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Biomarkers Predicting Clinical Benefit: Fact or Fiction?

Biomarkers Predicting Clinical Benefit: Fact or Fiction? Abstract Preoperative therapy is increasingly used in operable disease to improve the chance for breast-conservative surgery. Moreover, this strategy allows for a better definition of patient prognosis. Independently from stage at diagnosis and breast cancer subtype, the achievement of a pathological complete response (pCR) is a surrogate marker for long-term outcome. The likelihood of pCR depends on tumor biology, being poorly differentiated tumors with ductal histology, absence of hormone receptors, and high proliferation rate those with a higher chance of achieving a CR. However, pCR is a late efficacy parameter that can be evaluated at the end of the preoperative treatment; moreover, a pCR is achieved in a minority of patients and is not an appropriate efficacy measure for neoadjuvant endocrine therapy. The predictive role of tumor biomarkers such as p53, microtubule-associated tau protein, and poly (ADP-ribose) polymerase will be reviewed along with potential markers of early treatment effect. Defining Clinical Benefit in Primary Systemic Therapy Preoperative therapy is the standard treatment for locally advanced disease, where it can induce an important tumor shrinkage rendering amenable to locoregional control initially unresectable tumors. This strategy is also increasingly used in operable disease. In face of survival equivalence, there are two major clinical advantages in using primary systemic vs standard postoperative therapy in operable disease: The possibility for breast-conserving surgery in those patients initially candidates to mastectomy, and the opportunity for a better definition of patient prognosis. In fact, breast response improves the surgical options, increasing the chance for breast conservation (1,2). However, the eligibility for breast conservation is not only a result of treatment activity as measured as breast tumor shrinkage. Indeed, the recommendation for the type of surgery is generally based on several other parameters, including breast size, tumor location, presence of in situ disease, contraindication to radiation therapy, and patient willingness. Therefore, the rate of breast-conserving surgery is a relevant clinical endpoint, but it generally underestimates the clinical benefit achievable when using preoperative therapy. The response achieved in the primary tumor is a strong predictor of patient outcome. Independently from stage at diagnosis and breast cancer subtype (triple negative, hormone receptor [HR]-positive, or HER2-positive), the achievement of a pathological complete response (pCR) is a surrogate marker for long-term outcome (3–5). In fact, it has been shown that, when a pCR is achieved, the long-term outcome is similar for patients with triple-negative breast cancer, which is the more aggressive breast cancer subtype, as compared with other breast cancer subtypes (6). The definition of pCR varies across the studies, however, its prognostic role is maintained independently from the applied criteria. The most recent trials have adopted the rate of pCR as the primary endpoint, as defined as the complete disappearance of any invasive tumor in the breast and in axillary nodes. In case of neoadjuvant endocrine therapy, pCR is not the optimal way to measure clinical benefit. In fact, the rate of pCR in trials of neoadjuvant endocrine therapy is generally extremely low or not even reported (7–10). Indeed, endocrine therapy works by inhibiting cancer cell proliferation and is administered generally for 5 years in the adjuvant setting. Therefore, a complete eradication of the disease after 4–6 months neoadjuvant hormonal therapy is unlikely. Traditional and Emerging Predictors of pCR Several analyses have consistently shown that the likelihood of pCR depends on tumor biology. Tumor histology, grade, expression of HR, HER2 status, and tumor proliferation are traditional parameters used to predict chemotherapy benefit. Patients undergoing neoadjuvant chemotherapy are more likely to achieve a pCR in case of poorly differentiated tumors with ductal histology, absence of HR, and high proliferation rate (3,11). HER2 is a strong predictor of anti-HER2 therapy benefit, whereas its role in predicting pCR following chemotherapy alone is less clearly defined across studies, depending on the type of the agents investigated. On the other hand, tumors with a less aggressive phenotype such as lobular histotype and well-differentiated tumors with high expression of HR are less likely to achieve a pCR following chemotherapy. In an analysis including more than 1700 patients treated with preoperative chemotherapy at the MD Anderson Cancer Center, only 8% of HR-positive tumors achieved a pCR vs 24% of patients with HR-negative tumors (P > .001). Survival analyses in the HR-positive group confirmed that patients achieving a pCR had significantly prolonged disease-free and overall survival as compared with patients with less than pCR (3). Other biomarkers have been evaluated as potential predictors of pCR. The most frequent genetic events in human cancers are p53 mutations. In cells with altered p53 function, proliferation is no longer under control, with subsequent inefficiency in DNA repair and genetic instability. The predictive and prognostic role of p53 in breast cancer patients has been widely investigated, but a consistent association between p53 and responsiveness to neoadjuvant chemotherapy is still lacking (12,13). In a recently presented prospective study, p53 mutational status was tested in more than 1800 patients with locally advanced/inflammatory or large operable breast cancer randomized to receive anthracycline vs anthracycline- and taxane-based neoadjuvant therapy (14). The primary endpoint was to explore the role of p53 in predicting benefit from taxanes in terms of progression-free survival; secondary aims were the clinical and pathological responses. Patients with p53 mutations had significantly worse disease-free and overall survival, thus confirming the prognostic role of p53; however, no difference in progression-free survival between arms was observed according to p53 status. Data on clinical and pathological responses have not yet been reported; therefore, the possible association between p53 mutational and response to preoperative taxanes is still unknown. Tau protein promotes tubulin polymerization and stabilizes microtubules; therefore, low levels of tau protein should be associated with a higher sensitivity to taxanes. In a retrospective analysis of 122 patients treated with neoadjuvant chemotherapy and assessed for tau protein expression by immunohistochemistry, the vast majority of pCRs occurred in the tau protein–negative group, with an odds ratio for pCR of 3.7 (P < .0013) (15). By using gene expression analysis, tau has been recently associated with probability of response to the microtubule stabilizer ixabepilone (16). However, the predictive role of tau was not confirmed in the GeparTrio study: in a subset analysis conducted on 80 patients, tau gene expression was not associated with a higher pCR rate following preoperative chemotherapy with docetaxel, doxorubicin cyclophosphamide (17). The largest experience in the adjuvant setting derives from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-28 trial, where samples from 1942 patients were evaluated for tau expression. High tau-protein-expression was associated with better prognosis, but there was no significant interaction between tau expression and benefit from paclitaxel (18). The recent observation from the adjuvant BCIRG 001 trial, showing the prognostic role of tau protein, further reinforces the tight relation existing between prognostic and predictive parameters (19). More recently, a lot of interest has emerged on poly (ADP-ribose) polymerase (PARP), the nuclear enzyme that signals DNA damages and promotes single-strand breaks repair through the base excision pathway. A growing body of literature has shown the activity of PARP inhibitors, in particular in BRCA-associated tumors and triple-negative breast cancers. Cytoplasmic and nuclear PARP expression was evaluated by immunohistochemistry in 638 patients enrolled in the GeparTrio trial. Interestingly, PARP is expressed in all breast cancer subtypes: 51% of tumors have moderate cytoplasmic PARP expression and 24% show a high expression. The pCR rates were 8%, 19.1%, and 26% in the low vs moderate vs high PARP expressors (P < .0005). In the multivariable analysis, PARP, HER2, and HR were all independent predictors of pCR (20). What Beyond pCR? The achievement of a pCR, probably mirroring treatment effects on micrometastatic deposits, can reverse the prognosis of those patients diagnosed with an unfavorable tumor biology. However, pCR is far from being an optimal endpoint. First of all, a pCR is achieved in a minority of patients, and, even though these patients have an excellent prognosis, a few will eventually relapse. More importantly, the patients with less than pCR are a heterogeneous group in terms of prognosis. In fact, this group includes patients with truly chemoresistant disease, who are at high risk of relapse, and patients where preoperative therapy has induced an important tumor downstaging, thus having an excellent outcome (21). Therefore, the dichotomization of treatment efficacy in pCR vs non-pCR oversimplifies the different prognostic categories, representing an useful tool for patients with pCR, but with less clinical value for patients with residual disease. Indeed, pCR rates in HER2-positive patients receiving sequential anthracycline-, taxane-, and trastuzumab-preoperative chemotherapy range from 30% to 60% (22–24). In patients with triple-negative breast cancer, the pCR rate is in the range between 20% and 45%, whereas in case of HR–positive tumors, chemotherapy can induce a pCR in less than 10% of the patients (3,6,25). Therefore, the study of residual disease, and in particular of treatment-induced modifications in tumor biomarker expression, is becoming an intense field of research to refine patient prognosis as well as to identify potential markers of treatment resistance. The group from MD Anderson Cancer Center, by combining the pathological measurements of residual primary tumor and nodal metastases with tumor cellularity, has generated an index, the residual cancer burden, able to predict for distant disease-free survival (26). Three studies have shown that a high Ki67 on residual tumor after preoperative chemotherapy, in patient population including all breast cancer subtypes, was associated with a significantly worse outcome (27–29). In HER2-positive breast cancer patients treated with neoadjuvant trastuzumab and chemotherapy, the loss of HER2 expression on residual disease has been associated with a higher risk of relapse (30). Another limitation of pCR is that this is a “late” efficacy measure evaluated at the end of the treatment program. A true advantage would be an early prediction of treatment benefit. Moreover, as previously discussed, the pCR rate is not the more sensitive way to measure the efficacy of preoperative hormonal therapy. Up to now, preoperative endocrine therapy has been mainly recommended for elderly patients with large primaries and unfit for chemotherapy. However, in the adjuvant setting, patients with low-risk, HR-positive, and HER2-negative disease are generally offered endocrine therapy alone. Therefore, the use of preoperative endocrine therapy in patients with operable breast cancer will probably increase, reinforcing the need for appropriate measures of treatment efficacy. The IMPACT (Immediate Preoperative Anastrozole, Tamoxifen , or Combined with Tamoxifen) trial randomized 330 patients to preoperative anastrozole or tamoxifen or the combination of both drugs. No differences were observed in overall clinical responses and in the rate of breast-conserving surgery, which are classic parameters for chemotherapy efficacy. However, a greater inhibition of tumor proliferation (Ki67) was observed in the anastrozole arm as compared with tamoxifen or to the combination, anticipating the results of several hundreds of patients of the large adjuvant ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial (7). More interestingly, Ki67 level after 2 weeks of therapy was an independent predictive factor for relapse-free survival. A prognostic score generated on the basis of tumor size, nodal involvement, Ki67, and estrogen receptor Allred score after preoperative endocrine therapy has been generated (the preoperative endocrine prognostic index [PEPI]) (31). An adjuvant trial evaluating the role of adding chemotherapy on the basis of the PEPI score after neoadjuvant hormonal therapy is ongoing (9). Several randomized trials of hormonal therapy combined with targeted agents are incorporating the 2-week Ki67 assessment as an early marker of treatment efficacy. In this perspective, interesting data can be also obtained with new molecular imaging techniques, such as fluorodeoxyglucose positron emission tomography. In conclusion, facts are that we can predict clinical benefit from neoadjuvant therapies by evaluating tissue biomarkers and functional imaging techniques. Unfortunately, at the moment these parameters have been rarely incorporated into prospective trials, and additional data are needed to recommend the use of these biomarkers in the treatment decision process. References 1. Fisher B,  Brown A,  Mamounas E, et al.  Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18,  J Clin Oncol. ,  1997, vol.  15  7(pg.  2483- 2493) 2. Mauri D,  Pavlidis N,  Ioannidis JP.  Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis,  J Natl Cancer Inst. ,  2005, vol.  97  3(pg.  188- 194) 3. Guarneri V,  Broglio K,  Kau SW, et al.  Prognostic value of pathologic complete response after primary chemotherapy in relation to hormone receptor status and other factors,  J Clin Oncol. ,  2006, vol.  24  7(pg.  1037- 1044) 4. Rouzier R,  Extra JM,  Klijanienko J, et al.  Incidence and prognostic significance of complete axillary downstaging after primary chemotherapy in breast cancer patients with T1 to T3 tumors and cytologically proven axillary metastatic lymph nodes,  J Clin Oncol. ,  2002, vol.  20  5(pg.  1304- 1310) 5. Rastogi P,  Anderson SJ,  Bear HD, et al.  Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27,  J Clin Oncol. ,  2008, vol.  26  5(pg.  778- 785) 6. Liedtke C,  Mazouni C,  Hess KR, et al.  Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer,  J Clin Oncol. ,  2008, vol.  26  8(pg.  1275- 1281) 7. Dowsett M,  Ebbs SR,  Dixon JM, et al.  Biomarker changes during neoadjuvant anastrozole, tamoxifen, or the combination: influence of hormonal status and HER-2 in breast cancer—a study from the IMPACT trialists,  J Clin Oncol. ,  2005, vol.  23  11(pg.  2477- 2492) 8. Eiermann W,  Paepke S,  Appfelstaedt J, et al.  Preoperative treatment of postmenopausal breast cancer patients with letrozole: a randomized double-blind multicenter study,  Ann Oncol. ,  2001, vol.  12  11(pg.  1527- 1532) 9. Ellis MJ,  Buzdar A,  Unzeitig GW, et al.  ACOSOG Z1031: a randomized phase II trial comparing exemestane, letrozole, and anastrozole in postmenopausal women with clinical stage II/III estrogen receptor-positive breast cancer,  J Clin Oncol. ,  2010, vol.  28  supplpg.  7s   (Abstract LBA513) 10. Alba E,  Calvo L,  Albanell J, et al.  Chemotherapy (CT) versus hormone therapy (HT) as neoadjuvant treatment in luminal breast cancer: a multicenter, randomized phase II study (GEICAM/2006-03),  J Clin Oncol. ,  2010, vol.  28  supplpg.  7s   Abstract 500 11. Fisher ER,  Wang J,  Bryant J,  Fisher B,  Mamounas E,  Wolmark N.  Pathobiology of preoperative chemotherapy: findings from the National Surgical Adjuvant Breast and Bowel (NSABP) protocol B-18,  Cancer. ,  2002, vol.  95  4(pg.  681- 695) 12. Bidard FC,  Matthieu MC,  Chollet P, et al.  p53 status and efficacy of primary anthracyclines/alkylating agent-based regimen according to breast cancer molecular classes,  Ann Oncol. ,  2008, vol.  19  7(pg.  1261- 1265) 13. Guarneri V,  Barbieri E,  Piacentini F, et al.  Predictive and prognostic role of p53 according to tumor phenotype in breast cancer patients treated with preoperative chemotherapy: a single-institution analysis,  Int J Biol Markers. ,  2010, vol.  25  2(pg.  104- 111) 14. Bonnefoi HR,  Bogaerts J,  Piccart M, et al.  Phase III trial (EORTC 10994/BIG 00-01) assessing the value of p53 using a functional assay to predict sensitivity to a taxane versus nontaxane primary chemotherapy in breast cancer: final analysis,  J Clin Oncol. ,  2010, vol.  28  supplpg.  18s   Abstract LBA503 15. Rouzier R,  Rajan R,  Wagner P, et al.  Microtubule-associated protein tau: a marker of paclitaxel sensitivity in breast cancer,  Proc Natl Acad Sci U S A. ,  2005, vol.  102  23(pg.  8315- 8320) 16. Baselga J,  Zambetti M,  Llombart-Cussac A, et al.  Phase II genomics study of ixabepilone as neoadjuvant treatment for breast cancer,  J Clin Oncol. ,  2009, vol.  27  4(pg.  526- 534) 17. Rody A,  Karn T,  Gätje R, et al.  Gene expression profiling of breast cancer patients treated with docetaxel, doxorubicin, and cyclophosphamide within the GEPARTRIO trial: HER-2, but not topoisomerase II alpha and microtubule-associated protein tau, is highly predictive of tumor response,  Breast. ,  2007, vol.  16  1(pg.  86- 93) 18. Pusztai L,  Jeong JH,  Gong Y, et al.  Evaluation of microtubule associated protein-tau expression as prognostic and predictive marker in the NSABP-B 28 randomized clinical trial,  J Clin Oncol. ,  2009, vol.  27  26(pg.  4287- 4292) 19. Dumontet C,  Krajewska M,  Treilleux I, et al.  BCIRG 001 molecular analysis: prognostic factors in node-positive breast cancer patients receiving adjuvant chemotherapy,  Clin Cancer Res. ,  2010, vol.  16  15(pg.  3988- 3997) 20. Loibl S,  Mueller BG,  Von Minckwitz G, et al.  PARP expression in early breast cancer and its predictive value for response to neoadjuvant chemotherapy,  J Clin Oncol. ,  2010, vol.  28  supplpg.  15s   Abstract 10511 21. Carey LA,  Metzger R,  Dees EC, et al.  American Joint Committee on Cancer tumor-node-metastasis stage after neoadjuvant chemotherapy and breast cancer outcome,  J Natl Cancer Inst. ,  2005, vol.  97  15(pg.  1137- 1142) 22. Untch M,  Rezai M,  Loibl S, et al.  Neoadjuvant treatment with trastuzumab in HER-2 positive breast cancer: results from the GeparQuattro study,  J Clin Oncol. ,  2010, vol.  28  12(pg.  2024- 2031) 23. Buzdar A,  Ibrahim N,  Francis D, et al.  Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer,  J Clin Oncol. ,  2005, vol.  23  16(pg.  3676- 3685) 24. Gianni L,  Eiermann W,  Semiglazov V, et al.  Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort,  Lancet. ,  2010, vol.  375  9712(pg.  377- 384) 25. Rouzier R,  Perou CM,  Symmans WF, et al.  Breast cancer molecular subtypes respond differently to preoperative chemotherapy,  Clin Cancer Res. ,  2005, vol.  11  16(pg.  5678- 5685) 26. Symmans WF,  Peintinger F,  Hatzis C, et al.  Measurement of residual cancer burden to predict survival after neoadjuvant chemotherapy,  J Clin Oncol. ,  2007, vol.  25  28(pg.  4414- 4422) 27. Guarneri V,  Piacentini F,  Ficarra G.  A prognostic model based on nodal status and Ki-67 predicts the risk of recurrence and death in breast cancer patients with residual disease after preoperative chemotherapy,  Ann Oncol. ,  2009, vol.  20  7(pg.  1193- 1198) 28. Jones RL,  Salter J,  A’hern R, et al.  The prognostic significance of Ki67 before and after neoadjuvant chemotherapy in breast cancer,  Breast Cancer Res Treat. ,  2009, vol.  116  1(pg.  53- 68) 29. Guarneri V,  Chavez-Mac Gregor M,  Hsu L, et al.  Use of Ki-67 in residual disease following preoperative chemotherapy to predict the risk of recurrence and death in breast cancer patients,  J Clin Oncol. ,  2010, vol.  28  supplpg.  15s   Abstract 621 30. Mittendorf EA,  Wu Y,  Scaltriti M, et al.  Loss of HER2 amplification following trastuzumab-based neoadjuvant systemic therapy and survival outcomes,  Clin Cancer Res. ,  2009, vol.  15  23(pg.  7381- 7388) 31. Ellis MJ,  Tao Y,  Luo J, et al.  Outcome prediction for estrogen receptor-positive breast cancer based on postneoadjuvant endocrine therapy tumor characteristics,  J Natl Cancer Inst. ,  2008, vol.  100  19(pg.  1380- 1388) © The Author 2011. Published by Oxford University Press. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JNCI Monographs Oxford University Press

Biomarkers Predicting Clinical Benefit: Fact or Fiction?

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Oxford University Press
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© The Author 2011. Published by Oxford University Press.
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Abstract

Abstract Preoperative therapy is increasingly used in operable disease to improve the chance for breast-conservative surgery. Moreover, this strategy allows for a better definition of patient prognosis. Independently from stage at diagnosis and breast cancer subtype, the achievement of a pathological complete response (pCR) is a surrogate marker for long-term outcome. The likelihood of pCR depends on tumor biology, being poorly differentiated tumors with ductal histology, absence of hormone receptors, and high proliferation rate those with a higher chance of achieving a CR. However, pCR is a late efficacy parameter that can be evaluated at the end of the preoperative treatment; moreover, a pCR is achieved in a minority of patients and is not an appropriate efficacy measure for neoadjuvant endocrine therapy. The predictive role of tumor biomarkers such as p53, microtubule-associated tau protein, and poly (ADP-ribose) polymerase will be reviewed along with potential markers of early treatment effect. Defining Clinical Benefit in Primary Systemic Therapy Preoperative therapy is the standard treatment for locally advanced disease, where it can induce an important tumor shrinkage rendering amenable to locoregional control initially unresectable tumors. This strategy is also increasingly used in operable disease. In face of survival equivalence, there are two major clinical advantages in using primary systemic vs standard postoperative therapy in operable disease: The possibility for breast-conserving surgery in those patients initially candidates to mastectomy, and the opportunity for a better definition of patient prognosis. In fact, breast response improves the surgical options, increasing the chance for breast conservation (1,2). However, the eligibility for breast conservation is not only a result of treatment activity as measured as breast tumor shrinkage. Indeed, the recommendation for the type of surgery is generally based on several other parameters, including breast size, tumor location, presence of in situ disease, contraindication to radiation therapy, and patient willingness. Therefore, the rate of breast-conserving surgery is a relevant clinical endpoint, but it generally underestimates the clinical benefit achievable when using preoperative therapy. The response achieved in the primary tumor is a strong predictor of patient outcome. Independently from stage at diagnosis and breast cancer subtype (triple negative, hormone receptor [HR]-positive, or HER2-positive), the achievement of a pathological complete response (pCR) is a surrogate marker for long-term outcome (3–5). In fact, it has been shown that, when a pCR is achieved, the long-term outcome is similar for patients with triple-negative breast cancer, which is the more aggressive breast cancer subtype, as compared with other breast cancer subtypes (6). The definition of pCR varies across the studies, however, its prognostic role is maintained independently from the applied criteria. The most recent trials have adopted the rate of pCR as the primary endpoint, as defined as the complete disappearance of any invasive tumor in the breast and in axillary nodes. In case of neoadjuvant endocrine therapy, pCR is not the optimal way to measure clinical benefit. In fact, the rate of pCR in trials of neoadjuvant endocrine therapy is generally extremely low or not even reported (7–10). Indeed, endocrine therapy works by inhibiting cancer cell proliferation and is administered generally for 5 years in the adjuvant setting. Therefore, a complete eradication of the disease after 4–6 months neoadjuvant hormonal therapy is unlikely. Traditional and Emerging Predictors of pCR Several analyses have consistently shown that the likelihood of pCR depends on tumor biology. Tumor histology, grade, expression of HR, HER2 status, and tumor proliferation are traditional parameters used to predict chemotherapy benefit. Patients undergoing neoadjuvant chemotherapy are more likely to achieve a pCR in case of poorly differentiated tumors with ductal histology, absence of HR, and high proliferation rate (3,11). HER2 is a strong predictor of anti-HER2 therapy benefit, whereas its role in predicting pCR following chemotherapy alone is less clearly defined across studies, depending on the type of the agents investigated. On the other hand, tumors with a less aggressive phenotype such as lobular histotype and well-differentiated tumors with high expression of HR are less likely to achieve a pCR following chemotherapy. In an analysis including more than 1700 patients treated with preoperative chemotherapy at the MD Anderson Cancer Center, only 8% of HR-positive tumors achieved a pCR vs 24% of patients with HR-negative tumors (P > .001). Survival analyses in the HR-positive group confirmed that patients achieving a pCR had significantly prolonged disease-free and overall survival as compared with patients with less than pCR (3). Other biomarkers have been evaluated as potential predictors of pCR. The most frequent genetic events in human cancers are p53 mutations. In cells with altered p53 function, proliferation is no longer under control, with subsequent inefficiency in DNA repair and genetic instability. The predictive and prognostic role of p53 in breast cancer patients has been widely investigated, but a consistent association between p53 and responsiveness to neoadjuvant chemotherapy is still lacking (12,13). In a recently presented prospective study, p53 mutational status was tested in more than 1800 patients with locally advanced/inflammatory or large operable breast cancer randomized to receive anthracycline vs anthracycline- and taxane-based neoadjuvant therapy (14). The primary endpoint was to explore the role of p53 in predicting benefit from taxanes in terms of progression-free survival; secondary aims were the clinical and pathological responses. Patients with p53 mutations had significantly worse disease-free and overall survival, thus confirming the prognostic role of p53; however, no difference in progression-free survival between arms was observed according to p53 status. Data on clinical and pathological responses have not yet been reported; therefore, the possible association between p53 mutational and response to preoperative taxanes is still unknown. Tau protein promotes tubulin polymerization and stabilizes microtubules; therefore, low levels of tau protein should be associated with a higher sensitivity to taxanes. In a retrospective analysis of 122 patients treated with neoadjuvant chemotherapy and assessed for tau protein expression by immunohistochemistry, the vast majority of pCRs occurred in the tau protein–negative group, with an odds ratio for pCR of 3.7 (P < .0013) (15). By using gene expression analysis, tau has been recently associated with probability of response to the microtubule stabilizer ixabepilone (16). However, the predictive role of tau was not confirmed in the GeparTrio study: in a subset analysis conducted on 80 patients, tau gene expression was not associated with a higher pCR rate following preoperative chemotherapy with docetaxel, doxorubicin cyclophosphamide (17). The largest experience in the adjuvant setting derives from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-28 trial, where samples from 1942 patients were evaluated for tau expression. High tau-protein-expression was associated with better prognosis, but there was no significant interaction between tau expression and benefit from paclitaxel (18). The recent observation from the adjuvant BCIRG 001 trial, showing the prognostic role of tau protein, further reinforces the tight relation existing between prognostic and predictive parameters (19). More recently, a lot of interest has emerged on poly (ADP-ribose) polymerase (PARP), the nuclear enzyme that signals DNA damages and promotes single-strand breaks repair through the base excision pathway. A growing body of literature has shown the activity of PARP inhibitors, in particular in BRCA-associated tumors and triple-negative breast cancers. Cytoplasmic and nuclear PARP expression was evaluated by immunohistochemistry in 638 patients enrolled in the GeparTrio trial. Interestingly, PARP is expressed in all breast cancer subtypes: 51% of tumors have moderate cytoplasmic PARP expression and 24% show a high expression. The pCR rates were 8%, 19.1%, and 26% in the low vs moderate vs high PARP expressors (P < .0005). In the multivariable analysis, PARP, HER2, and HR were all independent predictors of pCR (20). What Beyond pCR? The achievement of a pCR, probably mirroring treatment effects on micrometastatic deposits, can reverse the prognosis of those patients diagnosed with an unfavorable tumor biology. However, pCR is far from being an optimal endpoint. First of all, a pCR is achieved in a minority of patients, and, even though these patients have an excellent prognosis, a few will eventually relapse. More importantly, the patients with less than pCR are a heterogeneous group in terms of prognosis. In fact, this group includes patients with truly chemoresistant disease, who are at high risk of relapse, and patients where preoperative therapy has induced an important tumor downstaging, thus having an excellent outcome (21). Therefore, the dichotomization of treatment efficacy in pCR vs non-pCR oversimplifies the different prognostic categories, representing an useful tool for patients with pCR, but with less clinical value for patients with residual disease. Indeed, pCR rates in HER2-positive patients receiving sequential anthracycline-, taxane-, and trastuzumab-preoperative chemotherapy range from 30% to 60% (22–24). In patients with triple-negative breast cancer, the pCR rate is in the range between 20% and 45%, whereas in case of HR–positive tumors, chemotherapy can induce a pCR in less than 10% of the patients (3,6,25). Therefore, the study of residual disease, and in particular of treatment-induced modifications in tumor biomarker expression, is becoming an intense field of research to refine patient prognosis as well as to identify potential markers of treatment resistance. The group from MD Anderson Cancer Center, by combining the pathological measurements of residual primary tumor and nodal metastases with tumor cellularity, has generated an index, the residual cancer burden, able to predict for distant disease-free survival (26). Three studies have shown that a high Ki67 on residual tumor after preoperative chemotherapy, in patient population including all breast cancer subtypes, was associated with a significantly worse outcome (27–29). In HER2-positive breast cancer patients treated with neoadjuvant trastuzumab and chemotherapy, the loss of HER2 expression on residual disease has been associated with a higher risk of relapse (30). Another limitation of pCR is that this is a “late” efficacy measure evaluated at the end of the treatment program. A true advantage would be an early prediction of treatment benefit. Moreover, as previously discussed, the pCR rate is not the more sensitive way to measure the efficacy of preoperative hormonal therapy. Up to now, preoperative endocrine therapy has been mainly recommended for elderly patients with large primaries and unfit for chemotherapy. However, in the adjuvant setting, patients with low-risk, HR-positive, and HER2-negative disease are generally offered endocrine therapy alone. Therefore, the use of preoperative endocrine therapy in patients with operable breast cancer will probably increase, reinforcing the need for appropriate measures of treatment efficacy. The IMPACT (Immediate Preoperative Anastrozole, Tamoxifen , or Combined with Tamoxifen) trial randomized 330 patients to preoperative anastrozole or tamoxifen or the combination of both drugs. No differences were observed in overall clinical responses and in the rate of breast-conserving surgery, which are classic parameters for chemotherapy efficacy. However, a greater inhibition of tumor proliferation (Ki67) was observed in the anastrozole arm as compared with tamoxifen or to the combination, anticipating the results of several hundreds of patients of the large adjuvant ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial (7). More interestingly, Ki67 level after 2 weeks of therapy was an independent predictive factor for relapse-free survival. A prognostic score generated on the basis of tumor size, nodal involvement, Ki67, and estrogen receptor Allred score after preoperative endocrine therapy has been generated (the preoperative endocrine prognostic index [PEPI]) (31). An adjuvant trial evaluating the role of adding chemotherapy on the basis of the PEPI score after neoadjuvant hormonal therapy is ongoing (9). Several randomized trials of hormonal therapy combined with targeted agents are incorporating the 2-week Ki67 assessment as an early marker of treatment efficacy. In this perspective, interesting data can be also obtained with new molecular imaging techniques, such as fluorodeoxyglucose positron emission tomography. In conclusion, facts are that we can predict clinical benefit from neoadjuvant therapies by evaluating tissue biomarkers and functional imaging techniques. Unfortunately, at the moment these parameters have been rarely incorporated into prospective trials, and additional data are needed to recommend the use of these biomarkers in the treatment decision process. References 1. Fisher B,  Brown A,  Mamounas E, et al.  Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18,  J Clin Oncol. ,  1997, vol.  15  7(pg.  2483- 2493) 2. 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JNCI Monographs – Oxford University Press

Published: Oct 1, 2011

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