Systemic treatment of early breast cancera biological perspective

Journal of Surgical Oncology 2011;103:619–626 Systemic Treatment of Early Breast Cancer—A Biological Perspective MBBS,1 ALISON STOPECK, MD,2 AND HOPE S. RUGO, MD * 1University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, California 2University of Arizona, Arizona Cancer Center, Tucson, Arizona Breast cancer is the most common non-skin cancer affecting women worldwide. In the United States, over 90% of tumors are diagnosed as either insitu or localized to the breast or regional lymph nodes. Surgical treatment and adjuvant radiotherapy play an important role in loco-regionaltreatment of early stage breast cancer. Systemic adjuvant therapy is targeted towards isolated circulating and/or disseminated tumor cells to preventsystemic recurrence. This review will describe the diverse tumor biology of human breast cancer and how it influences decisions with regard to theuse of adjuvant therapies.
J. Surg. Oncol. 2011;103:619–626. ß 2011 Wiley-Liss, Inc.
growth factor receptor 2 (HER-2) and more recently, gene expressionprofiles. The age of patient at diagnosis, menopausal status, co-morbid- Breast cancer is the most common non-cutaneous cancer affecting ities, and patient choice are also essential considerations.
women worldwide. In the United States over 90% of tumors are diag- This review will briefly describe our current understanding of the nosed as either in situ or localized to the breast or regional lymph nodes diversity of tumor biology and how it influences decisions with regard to [1]. Appropriate loco-regional management of early stage breast cancer the use of adjuvant therapy. We will discuss a number of ongoing trials in (ESBC) is of utmost importance. Complete surgical resection has been a women with ESBC designed to further delineate predicted response to critical part of management since the late 1800s [2]. Radiotherapy is an adjuvant treatment. With greater understanding of tumor biology, it is important adjunct to breast-conserving surgery that can reduce the hoped that individually targeted adjuvant treatment will allow greater incidence of local recurrence and may improve overall survival in benefit to patients while minimizing unnecessary toxicity.
Breast tumors that are clinically and by imaging limited to the breast and loco-regional lymph nodes and thereby considered surgically resectable are referred to as ESBC. Although these tumors are clinically restricted to loco-regional tissue, there is often early dissemination of Neo-adjuvant therapy refers to treatment administered prior to sur- potentially viable tumor cells [4,5]. The role of systemic adjuvant gical resection of a tumor; conversely, adjuvant treatment is adminis- therapy is to destroy these isolated circulating and/or disseminated cells tered post-operatively. Chemotherapy in the neo-adjuvant setting before they become viable distant recurrences. Once overt metastases significantly increases the number of patients who are able to have have occurred outside loco-regional lymph nodes, treatment can control breast-conserving surgery compared to mastectomy [10,11]. In but not eradicate disease and prognosis is generally poor.
addition, the delay in surgery required for administration of neo-adju- Systemic adjuvant therapy refers to hormonal, chemotherapy, and vant chemotherapy results in comparable recurrence and survival out- targeted biological agents given following resection of a primary tumor.
comes compared to post-operatively administered adjuvant therapies Randomized trials of adjuvant chemotherapy for ESBC have been [12]. Pathologic complete remission (pCR) in breast and axillary nodes conducted for over 50 years [6,7] with resulting substantial improve- following neo-adjuvant therapy strongly predicts long-term disease-free ments in morbidity and overall survival. In the United States, a 24% and overall survival, particularly in HR-negative disease, and thus acts reduction in death from breast cancer was seen between the year 1990 as an early biomarker for anti-tumor effects of therapy [12–15].
and 2000 due to both the implementation of widespread screening andadvances in adjuvant therapy [8]. By the year 2000, it was estimated thatapproximately 80% of women with node positive or locally advanced Biological Determinants Currently Utilized in disease received adjuvant hormonal and/or chemotherapy, directly reducing death from breast cancer by an estimated 12–22% [8]. Ameta-analysis of 194 randomized trials by The Early Breast Cancer Proliferation of breast tumors is most commonly determined in Trialist Group published in 2005 demonstrated a reduction in death by clinical practice by histologic grade and by expression of a nuclear up to 38% with addition of adjuvant hormonal and chemotherapy for protein, Ki-67. Proliferative or high-grade tumors are associated with significantly inferior survival compared with tumors with low Even in 1961, it was recognized that adjuvant chemotherapy appeared to be of greater benefit to some individuals, including younger *Correspondence to: Dr. Hope S. Rugo, University of California San women with node-positive disease [7]. Our understanding of the Francisco Helen Diller Family Comprehensive Cancer Center, San advantage of adjuvant systemic treatment remains dependent on numer- Francisco, CA. Fax: 415-353-9592. E-mail: [email protected] ous tumor and patient related variables which affect the prognosis, Received 8 November 2010; Accepted 24 November 2010 efficacy, and toxicity of treatment. Important variables include the stage and intrinsic biological features of the tumor including proliferation rate, hormone receptor (HR) status, expression of human epidermal histological grade [16]. In addition, high-grade tumors are more respon- with ESBC based on data from published, large phase III trials, the sive to chemotherapy which targets actively proliferating cells [17,18].
Overview Analysis, and the surveillance epidemiology and end-results These findings suggest a greater role of adjuvant chemotherapy in (SEER) database, as well as predicted benefits from systemic therapy patients with more highly proliferative tumors [19].
[44]. Problems with this tool include lack of HER-2 data, reporting of The proliferation of a tumor may be routinely classified more accu- overall recurrence rather than only distant recurrence, and the inability rately by an assay for cellular and/or nuclear proteins. A high versus low to vary predicted benefits of systemic therapy based on an improved Ki-67, has been demonstrated to separate grade II tumors into low- and understanding of the impact of tumor biology on response. In addition, high-risk groups, thereby predicting breast cancer specific recurrence the information initially obtained from the SEER database was and survival [20]. The difference in outcome with this classification was restricted to women aged 36–69 years. A population-based validation independent of other recognized prognostic variables.
study involving over 4,000 women found that the program did not HR positivity refers to tumors that express the estrogen receptor (ER) predict outcome accurately for women outside of this age-range, and and/or progesterone receptor (PR), as determined by immunohisto- for women younger than 36, the observed outcomes were approximately chemical staining (IHC). Although less common in premenopausal 10% worse than those predicted [45]. Thus, although Adjuvant! women, approximately 80% of tumors in post-menopausal women Online represents a helpful clinical tool, it has specific functional are HR positive [9]. Most but not all HR-positive tumors are of low histological grade [21]. These tumors can progress years and even Several newer tests may provide stronger prognostic and predictive decades post-primary surgery, and approximately 50% of recurrences information [46]. Molecular profiling is now being used to better define occur more than 5 years following initial diagnosis [9]. The benefit of prognosis and predict therapy response in breast tumors, in addition to adjuvant hormonal therapy is restricted to women with HR-positive standard clinicopathologic factors. Expression of certain genes has been tumors [22]. A number of clinical trials have demonstrated improved shown to correlate with biological behavior, outcome, and response to disease-free survival with adjuvant or neo-adjuvant aromatase inhibitors specific therapies. The 21 gene recurrence score assay, Oncotype DX compared to tamoxifen for post-menopausal women with HR-positive (Genomic Health, Redwood City, CA), is a commercially available test tumors [23–26]. However, improved survival has only been observed in that evaluates expression of 21 genes; 16 cancer related (including HRs, trials that compare sequential tamoxifen followed by an aromatase HER-2, and proliferation-associated genes as well as others), and 5 inhibitor for a total of 5 years to tamoxifen therapy alone or with reference. The resulting composite score, known as a recurrence score extended adjuvant hormonal therapy (i.e., 5 years of tamoxifen com- (RS) is associated with prognosis and response to hormone and chemo- pared to 5 years of tamoxifen followed by 5 years of aromatase inhi- bition) [27,28]. Interestingly, trials comparing 5 years of tamoxifen to Validation of this assay was undertaken utilizing a subset of patients 5 years of aromatase inhibition have not yet demonstrated survival enrolled in NSABP B14 and NSABP B21 for whom archived tumor benefit, likely due to a combination of the long natural history of tissue was available. In B21, patients with node-negative, HR-positive HR-positive disease in post-menopausal women, and competing mor- breast cancer were randomized to receive 5 years of tamoxifen with or bidities in this aging population [29,30]. Regardless of stage, HR- without adjuvant chemotherapy (predominantly cyclophosphamide, positive breast tumors are less likely to benefit from neo-adjuvant methotrexate, and fluorouracil). Tumor samples from 651 patients and adjuvant chemotherapy compared with HR-negative or HER-2- who had participated in the trial were available [47]. Depending on the gene expression score, patients were categorized as having low (54% In addition to HR status, HER-2 is an important determinant of of patients enrolled), intermediate (20.6%), or high (25.5%), risk of prognosis and treatment. HER-2 is a tyrosine kinase receptor involved in recurrence. The benefit of combining chemotherapy with hormone cell growth and proliferation that is over-expressed in 20–25% of breast therapy was only significant for patients with tumors assigned a high cancers due to amplification of the HER-2 gene [33–36]. HER-2- RS, in whom the 10-year Kaplan–Meier estimate for freedom from positive tumors are associated with higher grade, larger size, and have distant recurrence was improved from 60% to 88% (HR 0.26, CI 0.13– earlier lymph node involvement than HER-2-negative disease [36,37], 0.53). There was no significant benefit to receiving chemotherapy over and in the absence of HER-2-targeted treatment are associated with tamoxifen therapy alone in patients whose tumors had low RS.
earlier distant relapse and a reduction in overall survival [33,34].
Unfortunately, the study was underpowered to document potential small Interestingly, these tumors are also highly chemosensitive, in particular benefits from chemotherapy for patients whose tumors scored in the to anthracyclines and taxanes. The addition of 1 year of trastuzumab, a intermediate-risk category and thus a large cooperative group trial monoclonal antibody directed against the extracellular domain of the (TailoRx) is evaluating the ability of this test to predict chemotherapy HER-2 receptor, to adjuvant chemotherapy in women with HER-2- benefit in a modified intermediate-risk group. Recent data also suggest positive ESBC, results in a 33% reduction in the risk of death at 3 years that this test may be of value in predicting response to chemotherapy in patients with HR-positive, node-positive disease [48] as well as pCR in Triple-negative breast cancer refers to tumors lacking expression of HR and over-expression of HER-2. These tumors account for between The prognostic value of the 21 gene RS first demonstrated in B14 has 11% and 26% of breast cancer diagnoses [39–41], and occur more been validated in a large retrospective case control study involving frequently in young women, in particular African American women, almost 5,000 women with node-negative ER-positive breast cancer [50].
and are the most common form of breast cancer found in women The 10-year breast cancer death rates in patients who received tamox- carrying mutations in the BRCA1 gene. They are often of higher grade, ifen were 2.8% for those with low RS, 10.7% for those with intermediate and are associated with inferior overall survival [39–42]. Recurrence RS, and 15.5% with high RS. The RS also predicted prognosis for rates in these tumors are highest in the first 4 years [41], and although untreated patients as well as in post-menopausal patients treated with many are highly chemotherapy responsive, development of rapid resist- ance, early visceral metastases, and short survival characterize recurrent The 70-gene expression assay, MammoPrint (Agendia, Irvine, CA), is also commercially available to predict risk of distant recurrence in A free web-based computer tool, Adjuvant! Online is available for women with early stage breast cancer. This test, which was developed to health professionals to assist decisions about adjuvant treatment.
predict a short interval from diagnosis to distant recurrence in patients Using variables including age, co-morbidities, ER status, tumor size with breast cancer, requires fresh frozen tissue for microarray analysis, and grade, and node status, this program graphically displays predicted so tissue must be processed appropriately at the time of surgery or at risks of both recurrence and death at 10 years of follow-up for patients initial biopsy. The 70 genes analyzed include many involved in the Systemic Treatment of Early Breast Cancer regulation of cell cycle, invasion, metastasis, and angiogenesis [52].
who can then be treated with surgery or neo-adjuvant hormone therapy Tumors are categorized as having either a good or poor prognostic as indicated [61]. Patients with high-risk disease are randomized to a signature with a poor signature associated with a significantly higher menu of novel-targeted agents in combination with paclitaxel. Biopsies risk of distant metastases (HR 5.1; CI 2.9–9, P-value <0.001) [53]. On and MRI scans are performed during treatment to document tumor multi-variant analysis, the 70-gene prognostic signature was superior to response; and the trial utilizes an adaptive study design which allows standard prognostic factors such as tumor size, grade, HR status, and early indicators of response or resistance to therapy to drive subsequent lymph node involvement in predicting recurrence. The MINDACT trial is a large, international phase III trial which compares the genomic In general, current clinical trial designs are attempting to focus on prognostic test to traditional clinical-pathological methods for assessing tumor biology, both in patient selection as well as choice of targeted the risk of breast cancer recurring in women with lymph node negative agents and appropriate chemo- or hormone therapy partners. There are or 1–3 node-positive disease. It is hypothesised that using the genomic numerous other interventional neo-adjuvant and adjuvant clinical trials test in addition to traditional methods will result in more accurate risk currently recruiting patients with ESBC. A selection of these, focusing assessment and ultimately help physicians and patients make better particularly on those designed to focus on specific biologic subsets, are decisions about who can safely avoid chemotherapy and its potential side effects. A better understanding of the value that these tests add to standard IHC results including ER, PR, HER-2, and Ki67 is important with trastuzumab in combination with chemotherapy for the treatment for justifying the increased costs associated with molecular testing as of early stage, HER-2-positive cancers is now well established, with clear benefits seen in both disease-free and overall survival. Controversy The intrinsic subtype model represents another genomic assessment remains about the use of trastuzumab in very small HER-2-positive of tumor biology. This model, initially described by Perou et al. [54], tumors, the most effective and least toxic chemotherapy parter(s), and describes four classes of breast tumors on the basis of genomic profiles: the appropriate duration of trastuzumab therapy. Despite the success of luminal, basal, HER-2 over-expressing, and normal-like. Subsequently, this treatment, patients still experience distant recurrence and thus the luminal subtype has been further classified into at least two sub- current trials are exploring novel, rationally designed therapies for this groups: luminal A and luminal B [55]. These subtypes are associated disease. Lapatinib is an orally active tyrosine kinase inhibitor of both the with outcome [55–57] and response to neo-adjuvant chemotherapy HER-2 and epidermal growth factor (EGFR) receptors. Trials in patients [31,43,58]. The use of intrinsic genetic subtypes to predict prognosis with HER-2-positive metastatic breast cancer have demonstrated effi- and response to chemotherapy is not currently utilized in clinical cacy as a single agent and when combined with chemotherapy [62,63].
practice outside of clinical trials.
Despite dual inhibition of EGFR and HER-2, clinical activity appears to Concordance between various gene expression profiles, including be restricted to tumors with HER-2 over-expression [64]. Trials cur- MammoPrint, the 21 gene RS, and the intrinsic subtype model was rently underway in HER-2-positive ESBC include the randomized, demonstrated by Fan et al. [59]. All three molecular profiling methods multi-center, phase III trial ALTTO trial (adjuvant lapatinib and or predict prognosis and, at least to some degree, response to adjuvant trastuzumab treatment optimization). In this trial, patients with resected therapy. However, further delineation and characterization of particular HER-2-positive breast cancer receive anthracycline-based neo-adju- genomic characteristics which correlate with response to specific che- vant/adjuvant therapy and are randomized to paclitaxel with either motherapeutic and targeted agents is necessary for optimizing and lapatinib, trastuzumab, or trastuzumab in combination with lapatinib.
individualizing care and is the goal of the next generation of clinical Multiple neo-adjuvant trials with slightly different designs are studying lapatinib, trastuzumab, and the combination with standard chemother- The 2007 American Society of Clinical Oncology recommendations apy, including NeoALTTO, CALGB 40601, and NSABP B41; initial on use of tumor markers suggests that specific gene expression tests can data from NeoALTTO is expected at the end of 2010. Many of these be used to stratify women with ER positive, node negative, breast cancer trials will be examining gene expression profiles and correlative end- both in terms of prognosis and benefit of adjuvant chemotherapy, in points in an effort to predict improved outcomes or pCR [61].
addition to 5 years of tamoxifen [60]. Clearly this is just the beginning of In addition to predicting a benefit from HER-2-targeted therapy, being able to apply a better understanding of tumor biology to making over-expression of HER-2 may be associated with increased benefit appropriate treatment recommendations for the treatment of early stage from certain chemotherapeutic agents, especially anthracyclines. A randomized trial compared the outcomes for 710 women receivinganthracycline-based adjuvant chemotherapy to those who received anon-anthracycline regime [65]. HER-2 amplification was associated with inferior outcomes regardless of treatment administered, although Tailoring Treatment to Biological Aspects of Tumors this finding has not been demonstrated in all studies [66]. Interestingly,women with HER-2-positive tumors who received anthracycline-based In addition to increasing rates of breast-conserving therapy, neo- regimens had significantly improved outcomes, including relapse-free adjuvant systemic therapy potentially allows earlier systemic treatment and overall survival. In 2008, Gennari et al. [67] published a pooled of subclinical circulating and disseminated tumor cells. However, the analysis of eight randomized trials including over 5,000 patients, and most important benefit in terms of understanding tumor biology and compared chemotherapy regimens with or without anthracyclines.
development of novel therapeutics is the ability to assess response to Anthracycline-based regimens significantly improved disease-free treatment in vivo, and obtain serial tumor samples during treatment.
and overall survival in patients with HER-2-positive tumors but not This has become an increasingly popular trial design, with a relatively in those who had HER-2-negative disease. Because of the close prox- rapid read-out of efficacy based on in breast and axillary response to imity of the Her-2 and topoisomerase II genes on chromosome 17, co- specific therapy. Although historically, pathologic response to neo- amplification of both genes has been demonstrated in up to one-third of adjuvant chemotherapy has correlated with long-term outcome, this HER-2-positive breast cancers. As topoisomerase II is a specific target is not the case for relatively indolent tumors, as hormone therapy may of anthracycline therapy, this may be, at least in part, the mechanism result in excellent outcome despite a relatively poor response to chemo- behind the improved efficacy of anthracyclines desmontrated above in therapy in the neo-adjuvant setting. The multi-center and novel I-SPY2 trial initially obtains risk information using the 70-gene expression Because of the increased cardiac toxicity observed from both anthra- assay (MammoPrint) and excludes patients with low-risk disease, cyclines and trastuzumab therapy, there is interest in designing active, TABLE I. Examples of Currently Active Adjuvant Trials in Breast Cancer (Source Accessed 10/5/2010–10/11/2010) Compare four different schedules chemotherapy Randomized phase III: ACy(IV) 2nd weekly  6 -P 2nd weekly  6 or ACy(oral) weekly  15 -P 2nd weekly  6 or ACy(IV) 2nd weekly  6-P weekly  12 or ACy(oral) weekly  15-P weekly  12 H given to all HER-2 positive Compare different schedules of chemotherapy Compare various chemotherapy regimens and 8 chemotherapy regimens followed by oralCy and M for 12 months H given to allHER-2 positive Investigate the role of adding B to chemotherapy Randomized phase III: TCy or TACy or TCyB Investigate role of ovarian suppression in addition Randomized phase III trial: Ta or TaOS or ExOS Investigate the benefit of chemotherapy in patients Randomized phase III trial: RS: <11 Ta or Ai Æ chemotherapy, RS: 11–25 randomized to Ta or Ai plus chemotherapy or Ta or Ai alone,RS: >25 T or Ai þ chemotherapy Randomized phase III: ACy-P or ACyB-PB or Investigate the role of D in reducing bone metastases Randomized phase III: DVdc or Vdc HER-2 positive: Investigate the role of adding B to Randomized phase III: TCH-H or TCHB-HB or Investigate difference between 6 and 12 months of H Randomized phase III: FEC-TH-H (12 months) or Randomized phase III: T or L or T-L or TL Triple negative: investigate the role of B Hormone therapy: Ta—Tamoxifen: selective estrogen receptor modulator; Os—ovarian suppression either chemically, surgically, or via radiotherapy; Ex—Exemestane: aromatase inhibitor; Le—Letrozole: aromatase inhibitor; An—Anastrozole: aromatase inhibitor; Ai—aromatase inhibitor (physician choice).
Chemotherapy: T—Docetaxel: taxane chemotherapy, microtubule inhibitor; P—Paclitaxel: taxane chemotherapy, microtubule inhibitor; I—Ixabepilone: microtubulestabilizer; C—Carboplatin: platinum chemotherapy; A—doxorubicin: anthracycline chemotherapy; E—Epirubicin: anthracycline chemotherapy; Cy—Cyclophosphamide: alkalating chemotherapy; F—Fluorouracil: anti-metabolite chemotherapy; M—Methotrexate: anti-metabolite chemotherapy; G—Gemcitabine: anti-metabolite chemotherapy.
Biological therapy: B—Bevacizumab: antibody to vascular endothelial growth factor; H—Trastuzumab: antibody to HER-2; L—Lapatinib: inhibits tyrosine kinase ofHER-2 and EGFR; N—Neratinib: inhibits tyrosine kinase of HER-2 and EGFR; F—Figitumab: monoclonal antibody to insulin-like growth factor; Abt—ABT-888:PARP (polyADP-ribose polymerase) inhibitor; In—Iniparib: PARP inhibitor; Amg—AMG-386: angiopoietin 1/2 neutralizing peptibody; Co—Conatumumab:monoclonal antibody to TRAIL (tumor necrosis factor-related apoptosis inducing ligand) receptor 2.
Other: ZA—Zoledronic acid: Bisphosphonate; D—Denosunab: Monoclonal antibody to RANK ligand; Vdc—Vitamin D and Calcium; RS—recurrence score:Calculated from 21 gene recurrence score assay (OncotypeDx); IV—intravenous.
non-anthracycline containing regimens for patients with HER-2- An association between resistance to tamoxifen in tumors that are positive cancer. TCH (docetaxel, carboplatin, and trastuzumab) is HR positive and over-express HER-2 has been reported in some [36,71] one combination which has been investigated in the adjuvant and but not all studies [72,73]. It has been suggested that aromatase inhibi- metastatic settings based on marked synergy in preclinical studies tors may be superior to tamoxifen in HER-2-positive tumors but this has [68]. In the adjuvant setting, treatment with TCH resulted in superior not been proven in large adjuvant trials comparing tamoxifen to aroma- DFS and OS compared to doxorubicin and cyclophosphamide followed tase inhibitors [71]. Consequently, there is currently insufficient evi- by docetaxel (AC/D), as did the addition of trastuzumab to the AC/D dence to change current recommendations regarding adjuvant hormone regimen. TCH resulted in less cardiac toxicity, although toxicity from therapy options for women with HR positive, HER-2 over-expressing AC/D with trastuzumab was rare. This trial was not designed to directly compare TCH to the anthracycline plus trastuzumab regimen, so possible differences in efficacy between these regimens remains a of particular benefit to patients with triple-negative tumors. A small neo- question. In addition, the prospective, phase III BETH trial is investi- adjuvant trial which investigated the combination of paclitaxel and gating trastuzumab in combination with chemotherapy regimens with carboplatin chemotherapy, plus the addition of trastuzumab in patients or without an anthracycline and also with or without bevacizumab, with HER-2 disease demonstrated improved response in patients with an antibody to the vascular endothelial growth factor (VEGF) [61].
triple-negative tumors [74]. pCR in these patients was 67%, which was over-expression of VEGF has been associated with poorer outcome in significantly higher than the 45% seen in study participants overall.
HER-2-positive disease [69], and preliminary data in the metastatic Cisplatin appears to be particularly effective in patients with triple- setting suggests efficacy from combined blockade of these two path- negative breast cancer associated with mutations in the BRCA1 gene but the effectiveness in sporadic disease is less impressive [75,76]. Trials Systemic Treatment of Early Breast Cancer TABLE II. Examples of Currently Active Neo-Adjuvant Trials in Breast Cancer (Source Accessed 10/5/2010–10/11/2010) HER-2 positive: investigate the difference Investigate the role of combining P to T, L, Triple negative: investigate the role of the Investigate the role of different schedules of In Randomized phase II trial: P or PIn (weekly) Hormone therapy: Ta—Tamoxifen: selective estrogen receptor modulator; Os—ovarian suppression either chemically, surgically, or via radiotherapy; Ex—Exemestane: aromatase inhibitor; Le—Letrozole: aromatase inhibitor; An—Anastrozole: aromatase inhibitor; Ai—aromatase inhibitor (physician choice).
Chemotherapy: T—Docetaxel: taxane chemotherapy, microtubule inhibitor; P—Paclitaxel: taxane chemotherapy, microtubule inhibitor; I—Ixabepilone: microtubulestabilizer; C—Carboplatin: platinum chemotherapy; A—doxorubicin: anthracycline chemotherapy; E—Epirubicin: anthracycline chemotherapy; Cy—Cyclophosphamide: alkalating chemotherapy; F—Fluorouracil: anti-metabolite chemotherapy; M—Methotrexate: anti-metabolite chemotherapy; G—Gemcitabine: anti-metabolite chemotherapy.
Biological therapy: B—Bevacizumab: antibody to vascular endothelial growth factor; H—Trastuzumab: antibody to HER-2; L—Lapatinib: inhibits tyrosine kinase ofHER-2 and EGFR; N—Neratinib: inhibits tyrosine kinase of HER-2 and EGFR; F—Figitumab: monoclonal antibody to insulin-like growth factor; Abt—ABT-888:PARP (polyADP-ribose polymerase) inhibitor; In—Iniparib: PARP inhibitor; Amg—AMG-386: angiopoietin 1/2 neutralizing peptibody; Co—Conatumumab:monoclonal antibody to TRAIL (tumor necrosis factor-related apoptosis inducing ligand) receptor 2.
Other: ZA—Zoledronic acid: Bisphosphonate; D—Denosunab: Monoclonal antibody to RANK ligand; Vdc—Vitamin D and Calcium; RS—recurrence score:Calculated from 21 gene recurrence score assay (OncotypeDx); IV—intravenous.
exploring the effect of platinum-based chemotherapy on pathological metastatic setting have been promising [83,84], and a pivotal phase III response in triple-negative tumors are currently underway [61].
trial has completed accrual with results expected in early 2011. The role The development of new blood vessels from existing tissue—or of PARP inhibition in early stage triple-negative and BRCA-associated angiogenesis—is an important factor in tumor growth [77]. This process breast cancer is also under investigation in the neo-adjuvant trial setting, may be particularly important in triple-negative breast cancer, in which including several trials testing various PARP inhibitors with different higher levels of VEGF have been demonstrated [78]. Small numbers of chemotherapy regimens and dosing schedules [61].
patients involved in subset analysis from first line metastatic trials havedemonstrated a non-significant improvement in progression-free sur- vival for patients with triple-negative tumors [79]. Interim analysis froma small neo-adjuvant phase II trial evaluating the combination of Systemic adjuvant therapy for breast cancer improves survival for bevacizumab to platinum-based chemotherapy in women with triple- many patients with ESBC. The balance of the risks of these therapies negative disease, included demonstration of a pCR or near pCR in 37% against the potential benefits is paramount to any treatment recommen- of patients [80]. A large phase III trial, BEATRICE, is currently eval- dation. Understanding the importance of individual biological features uating the benefit of the addition of 12 months of bevacizumab to of tumors and their impact on prognosis and treatment responses is now adjuvant chemotherapy in this patient population. CALGB 40603 is required for providing patients with optimal and individualized care.
a randomized, phase II trial in the neo-adjuvant setting which is inves- Improved methods for tumor profiling has become a priority for the next tigating the effect of bevacizumab, carboplatin, or the combination generation of clinical trials that select patients and treatments based on along with standard taxane and anthracycline-based chemotherapy in tumor biology, rather than anatomy. Although beyond the scope of this patients with triple-negative breast cancer, with a primary endpoint of review, variations in host metabolism, manifested by polymorphisms in key enzymes, also appears to have a significant role in determining Poly(ADP-ribose) poymerase (PARP) inhibitors are one of the most toxicity and potential efficacy of specific anti-tumor therapies [85].
exciting targeted therapies for triple-negative breast cancer. A major Work in this fascinating area is ongoing.
mechanism used to repair single strand breaks in DNA is base excision Maximizing the benefit of adjuvant therapy while minimizing repair, via the PARP enzyme. When PARP is inhibited, single strand toxicity remains the ultimate goal of therapy. Although there has been DNA breaks are not repaired and can lead to double stranded breaks.
significant progress in this area, future research will provide insights Many triple-negative tumor share various biological features with into the diversity of breast tumors, further our understanding of the tumors occurring in BRCA carriers and BRCA is important in repairing complex relationships between the host and its response to cancer, double stranded DNA. Apoptosis results if DNA is not repaired satis- and will help predict response to anti-tumor therapies and their factorily in a tumor cell [81,82]. Phase II trials of PARP inhibitors in the Immunohistochemistry of estrogen and progesterone receptors 1. Surveillance, Epidemiology and End Results (SEER). http://seer.- reconsidered: Experience with 5,993 breast cancers. Am J Clin National Cancer Institute.
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