Key Points
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Neoadjuvant therapy (NAT) provides a unique opportunity to assess the response of patients with breast cancer to different treatments
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Standards for pathological examination need to be standardized in order to enable reproducible evaluation of the residual disease that persists after NAT
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Residual disease remaining after NAT is different from treatment-naive breast cancer
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'Classic' histopathological parameters, such as ypTNM, grade, mitotic index, and hormone-receptor, HER2 and Ki67 status, provide valuable prognostic and predictive information when assessed in residual breast cancer tissue after NAT
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Genomic and proteomic markers of residual breast cancer are currently under development, and might inform patient stratification for adjuvant treatment
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Immune markers are among the most-promising biomarkers in the post NAT setting, in which extensive tumour infiltration by lymphocytes indicates a good prognosis, irrespective of residual tumour size
Abstract
Nowadays, the decision of which adjuvant treatment should be given to patients with residual breast cancer after neoadjuvant therapy is based on the initial, pretreatment breast cancer molecular subtype and on the estimated residual tumour burden after neoadjuvant therapy. Substantial biological differences exist, however, between treatment-naive breast cancer and the residual tissue that remains after neoadjuvant therapy. In addition, the evaluation of relapse risk in patients is subject to a lack of uniformity in pathological qualification and quantification of remnant breast cancer following neoadjuvant treatment. In this Review, we present the recent recommendations for standardized evaluation of response to neoadjuvant therapy in patients with breast cancer, followed by a comprehensive overview of the pathobiological features of the residual disease after neoadjuvant therapy, which could serve as prognostic biomarkers or guide the choice of targeted adjuvant approaches. These biomarker candidates are at different stages of development, but some already have demonstrated superior prognostic value compared with biomarkers derived from pretreatment breast-cancer characteristics. The evidence presented herein indicates that further research on the biology of breast cancer that persists after neoadjuvant therapy is necessary to improve the management of this disease.
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References
Lakhani, S. R., Ellis, I. O., Schnitt, S. J., Tan, P. H. & van de Vijver, M. J. WHO Classification of Tumours of the Breast (IARC Press, 2012).
Perou, C. M. et al. Molecular portraits of human breast tumours. Nature 406, 747–752 (2000).
Goldhirsch, A. et al. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann. Oncol. 24, 2206–2223 (2013).
Zardavas, D., Irrthum, A., Swanton, C. & Piccart, M. Clinical management of breast cancer heterogeneity. Nat. Rev. Clin. Oncol. 12, 381–394 (2015).
Cortazar, P. et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 384, 164–172 (2014).
Cortazar, P. & Geyer, C. E. Jr. Pathological complete response in neoadjuvant treatment of breast cancer. Ann. Surg. Oncol. 22, 1441–1446 (2015).
Esserman, L. J. & Woodcock, J. Accelerating identification and regulatory approval of investigational cancer drugs. JAMA 306, 2608–2609 (2011).
US Food and Drug Administration. Guidance for industry. Pathological complete response in neoadjuvant treatment of high-risk early-stage breast cancer: use as an endpoint to support accelerated approval. [online], (2014).
Kim, S. New and emerging factors in tumorigenesis: an overview. Cancer Manag. Res. 7, 225–239 (2015).
Schmitt, M. W., Loeb, L. A. & Salk, J. J. The influence of subclonal resistance mutations on targeted cancer therapy. Nat. Rev. Clin. Oncol. http://dx.doi.org/10.1038/nrclinonc.2015.175 (2015).
Balko, J. M. et al. Molecular profiling of the residual disease of triple-negative breast cancers after neoadjuvant chemotherapy identifies actionable therapeutic targets. Cancer Discov. 4, 232–245 (2014).
Bossuyt, V. et al. Recommendations for standardized pathological characterization of residual disease for neoadjuvant clinical trials of breast cancer by the BIG-NABCG collaboration. Ann. Oncol. 26, 1280–1291 (2015).
Provenzano, E. et al. Standardization of pathologic evaluation and reporting of postneoadjuvant specimens in clinical trials of breast cancer: recommendations from an international working group. Mod. Pathol. 28, 1185–1201 (2015).
Wang, S. et al. Shrink pattern of breast cancer after neoadjuvant chemotherapy and its correlation with clinical pathological factors. World J. Surg. Oncol. 11, 166 (2013).
Kim, T. H. et al. Magnetic resonance imaging patterns of tumor regression after neoadjuvant chemotherapy in breast cancer patients: correlation with pathological response grading system based on tumor cellularity. J. Comput. Assist. Tomogr. 36, 200–206 (2012).
Tomida, K. et al. Magnetic resonance imaging shrinkage patterns following neoadjuvant chemotherapy for breast carcinomas with an emphasis on the radiopathological correlations. Mol. Clin. Oncol. 2, 783–788 (2014).
Groheux, D. et al. HER2-overexpressing breast cancer: FDG uptake after two cycles of chemotherapy predicts the outcome of neoadjuvant treatment. Br. J. Cancer 109, 1157–1164 (2013).
Groheux, D. et al. Baseline tumor 18F-FDG uptake and modifications after 2 cycles of neoadjuvant chemotherapy are prognostic of outcome in ER+/HER2− breast cancer. J. Nucl. Med. 56, 824–831 (2015).
Coudert, B. et al. Use of [18F]-FDG PET to predict response to neoadjuvant trastuzumab and docetaxel in patients with HER2-positive breast cancer, and addition of bevacizumab to neoadjuvant trastuzumab and docetaxel in [18F]-FDG PET-predicted non-responders (AVATAXHER): an open-label, randomised phase 2 trial. Lancet Oncol. 15, 1493–1502 (2014).
Groheux, D. et al. Prognostic impact of 18F-FDG PET/CT staging and of pathological response to neoadjuvant chemotherapy in triple-negative breast cancer. Eur. J. Nucl. Med. Mol. Imaging 42, 377–385 (2015).
Edge, S. B. et al. AJCC Cancer Staging Manual (Springer, 2010).
Carder, P. Typing breast cancer following primary chemotherapy. Histopathology 35, 584–585 (1999).
Sataloff, D. M. et al. Pathologic response to induction chemotherapy in locally advanced carcinoma of the breast: a determinant of outcome. J. Am. Coll. Surg. 180, 297–306 (1995).
Pinder, S. E., Provenzano, E., Earl, H. & Ellis, I. O. Laboratory handling and histology reporting of breast specimens from patients who have received neoadjuvant chemotherapy. Histopathology 50, 409–417 (2007).
Symmans, W. F. et al. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J. Clin. Oncol. 25, 4414–4422 (2007).
Chevallier, B., Roche, H., Olivier, J. P., Chollet, P. & Hurteloup, P. Inflammatory breast cancer. Pilot study of intensive induction chemotherapy (FEC-HD) results in a high histologic response rate. Am. J. Clin. Oncol. 16, 223–228 (1993).
Rouzier, R. 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. 20, 1304–1310 (2002).
Sharkey, F. E., Addington, S. L., Fowler, L. J., Page, C. P. & Cruz, A. B. Effects of preoperative chemotherapy on the morphology of resectable breast carcinoma. Mod. Pathol. 9, 893–900 (1996).
Ogston, K. N. et al. A new histological grading system to assess response of breast cancers to primary chemotherapy: prognostic significance and survival. Breast 12, 320–327 (2003).
von Minckwitz, G. et al. Dose-dense doxorubicin, docetaxel, and granulocyte colony-stimulating factor support with or without tamoxifen as preoperative therapy in patients with operable carcinoma of the breast: a randomized, controlled, open phase IIb study. J. Clin. Oncol. 19, 3506–3515 (2001).
Kurosumi, M. Significance and problems in evaluations of pathological responses to neoadjuvant therapy for breast cancer. Breast Cancer 13, 254–259 (2006).
Fisher, E. R. et al. Pathobiology of preoperative chemotherapy: findings from the National Surgical Adjuvant Breast and Bowel (NSABP) protocol B-18. Cancer 95, 681–695 (2002).
Honkoop, A. H. et al. Effects of chemotherapy on pathologic and biologic characteristics of locally advanced breast cancer. Am. J. Clin. Pathol. 107, 211–218 (1997).
Green, M. C. et al. Weekly paclitaxel improves pathologic complete remission in operable breast cancer when compared with paclitaxel once every 3 weeks. J. Clin. Oncol. 23, 5983–5992 (2005).
Kuerer, H. M. et al. Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy. J. Clin. Oncol. 17, 460–469 (1999).
Feldman, L. D., Hortobagyi, G. N., Buzdar, A. U., Ames, F. C. & Blumenschein, G. R. Pathological assessment of response to induction chemotherapy in breast cancer. Cancer Res. 46, 2578–2581 (1986).
von Minckwitz, G. et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J. Clin. Oncol. 30, 1796–1804 (2012).
Jones, R. L. et al. Pathological complete response and residual DCIS following neoadjuvant chemotherapy for breast carcinoma. Br. J. Cancer 94, 358–362 (2006).
Mazouni, C. et al. Residual ductal carcinoma in situ in patients with complete eradication of invasive breast cancer after neoadjuvant chemotherapy does not adversely affect patient outcome. J. Clin. Oncol. 25, 2650–2655 (2007).
Penault-Llorca, F. et al. Comparison of the prognostic significance of Chevallier and Sataloff's pathologic classifications after neoadjuvant chemotherapy of operable breast cancer. Hum. Pathol. 39, 1221–1228 (2008).
Kaufmann, M. et al. Recommendations from an international consensus conference on the current status and future of neoadjuvant systemic therapy in primary breast cancer. Ann. Surg. Oncol. 19, 1508–1516 (2012).
Simmons, C. E. et al. A Canadian national expert consensus on neoadjuvant therapy for breast cancer: linking practice to evidence and beyond. Curr. Oncol. 22, S43–S53 (2015).
Wang-Lopez, Q. et al. Can pathologic complete response (pCR) be used as a surrogate marker of survival after neoadjuvant therapy for breast cancer? Crit. Rev. Oncol. Hematol. 95, 88–104 (2015).
Bonnefoi, H. et al. Pathological complete response after neoadjuvant chemotherapy is an independent predictive factor irrespective of simplified breast cancer intrinsic subtypes: a landmark and two-step approach analyses from the EORTC 10994/BIG 1-00 phase III trial. Ann. Oncol. 25, 1128–1136 (2014).
Esserman, L. J. et al. Pathologic complete response predicts recurrence-free survival more effectively by cancer subset: results from the I-SPY 1 TRIAL — CALGB 150007/150012, ACRIN 6657. J. Clin. Oncol. 30, 3242–3249 (2012).
Peintinger, F. et al. Reproducibility of residual cancer burden for prognostic assessment of breast cancer after neoadjuvant chemotherapy. Mod. Pathol. 28, 913–920 (2015).
Elston, C. W. & Ellis, I. O. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 19, 403–410 (1991).
Chollet, P. et al. A new prognostic classification after primary chemotherapy for breast cancer: residual disease in breast and nodes (RDBN). Cancer J. 14, 128–132 (2008).
Bear, H. D. et al. Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J. Clin. Oncol. 24, 2019–2027 (2006).
Mamounas, E. P. et al. Predictors of locoregional recurrence after neoadjuvant chemotherapy: results from combined analysis of National Surgical Adjuvant Breast and Bowel Project B-18 and B-27. J. Clin. Oncol. 30, 3960–3966 (2012).
Le Doussal, V. et al. Prognostic value of histologic grade nuclear components of Scarff–Bloom–Richardson (SBR). An improved score modification based on a multivariate analysis of 1262 invasive ductal breast carcinomas. Cancer 64, 1914–1921 (1989).
Abrial, S. C. et al. High prognostic significance of residual disease after neoadjuvant chemotherapy: a retrospective study in 710 patients with operable breast cancer. Breast Cancer Res. Treat. 94, 255–263 (2005).
Penault-Llorca, F. et al. Changes and predictive and prognostic value of the mitotic index, Ki-67, cyclin D1, and cyclo-oxygenase-2 in 710 operable breast cancer patients treated with neoadjuvant chemotherapy. Oncologist 13, 1235–1245 (2008).
Diaz, J. et al. Mitotic counts in breast cancer after neoadjuvant systemic chemotherapy and development of metastatic disease. Breast Cancer Res. Treat. 138, 91–97 (2013).
Beresford, M. J., Wilson, G. D. & Makris, A. Measuring proliferation in breast cancer: practicalities and applications. Breast Cancer Res. 8, 216 (2006).
Yerushalmi, R., Woods, R., Ravdin, P. M., Hayes, M. M. & Gelmon, K. A. Ki67 in breast cancer: prognostic and predictive potential. Lancet Oncol. 11, 174–183 (2010).
Luporsi, E. et al. Ki-67: level of evidence and methodological considerations for its role in the clinical management of breast cancer: analytical and critical review. Breast Cancer Res. Treat. 132, 895–915 (2012).
Dowsett, M. et al. Prognostic value of Ki67 expression after short-term presurgical endocrine therapy for primary breast cancer. J. Natl Cancer Inst. 99, 167–170 (2007).
Jones, R. L. et al. The prognostic significance of Ki67 before and after neoadjuvant chemotherapy in breast cancer. Breast Cancer Res. Treat. 116, 53–68 (2009).
Ellis, M. J. et al. Outcome prediction for estrogen receptor-positive breast cancer based on postneoadjuvant endocrine therapy tumor characteristics. J. Natl Cancer Inst. 100, 1380–1388 (2008).
Suman, V. J., Ellis, M. J. & Ma, C. X. The ALTERNATE trial: assessing a biomarker driven strategy for the treatment of post-menopausal women with ER+/Her2– invasive breast cancer. Chin. Clin. Oncol. 4, 34 (2015).
Sheri, A. et al. Residual proliferative cancer burden to predict long-term outcome following neoadjuvant chemotherapy. Ann. Oncol. 26, 75–80 (2015).
von Minckwitz, G. et al. Ki67 measured after neoadjuvant chemotherapy for primary breast cancer. Clin. Cancer Res. 19, 4521–4531 (2013).
Dowsett, M. et al. Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in Breast Cancer Working Group. J. Natl Cancer Inst. 103, 1656–1664 (2011).
Polley, M. Y. et al. An international Ki67 reproducibility study. J. Natl Cancer Inst. 105, 1897–1906 (2013).
Polley, M. Y. et al. An international study to increase concordance in Ki67 scoring. Mod. Pathol. 28, 778–786 (2015).
van de Ven, S., Smit, V. T., Dekker, T. J., Nortier, J. W. & Kroep, J. R. Discordances in ER, PR and HER2 receptors after neoadjuvant chemotherapy in breast cancer. Cancer Treat. Rev. 37, 422–430 (2011).
Zhang, N., Moran, M. S., Huo, Q., Haffty, B. G. & Yang, Q. The hormonal receptor status in breast cancer can be altered by neoadjuvant chemotherapy: a meta-analysis. Cancer Invest. 29, 594–598 (2011).
Hirata, T. et al. Change in the hormone receptor status following administration of neoadjuvant chemotherapy and its impact on the long-term outcome in patients with primary breast cancer. Br. J. Cancer 101, 1529–1536 (2009).
Tacca, O. et al. Changes in and prognostic value of hormone receptor status in a series of operable breast cancer patients treated with neoadjuvant chemotherapy. Oncologist 12, 636–643 (2007).
Hurley, J. et al. Docetaxel, cisplatin, and trastuzumab as primary systemic therapy for human epidermal growth factor receptor 2-positive locally advanced breast cancer. J. Clin. Oncol. 24, 1831–1838 (2006).
Mittendorf, E. A. et al. Loss of HER2 amplification following trastuzumab-based neoadjuvant systemic therapy and survival outcomes. Clin. Cancer Res. 15, 7381–7388 (2009).
Jin, X. et al. Prognostic value of receptor conversion after neoadjuvant chemotherapy in breast cancer patients: a prospective observational study. Oncotarget 6, 9600–9611 (2015).
Guarneri, V. et al. Loss of HER2 positivity and prognosis after neoadjuvant therapy in HER2-positive breast cancer patients. Ann. Oncol. 24, 2990–2994 (2013).
Hanna, W. M. et al. HER2 in situ hybridization in breast cancer: clinical implications of polysomy 17 and genetic heterogeneity. Mod. Pathol. 27, 4–18 (2014).
Ng, C. K. et al. Intra-tumor genetic heterogeneity and alternative driver genetic alterations in breast cancers with heterogeneous HER2 gene amplification. Genome Biol. 16, 107 (2015).
Pernas Simon, S. Neoadjuvant therapy of early stage human epidermal growth factor receptor 2 positive breast cancer: latest evidence and clinical implications. Ther. Adv. Med. Oncol. 6, 210–221 (2014).
Giuliano, M. et al. Upregulation of ER signaling as an adaptive mechanism of cell survival in HER2-positive breast tumors treated with anti-HER2 therapy. Clin. Cancer Res. 21, 3995–4003 (2015).
Lim, S. K. et al. Impact of molecular subtype conversion of breast cancers after neoadjuvant chemotherapy on clinical outcome. Cancer Res. Treat. http://dx.doi.org/10.4143/crt.2014.262 (2015).
Provenzano, E. et al. Standardization of pathologic evaluation and reporting of post-neoadjuvant specimens in breast cancer: recommendations from an international working group. Mod. Pathol. 28, 1185–1201 (2015).
Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 490, 61–70 (2012).
Chen, M. B. et al. Value of TP53 status for predicting response to neoadjuvant chemotherapy in breast cancer: a meta-analysis. PLoS ONE 7, e39655 (2012).
Loibl, S. et al. PIK3CA mutations are associated with lower rates of pathologic complete response to anti-human epidermal growth factor receptor 2 (HER2) therapy in primary HER2-overexpressing breast cancer. J. Clin. Oncol. 32, 3212–3220 (2014).
Majewski, I. J. et al. PIK3CA mutations are associated with decreased benefit to neoadjuvant human epidermal growth factor receptor 2-targeted therapies in breast cancer. J. Clin. Oncol. 33, 1334–1339 (2015).
Jiang, Y. Z., Yu, K. D., Bao, J., Peng, W. T. & Shao, Z. M. Favorable prognostic impact in loss of TP53 and PIK3CA mutations after neoadjuvant chemotherapy in breast cancer. Cancer Res. 74, 3399–3407 (2014).
Yuan, H. et al. Association of PIK3CA mutation status before and after neoadjuvant chemotherapy with response to chemotherapy in women with breast cancer. Clin. Cancer Res. 21, 4365–4372 (2015).
Gonzalez-Angulo, A. M. et al. Gene expression, molecular class changes, and pathway analysis after neoadjuvant systemic therapy for breast cancer. Clin. Cancer Res. 18, 1109–1119 (2012).
Dunbier, A. K. et al. Molecular profiling of aromatase inhibitor-treated postmenopausal breast tumors identifies immune-related correlates of resistance. Clin. Cancer Res. 19, 2775–2786 (2013).
Gao, Q. et al. Effect of aromatase inhibition on functional gene modules in estrogen receptor-positive breast cancer and their relationship with antiproliferative response. Clin. Cancer Res. 20, 2485–2494 (2014).
Balko, J. M. et al. Profiling of residual breast cancers after neoadjuvant chemotherapy identifies DUSP4 deficiency as a mechanism of drug resistance. Nat. Med. 18, 1052–1059 (2012).
Podsypanina, K., Politi, K., Beverly, L. J. & Varmus, H. E. Oncogene cooperation in tumor maintenance and tumor recurrence in mouse mammary tumors induced by Myc and mutant Kras. Proc. Natl Acad. Sci. USA 105, 5242–5247 (2008).
Han, G., Wang, Y. & Bi, W. C-Myc overexpression promotes osteosarcoma cell invasion via activation of MEK–ERK pathway. Oncol. Res. 20, 149–156 (2012).
Yu, K. D. et al. Identification of prognosis-relevant subgroups in patients with chemoresistant triple-negative breast cancer. Clin. Cancer Res. 19, 2723–2733 (2013).
Magbanua, M. J. et al. Serial expression analysis of breast tumors during neoadjuvant chemotherapy reveals changes in cell cycle and immune pathways associated with recurrence and response. Breast Cancer Res. 17, 73 (2015).
Chae, Y. K. & Gonzalez-Angulo, A. M. Implications of functional proteomics in breast cancer. Oncologist 19, 328–335 (2014).
Masuda, M. & Yamada, T. Signaling pathway profiling by reverse-phase protein array for personalized cancer medicine. Biochim. Biophys. Acta 1854, 651–657 (2015).
Gonzalez-Angulo, A. M. et al. Functional proteomics characterization of residual breast cancer after neoadjuvant systemic chemotherapy. Ann. Oncol. 24, 909–916 (2013).
Sohn, J. et al. Functional proteomics characterization of residual triple-negative breast cancer after standard neoadjuvant chemotherapy. Ann. Oncol. 24, 2522–2526 (2013).
Hanahan, D. & Coussens, L. M. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21, 309–322 (2012).
Quail, D. F. & Joyce, J. A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19, 1423–1437 (2013).
Klemm, F. & Joyce, J. A. Microenvironmental regulation of therapeutic response in cancer. Trends Cell Biol. 25, 198–213 (2015).
Gajewski, T. F., Schreiber, H. & Fu, Y. X. Innate and adaptive immune cells in the tumor microenvironment. Nat. Immunol. 14, 1014–1022 (2013).
Denkert, C. et al. Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J. Clin. Oncol. 28, 105–113 (2010).
Issa-Nummer, Y. et al. Prospective validation of immunological infiltrate for prediction of response to neoadjuvant chemotherapy in HER2-negative breast cancer — a substudy of the neoadjuvant GeparQuinto trial. PLoS ONE 8, e79775 (2013).
Loi, S. et al. Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial. Ann. Oncol. 25, 1544–1550 (2014).
Denkert, C. et al. Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2-positive and triple-negative primary breast cancers. J. Clin. Oncol. 33, 983–991 (2015).
Demaria, S. et al. Development of tumor-infiltrating lymphocytes in breast cancer after neoadjuvant paclitaxel chemotherapy. Clin. Cancer Res. 7, 3025–3030 (2001).
Ladoire, S. et al. In situ immune response after neoadjuvant chemotherapy for breast cancer predicts survival. J. Pathol. 224, 389–400 (2011).
Fontenot, J. D., Gavin, M. A. & Rudensky, A. Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 4, 330–336 (2003).
Facciabene, A., Motz, G. T. & Coukos, G. T-regulatory cells: key players in tumor immune escape and angiogenesis. Cancer Res. 72, 2162–2171 (2012).
Jeruss, J. S. et al. Combined use of clinical and pathologic staging variables to define outcomes for breast cancer patients treated with neoadjuvant therapy. J. Clin. Oncol. 26, 246–252 (2008).
Aruga, T. et al. A low number of tumor-infiltrating FOXP3-positive cells during primary systemic chemotherapy correlates with favorable anti-tumor response in patients with breast cancer. Oncol. Rep. 22, 273–278 (2009).
Liu, F. et al. Peritumoral FOXP3+ regulatory T cell is sensitive to chemotherapy while intratumoral FOXP3+ regulatory T cell is prognostic predictor of breast cancer patients. Breast Cancer Res. Treat. 135, 459–467 (2012).
Garcia-Martinez, E. et al. Tumor-infiltrating immune cell profiles and their change after neoadjuvant chemotherapy predict response and prognosis of breast cancer. Breast Cancer Res. 16, 488 (2014).
Mahmoud, S. M. et al. Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J. Clin. Oncol. 29, 1949–1955 (2011).
Liu, S. et al. CD8+ lymphocyte infiltration is an independent favorable prognostic indicator in basal-like breast cancer. Breast Cancer Res. 14, R48 (2012).
Chen, Z. et al. Intratumoral CD8+ cytotoxic lymphocyte is a favorable prognostic marker in node-negative breast cancer. PLoS ONE 9, e95475 (2014).
Ali, H. R. et al. Association between CD8+ T-cell infiltration and breast cancer survival in 12,439 patients. Ann. Oncol. 25, 1536–1543 (2014).
DeNardo, D. G. et al. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov. 1, 54–67 (2011).
Dieci, M. V. et al. Prognostic value of tumor-infiltrating lymphocytes on residual disease after primary chemotherapy for triple-negative breast cancer: a retrospective multicenter study. Ann. Oncol. 25, 611–618 (2014).
Kepp, O. et al. Immunogenic cell death modalities and their impact on cancer treatment. Apoptosis 14, 364–375 (2009).
Salgado, R. et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann. Oncol. 26, 259–271 (2015).
Mayer, I. A. et al. Stand up to cancer phase Ib study of pan-phosphoinositide-3-kinase inhibitor buparlisib with letrozole in estrogen receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. J. Clin. Oncol. 32, 1202–1209 (2014).
Verstovsek, S. et al. Long-term outcomes of 107 patients with myelofibrosis receiving JAK1/JAK2 inhibitor ruxolitinib: survival advantage in comparison to matched historical controls. Blood 120, 1202–1209 (2012).
Coupe, N. et al. PACMEL: a phase 1 dose escalation trial of trametinib (GSK1120212) in combination with paclitaxel. Eur. J. Cancer 51, 359–366 (2015).
Acknowledgements
The authors thank Professor P. Chollet for initiating research on the evaluation and biology of residual breast cancer after neoadjuvant treatment some 20 years ago at Jean Perrin Comprehensive Cancer Centre in Clermont-Ferrand, France.
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F.P.-L. and N.R.-R. contributed equally to researching data for this article, discussions of content, writing the article and reviewing/editing the manuscript before submission.
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Penault-Llorca, F., Radosevic-Robin, N. Biomarkers of residual disease after neoadjuvant therapy for breast cancer. Nat Rev Clin Oncol 13, 487–503 (2016). https://doi.org/10.1038/nrclinonc.2016.1
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