- Email: [email protected]
Lessons in precision oncology from neoadjuvant endocrine therapy trials in ER+ breast cancer
The Breast xxx (2017) 1e4
Contents lists available at ScienceDirect
The Breast journal homepage: www.elsevier.com/brst
Lessons in precision oncology from neoadjuvant endocrine therapy trials in ERþ breast cancer Matthew J. Ellis Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA
a r t i c l e i n f o
a b s t r a c t
Article history: Available online xxx
For post-menopausal women with clinical stage II/III estrogen receptor positive (ERþ) breast cancer neoadjuvant endocrine therapy (NET) is an under-utilized and low-toxicity alternative to chemotherapy for increasing breast conservation rates. Individual responses to endocrine therapy can also be used to tailor systemic treatment. The Preoperative Endocrine Prognostic Index (PEPI) was developed to identify patients at low risk of relapse after NET so that adjuvant chemotherapy can safely be avoided. In a recent validation study, patients with pathological stage 1 or 2A breast cancers with a Ki67 value of 2.7% or less in the surgical specimen (PEPI ¼ 0) after 16e18 weeks of aromatase inhibitor therapy had a 97% disease free survival after 5.5 years of median follow up. Two approaches are currently underway to extend the PEPI model. The first is to determine whether fulvestrant increases the PEPI-0 rate versus anastrozole, as this would increase the number of patients who could be safely managed without adjuvant chemotherapy. The second is to develop new approaches for tumors that exhibit endocrine therapy resistance identified during NET. Preliminary studies demonstrate that tumors that exhibit AI resistant proliferation in the neoadjuvant setting is often sensitive to palbociclib, a CDK4/6 inhibitor. Serial Ki67 monitoring before surgery is therefore logical approach to tailored use of adjuvant CDK4/6i adjuvant treatment. Finally serial sampling of the tumor inherent in the PEPI approach facilitates the identification of new therapeutic targets, mechanisms of resistance and monitoring of tumor evolution in response to AI therapy. © 2017 The Author. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
1. Pragmatic individualized therapy based on response to neoadjuvant systemic treatment The results of the NSABP B18 trial concluded there was no survival difference between preoperative doxorubicin cyclophosphamide chemotherapy versus the same chemotherapy given postoperatively. There was, however, a reduction in mastectomy rate. Initial arguments for neoadjuvant chemotherapy (NAC) therapy therefore focused on improvements in surgical outcomes [1]. Subsequently it became clear that patients who had a complete remission with NAC had markedly improved outcomes compared to those with residual disease [2]. The emphasis therefore shifted towards the hypothesis that the treatment of patients who have a pathological response in breast and nodes can be modified to reduce toxicity (Fig. 1A). For example, omitting regional nodal radiotherapy for patients who were initially node positive but become node negative after NAC
E-mail address: [email protected].
is under active investigation (NSABP B51). On the other hand, patients with significant residual disease post NAC require intensification of their systemic therapy. An advantage for adjuvant capecitabine in the trial patients with triple negative breast cancer with residual disease after NAC is a recent example of this approach [3].
2. Neoadjuvant endocrine therapy: an under utilized approach for improving surgical outcomes It is increasingly accepted that many patients with ER positive HER2 negative (ERþ HER2) disease do not benefit from chemotherapy as much as ER or HER2þ disease even for higher stage disease. Furthermore pCR rates are low in this disease subset limiting the value of pCR as a surrogate endpoint for the effectiveness of systemic treatment. Thus, neoadjuvant endocrine therapy is a reasonable alternative, particularly for postmenopausal women with high levels of ER expression. Several studies from a decade or more ago showed marked
http://dx.doi.org/10.1016/j.breast.2017.06.039 0960-9776/© 2017 The Author. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: Ellis MJ, Lessons in precision oncology from neoadjuvant endocrine therapy trials in ERþ breast cancer, The Breast (2017), http://dx.doi.org/10.1016/j.breast.2017.06.039
2
M.J. Ellis / The Breast xxx (2017) 1e4
Fig. 1. Progressive modifications to the neoadjuvant endocrine therapy approaches to increase the precision of therapy according to the biology of individual tumors.
improvements in breast conservation after 3e4 months of treatment with an aromatase inhibitor with a 50% reduction in the mastectomy rate in patients designated for a mastectomy at presentation [4]. More recently the American College of Surgeons
Oncology Group (ACOSOG) Z1031 study confirmed that for patients who are told they need a mastectomy, about half can undergo successful breast conserving surgery after 16e18 weeks of AI treatment [5].
Please cite this article in press as: Ellis MJ, Lessons in precision oncology from neoadjuvant endocrine therapy trials in ERþ breast cancer, The Breast (2017), http://dx.doi.org/10.1016/j.breast.2017.06.039
M.J. Ellis / The Breast xxx (2017) 1e4
3. The Preoperative Endocrine Prognostic Index (PEPI): an alternative to pCR for assessing systemic response for ER þ HER2 negative breast cancer Improvements in surgical outcomes are not the only advantage of NET since individual responses to endocrine therapy can be used to tailor patient treatment. The Preoperative Endocrine Prognostic Index (PEPI) was developed to identify extreme responders to endocrine therapy such that subsequent management could be modified to avoid chemotherapy in a population at low risk of relapse post NET [6]. Patients in the lowest risk PEPI group are referred to as PEPI ¼ 0. To meet PEPI ¼ 0 criteria the pathological specimen after NET must be node negative, pathological stage 1 or 2A (<5 cm) and the Ki67 value 2.7% or less. Also the tumor must be persistently ERþ. The long-term outcomes of the Z1031 trial (a comparison of three aromatase inhibitors) provided an opportunity to further evaluate the PEPI. After 5.5 years of median follow-up, 4 of the 109 (3.7%) patients with a PEPI ¼ 0 score relapsed versus 49 of 341 (14.4%) PEPI>0 patients, recurrence hazard ratio (PEPI ¼ 0/ PEPI>0) ¼ 0.27 (p ¼ 0.014; 95%CI: 0.092e0.764). We concluded that for patients with PEPI ¼ 0 disease the relapse risk over 5 years is so low without chemotherapy that the further study of adjuvant endocrine monotherapy is justifiable [7]. The PEPI approach therefore has similar operational characteristics as pCR with escalation of therapy a reasonable approach for PEPI >0 patients and de-escalation of therapy, i.e. no chemotherapy, for patients with PEPI-0 status (Fig. 1B). 4. A 2e4 week biopsy to identify patients with a low chance of experiencing PEPI-0 status and thereby avoiding intensification of systemic therapy A drawback of the PEPI approach is that the triage point for treatment intensification or de-intensification occurs at 4 or more months after starting neoadjuvant endocrine therapy. Ideally patients with resistant disease should be identified earlier for triage to alternate systemic treatment. We therefore explored early on treatment Ki67 levels to determine a threshold where an early Ki67 value, 2e4 weeks after starting endocrine therapy, was high enough such that the chance of a PEPI-0 tumor was very low (since 2e4 week Ki67 levels are highly correlated with Ki67 levels in the surgical specimen, 3e4 months later). Examining data from the IMPACT trial [8] and the POL trial [9] led to the definition of a 10% threshold as above this value the chance of a PEPI ¼ 0 tumor was less than 2%. Thus the PEPI treatment paradigm was altered to include an early biopsy to identify the most resistant tumors (Fig. 1C). About 20% of patients come into this category. 5. Triage to chemotherapy for patients with Ki67 >10% at 2e4 weeks is less effective than expected The Z1031B protocol was amended to include a tumor Ki67 determination after 2e4 weeks of AI to conduct a Phase 2 trial of standard of care chemotherapy. A pCR rate of >20% was the predefined efficacy threshold. However only two of the 35 patients on Z1031B switched to neoadjuvant chemotherapy experienced a pCR (5.7%, 95%CI: 0.7e19.1%) excluding a pCR rate of 20%, which was the minimally effective threshold in the predefined Phase 2 design. Reasons for the poor chemotherapy response rate include the ER rich nature of the tumors enrolled and the postmenopausal status of the patients. Both are established factors that reduce the efficacy of chemotherapy. The prognosis of patients with a Ki67 value > 10% proved to be poor despite the use of chemotherapy, underscoring the treatment resistant nature of tumors with intrinsically endocrine therapy resistant disease [7].
3
6. Ongoing studies of treatment de-escalation for patients with PEPI ¼ 0 tumors One approach to improving the PEPI paradigm is to identify alternative endocrine therapies that can increase the PEPI-0 rate over AI alone (Fig. 1D). This would allow more patients to be treated without chemotherapy and possibly further increase the breast conservation rate. The ALTERNATE trial is addressing this possibility by randomizing patient treatment between anastrozole, fulvestrant or the combination. Eligibility includes postmenopausal status, ER Allred score 6 to 8 and palpable disease so patients can be followed clinically. The basis for testing fulvestrant in this setting are the positive results of the FALCON [10] and FIRST studies [11], that found that fulvestrant is more effective than anastrozole for treatment naïve advanced breast cancer. 7. Alternatives to chemotherapy for patients with nonPEPI ¼ 0 disease Given the poor performance of triage to chemotherapy in Z1031B, alternative systemic therapies need to be sought (Fig. 1E). Recently CDK4/6 inhibitors have been explored in the neoadjuvant setting. NeoPalAna is a sequential biopsy study for patients with clinical stage 2 and 3 ER þ HER2 negative breast cancer [12]. Premenopausal women were eligible if treated with an LHRH agonist and estradiol monitoring confirmed ovarian function was successfully suppressed. After a pretreatment biopsy, patients were treated with anastrozole for a month and then a second biopsy was taken followed by the addition of palbociclib to the regimen. A further biopsy was taken after 14 days to assess the antiproliferative effect of the addition of the CDK4/6 inhibitor over the effect observed with the AI alone. Palbociclib addition was found to be effective at enhancing the number of tumors in cell cycle complete response (CCCR), defined as a Ki67 of <2.7%. Interestingly from the perspective of adjuvant therapy, three patterns of response were observed; tumors that underwent CCCR with AI alone; tumors in CCCR from the addition of palbociclib to AI and a group that was resistant to both therapies. One might therefore postulate that patients in the first group do not require palbociclib, the second group require the combination and the third an entirely different treatment approach. Trials that tailor the use of CDK4/6i treatment this way are under active consideration. 8. Treatment based on next generation genomic technologies Serial sampling of the tumor inherent in the PEPI approach allows the study of the genomic evolution of the tumor and to identify new therapeutic targets [13] and monitor tumor evolution in response to AI therapy [14]. While the PEPI approach is promising, a return to pCR as a surrogate endpoint for long term outcome is always possible if treatments emerge that induce higher rates of pCR in ER þ HER2- breast cancer. New studies for intrinsically endocrine therapy resistant disease with pCR as a goal are therefore important as the weakness of both endocrine therapy and CDK4/6 therapy are that they are maintenance treatments requiring long term therapy e which is an open invitation for resistance to develop. Perhaps the next generation of NET trials will incorporate not only Ki67-based triage, but genomic analysis so that the therapeutic approach for poor prognosis patients can be more precise (Fig. 1F). References [1] Fisher B, et al. Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical
Please cite this article in press as: Ellis MJ, Lessons in precision oncology from neoadjuvant endocrine therapy trials in ERþ breast cancer, The Breast (2017), http://dx.doi.org/10.1016/j.breast.2017.06.039
4
M.J. Ellis / The Breast xxx (2017) 1e4
[2]
[3]
[4]
[5]
[6]
[7]
Adjuvant Breast and Bowel Project B-18. J Clin Oncol 1997;15:2483e93. http://dx.doi.org/10.1200/JCO.1997.15.7.2483. Fisher B, et al. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 1998;16:2672e85. http://dx.doi.org/ 10.1200/JCO.1998.16.8.2672. Toi M, et al. A phase III trial of adjuvant capecitabine in breast cancer patients with HER2-negative pathologic residual invasive disease after neoadjuvant chemotherapy (CREATE-X, JBCRG-04). Cancer Res 2016;76. http://dx.doi.org/ 10.1158/1538-7445.SABCS15-S1-07. Abstract S1e07. Ellis MJ, et al. Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: evidence from a phase III randomized trial. J Clin Oncol 2001;19:3808e16. http://dx.doi.org/10.1200/JCO.2001.19.18.3808. Ellis MJ, et al. Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtypeeACOSOG Z1031. J Clin Oncol 2011;29:2342e9. http://dx.doi.org/10.1200/ JCO.2010.31.6950. Ellis MJ, et al. Outcome prediction for estrogen receptor-positive breast cancer based on postneoadjuvant endocrine therapy tumor characteristics. J Natl Cancer Inst 2008;100:1380e8. http://dx.doi.org/10.1093/jnci/djn309. Ellis MJ, et al. Ki67 proliferation Index as a tool for chemotherapy decisions during and after neoadjuvant aromatase inhibitor treatment of breast cancer: results from the american College of Surgeons Oncology group Z1031 trial (alliance). J Clin Oncol 2017. JCO2016694406.
[8] Dowsett M, et al. Prognostic value of Ki67 expression after short-term presurgical endocrine therapy for primary breast cancer. J Natl Cancer Inst 2007;99:167e70. http://dx.doi.org/10.1093/jnci/djk020. [9] Olson Jr JA, et al. Improved surgical outcomes for breast cancer patients receiving neoadjuvant aromatase inhibitor therapy: results from a multicenter phase II trial. J Am Coll Surg 2009;208:906e14. http://dx.doi.org/ 10.1016/j.jamcollsurg.2009.01.035. discussion 915-906. [10] Robertson JF, et al. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet 2016;388:2997e3005. http:// dx.doi.org/10.1016/S0140-6736(16)32389-3. [11] Ellis MJ, et al. Fulvestrant 500 mg versus anastrozole 1 mg for the first-line treatment of advanced breast cancer: overall survival analysis from the phase II first study. J Clin Oncol 2015;33:3781e7. http://dx.doi.org/10.1200/ JCO.2015.61.5831. [12] Ma CX, et al. NeoPalAna: neoadjuvant palbociclib, a cyclin-dependent kinase 4/6 inhibitor, and anastrozole for clinical stage 2 or 3 estrogen receptor positive breast cancer. Clin Cancer Res 2017. http://dx.doi.org/10.1158/10780432.CCR-16-3206. [13] Ellis MJ, et al. Whole-genome analysis informs breast cancer response to aromatase inhibition. Nature 2012;486:353e60. http://dx.doi.org/10.1038/ nature11143. [14] Miller CA, et al. Aromatase inhibition remodels the clonal architecture of estrogen-receptor-positive breast cancers. Nat Commun 2016;7:12498,. http://dx.doi.org/10.1038/ncomms12498.
Please cite this article in press as: Ellis MJ, Lessons in precision oncology from neoadjuvant endocrine therapy trials in ERþ breast cancer, The Breast (2017), http://dx.doi.org/10.1016/j.breast.2017.06.039
Contents lists available at ScienceDirect
The Breast journal homepage: www.elsevier.com/brst
Lessons in precision oncology from neoadjuvant endocrine therapy trials in ERþ breast cancer Matthew J. Ellis Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA
a r t i c l e i n f o
a b s t r a c t
Article history: Available online xxx
For post-menopausal women with clinical stage II/III estrogen receptor positive (ERþ) breast cancer neoadjuvant endocrine therapy (NET) is an under-utilized and low-toxicity alternative to chemotherapy for increasing breast conservation rates. Individual responses to endocrine therapy can also be used to tailor systemic treatment. The Preoperative Endocrine Prognostic Index (PEPI) was developed to identify patients at low risk of relapse after NET so that adjuvant chemotherapy can safely be avoided. In a recent validation study, patients with pathological stage 1 or 2A breast cancers with a Ki67 value of 2.7% or less in the surgical specimen (PEPI ¼ 0) after 16e18 weeks of aromatase inhibitor therapy had a 97% disease free survival after 5.5 years of median follow up. Two approaches are currently underway to extend the PEPI model. The first is to determine whether fulvestrant increases the PEPI-0 rate versus anastrozole, as this would increase the number of patients who could be safely managed without adjuvant chemotherapy. The second is to develop new approaches for tumors that exhibit endocrine therapy resistance identified during NET. Preliminary studies demonstrate that tumors that exhibit AI resistant proliferation in the neoadjuvant setting is often sensitive to palbociclib, a CDK4/6 inhibitor. Serial Ki67 monitoring before surgery is therefore logical approach to tailored use of adjuvant CDK4/6i adjuvant treatment. Finally serial sampling of the tumor inherent in the PEPI approach facilitates the identification of new therapeutic targets, mechanisms of resistance and monitoring of tumor evolution in response to AI therapy. © 2017 The Author. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
1. Pragmatic individualized therapy based on response to neoadjuvant systemic treatment The results of the NSABP B18 trial concluded there was no survival difference between preoperative doxorubicin cyclophosphamide chemotherapy versus the same chemotherapy given postoperatively. There was, however, a reduction in mastectomy rate. Initial arguments for neoadjuvant chemotherapy (NAC) therapy therefore focused on improvements in surgical outcomes [1]. Subsequently it became clear that patients who had a complete remission with NAC had markedly improved outcomes compared to those with residual disease [2]. The emphasis therefore shifted towards the hypothesis that the treatment of patients who have a pathological response in breast and nodes can be modified to reduce toxicity (Fig. 1A). For example, omitting regional nodal radiotherapy for patients who were initially node positive but become node negative after NAC
E-mail address: [email protected].
is under active investigation (NSABP B51). On the other hand, patients with significant residual disease post NAC require intensification of their systemic therapy. An advantage for adjuvant capecitabine in the trial patients with triple negative breast cancer with residual disease after NAC is a recent example of this approach [3].
2. Neoadjuvant endocrine therapy: an under utilized approach for improving surgical outcomes It is increasingly accepted that many patients with ER positive HER2 negative (ERþ HER2) disease do not benefit from chemotherapy as much as ER or HER2þ disease even for higher stage disease. Furthermore pCR rates are low in this disease subset limiting the value of pCR as a surrogate endpoint for the effectiveness of systemic treatment. Thus, neoadjuvant endocrine therapy is a reasonable alternative, particularly for postmenopausal women with high levels of ER expression. Several studies from a decade or more ago showed marked
http://dx.doi.org/10.1016/j.breast.2017.06.039 0960-9776/© 2017 The Author. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: Ellis MJ, Lessons in precision oncology from neoadjuvant endocrine therapy trials in ERþ breast cancer, The Breast (2017), http://dx.doi.org/10.1016/j.breast.2017.06.039
2
M.J. Ellis / The Breast xxx (2017) 1e4
Fig. 1. Progressive modifications to the neoadjuvant endocrine therapy approaches to increase the precision of therapy according to the biology of individual tumors.
improvements in breast conservation after 3e4 months of treatment with an aromatase inhibitor with a 50% reduction in the mastectomy rate in patients designated for a mastectomy at presentation [4]. More recently the American College of Surgeons
Oncology Group (ACOSOG) Z1031 study confirmed that for patients who are told they need a mastectomy, about half can undergo successful breast conserving surgery after 16e18 weeks of AI treatment [5].
Please cite this article in press as: Ellis MJ, Lessons in precision oncology from neoadjuvant endocrine therapy trials in ERþ breast cancer, The Breast (2017), http://dx.doi.org/10.1016/j.breast.2017.06.039
M.J. Ellis / The Breast xxx (2017) 1e4
3. The Preoperative Endocrine Prognostic Index (PEPI): an alternative to pCR for assessing systemic response for ER þ HER2 negative breast cancer Improvements in surgical outcomes are not the only advantage of NET since individual responses to endocrine therapy can be used to tailor patient treatment. The Preoperative Endocrine Prognostic Index (PEPI) was developed to identify extreme responders to endocrine therapy such that subsequent management could be modified to avoid chemotherapy in a population at low risk of relapse post NET [6]. Patients in the lowest risk PEPI group are referred to as PEPI ¼ 0. To meet PEPI ¼ 0 criteria the pathological specimen after NET must be node negative, pathological stage 1 or 2A (<5 cm) and the Ki67 value 2.7% or less. Also the tumor must be persistently ERþ. The long-term outcomes of the Z1031 trial (a comparison of three aromatase inhibitors) provided an opportunity to further evaluate the PEPI. After 5.5 years of median follow-up, 4 of the 109 (3.7%) patients with a PEPI ¼ 0 score relapsed versus 49 of 341 (14.4%) PEPI>0 patients, recurrence hazard ratio (PEPI ¼ 0/ PEPI>0) ¼ 0.27 (p ¼ 0.014; 95%CI: 0.092e0.764). We concluded that for patients with PEPI ¼ 0 disease the relapse risk over 5 years is so low without chemotherapy that the further study of adjuvant endocrine monotherapy is justifiable [7]. The PEPI approach therefore has similar operational characteristics as pCR with escalation of therapy a reasonable approach for PEPI >0 patients and de-escalation of therapy, i.e. no chemotherapy, for patients with PEPI-0 status (Fig. 1B). 4. A 2e4 week biopsy to identify patients with a low chance of experiencing PEPI-0 status and thereby avoiding intensification of systemic therapy A drawback of the PEPI approach is that the triage point for treatment intensification or de-intensification occurs at 4 or more months after starting neoadjuvant endocrine therapy. Ideally patients with resistant disease should be identified earlier for triage to alternate systemic treatment. We therefore explored early on treatment Ki67 levels to determine a threshold where an early Ki67 value, 2e4 weeks after starting endocrine therapy, was high enough such that the chance of a PEPI-0 tumor was very low (since 2e4 week Ki67 levels are highly correlated with Ki67 levels in the surgical specimen, 3e4 months later). Examining data from the IMPACT trial [8] and the POL trial [9] led to the definition of a 10% threshold as above this value the chance of a PEPI ¼ 0 tumor was less than 2%. Thus the PEPI treatment paradigm was altered to include an early biopsy to identify the most resistant tumors (Fig. 1C). About 20% of patients come into this category. 5. Triage to chemotherapy for patients with Ki67 >10% at 2e4 weeks is less effective than expected The Z1031B protocol was amended to include a tumor Ki67 determination after 2e4 weeks of AI to conduct a Phase 2 trial of standard of care chemotherapy. A pCR rate of >20% was the predefined efficacy threshold. However only two of the 35 patients on Z1031B switched to neoadjuvant chemotherapy experienced a pCR (5.7%, 95%CI: 0.7e19.1%) excluding a pCR rate of 20%, which was the minimally effective threshold in the predefined Phase 2 design. Reasons for the poor chemotherapy response rate include the ER rich nature of the tumors enrolled and the postmenopausal status of the patients. Both are established factors that reduce the efficacy of chemotherapy. The prognosis of patients with a Ki67 value > 10% proved to be poor despite the use of chemotherapy, underscoring the treatment resistant nature of tumors with intrinsically endocrine therapy resistant disease [7].
3
6. Ongoing studies of treatment de-escalation for patients with PEPI ¼ 0 tumors One approach to improving the PEPI paradigm is to identify alternative endocrine therapies that can increase the PEPI-0 rate over AI alone (Fig. 1D). This would allow more patients to be treated without chemotherapy and possibly further increase the breast conservation rate. The ALTERNATE trial is addressing this possibility by randomizing patient treatment between anastrozole, fulvestrant or the combination. Eligibility includes postmenopausal status, ER Allred score 6 to 8 and palpable disease so patients can be followed clinically. The basis for testing fulvestrant in this setting are the positive results of the FALCON [10] and FIRST studies [11], that found that fulvestrant is more effective than anastrozole for treatment naïve advanced breast cancer. 7. Alternatives to chemotherapy for patients with nonPEPI ¼ 0 disease Given the poor performance of triage to chemotherapy in Z1031B, alternative systemic therapies need to be sought (Fig. 1E). Recently CDK4/6 inhibitors have been explored in the neoadjuvant setting. NeoPalAna is a sequential biopsy study for patients with clinical stage 2 and 3 ER þ HER2 negative breast cancer [12]. Premenopausal women were eligible if treated with an LHRH agonist and estradiol monitoring confirmed ovarian function was successfully suppressed. After a pretreatment biopsy, patients were treated with anastrozole for a month and then a second biopsy was taken followed by the addition of palbociclib to the regimen. A further biopsy was taken after 14 days to assess the antiproliferative effect of the addition of the CDK4/6 inhibitor over the effect observed with the AI alone. Palbociclib addition was found to be effective at enhancing the number of tumors in cell cycle complete response (CCCR), defined as a Ki67 of <2.7%. Interestingly from the perspective of adjuvant therapy, three patterns of response were observed; tumors that underwent CCCR with AI alone; tumors in CCCR from the addition of palbociclib to AI and a group that was resistant to both therapies. One might therefore postulate that patients in the first group do not require palbociclib, the second group require the combination and the third an entirely different treatment approach. Trials that tailor the use of CDK4/6i treatment this way are under active consideration. 8. Treatment based on next generation genomic technologies Serial sampling of the tumor inherent in the PEPI approach allows the study of the genomic evolution of the tumor and to identify new therapeutic targets [13] and monitor tumor evolution in response to AI therapy [14]. While the PEPI approach is promising, a return to pCR as a surrogate endpoint for long term outcome is always possible if treatments emerge that induce higher rates of pCR in ER þ HER2- breast cancer. New studies for intrinsically endocrine therapy resistant disease with pCR as a goal are therefore important as the weakness of both endocrine therapy and CDK4/6 therapy are that they are maintenance treatments requiring long term therapy e which is an open invitation for resistance to develop. Perhaps the next generation of NET trials will incorporate not only Ki67-based triage, but genomic analysis so that the therapeutic approach for poor prognosis patients can be more precise (Fig. 1F). References [1] Fisher B, et al. Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical
Please cite this article in press as: Ellis MJ, Lessons in precision oncology from neoadjuvant endocrine therapy trials in ERþ breast cancer, The Breast (2017), http://dx.doi.org/10.1016/j.breast.2017.06.039
4
M.J. Ellis / The Breast xxx (2017) 1e4
[2]
[3]
[4]
[5]
[6]
[7]
Adjuvant Breast and Bowel Project B-18. J Clin Oncol 1997;15:2483e93. http://dx.doi.org/10.1200/JCO.1997.15.7.2483. Fisher B, et al. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 1998;16:2672e85. http://dx.doi.org/ 10.1200/JCO.1998.16.8.2672. Toi M, et al. A phase III trial of adjuvant capecitabine in breast cancer patients with HER2-negative pathologic residual invasive disease after neoadjuvant chemotherapy (CREATE-X, JBCRG-04). Cancer Res 2016;76. http://dx.doi.org/ 10.1158/1538-7445.SABCS15-S1-07. Abstract S1e07. Ellis MJ, et al. Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: evidence from a phase III randomized trial. J Clin Oncol 2001;19:3808e16. http://dx.doi.org/10.1200/JCO.2001.19.18.3808. Ellis MJ, et al. Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtypeeACOSOG Z1031. J Clin Oncol 2011;29:2342e9. http://dx.doi.org/10.1200/ JCO.2010.31.6950. Ellis MJ, et al. Outcome prediction for estrogen receptor-positive breast cancer based on postneoadjuvant endocrine therapy tumor characteristics. J Natl Cancer Inst 2008;100:1380e8. http://dx.doi.org/10.1093/jnci/djn309. Ellis MJ, et al. Ki67 proliferation Index as a tool for chemotherapy decisions during and after neoadjuvant aromatase inhibitor treatment of breast cancer: results from the american College of Surgeons Oncology group Z1031 trial (alliance). J Clin Oncol 2017. JCO2016694406.
[8] Dowsett M, et al. Prognostic value of Ki67 expression after short-term presurgical endocrine therapy for primary breast cancer. J Natl Cancer Inst 2007;99:167e70. http://dx.doi.org/10.1093/jnci/djk020. [9] Olson Jr JA, et al. Improved surgical outcomes for breast cancer patients receiving neoadjuvant aromatase inhibitor therapy: results from a multicenter phase II trial. J Am Coll Surg 2009;208:906e14. http://dx.doi.org/ 10.1016/j.jamcollsurg.2009.01.035. discussion 915-906. [10] Robertson JF, et al. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet 2016;388:2997e3005. http:// dx.doi.org/10.1016/S0140-6736(16)32389-3. [11] Ellis MJ, et al. Fulvestrant 500 mg versus anastrozole 1 mg for the first-line treatment of advanced breast cancer: overall survival analysis from the phase II first study. J Clin Oncol 2015;33:3781e7. http://dx.doi.org/10.1200/ JCO.2015.61.5831. [12] Ma CX, et al. NeoPalAna: neoadjuvant palbociclib, a cyclin-dependent kinase 4/6 inhibitor, and anastrozole for clinical stage 2 or 3 estrogen receptor positive breast cancer. Clin Cancer Res 2017. http://dx.doi.org/10.1158/10780432.CCR-16-3206. [13] Ellis MJ, et al. Whole-genome analysis informs breast cancer response to aromatase inhibition. Nature 2012;486:353e60. http://dx.doi.org/10.1038/ nature11143. [14] Miller CA, et al. Aromatase inhibition remodels the clonal architecture of estrogen-receptor-positive breast cancers. Nat Commun 2016;7:12498,. http://dx.doi.org/10.1038/ncomms12498.
Please cite this article in press as: Ellis MJ, Lessons in precision oncology from neoadjuvant endocrine therapy trials in ERþ breast cancer, The Breast (2017), http://dx.doi.org/10.1016/j.breast.2017.06.039