phase 3 clinical trials strongly supportsthe routine addition of trastuzumab to NAC inthis setting [60].5

uniformly accepted standard adjuvant chemo-therapy regimen. Commonly used regimens for breast cancer are summarized in Table 23.1 and can broadly be divided into: 1. Non-anthracycline-containing regimens (i.e., CMF and TC) 2. Anthracycline-containing regimens (i.e., AC, FAC, FEC) 3. Anthracycline- and taxane-containing regimens