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The standard of care for locally advanced breast cancer (LABC) is neoadjuvant chemotherapy,1 with LABC including clinical stages IIA, IIB, and IIIA. The goals of preoperative chemotherapy are to downstage so as to render breast conservation feasible, to eradicate disease in the axillary nodes, and to allow in vivo testing of tumor drug sensitivity, all with the ultimate aim of improving prognosis. Clinical trials have demonstrated that the pathologic in-breast response generally correlates with pathologic response in the lymph nodes. Furthermore, nodal status at the time of surgery correlates with overall survival (OS) and disease-free survival (DFS).2,3 A combined analysis of two large prospective neoadjuvant chemotherapy trials demonstrated significantly higher 5-year OS and DFS in patients achieving in-breast pathologic complete response (pCR), compared with those who did not (OS, 89% vs 64%; DFS, 87% vs 58%, respectively).4
At the start of this trial, the most effective neoad- juvant regimen remained in question. Even now, National Comprehensive Cancer Center guidelines suggest that any recommended adjuvant regimen can be used in the neoadjuvant setting.1 Numerous phase II and III trials have evaluated single-agent5–8 and combination9– 32 chemotherapies, most of which are anthracycline- based, with pCR rates reported between 7% and 36%. In the NSABP-B27 study, patients treated preoperatively with four cycles of doxorubicin and cyclophosphamide (AC) followed by four cycles of docetaxel (Taxotere) had a 26% pCR rate versus a 13% pCR rate in those receiving preoperative AC and postoperative docetaxel. Despite the doubling of pCR with neoadjuvant docetaxel, there was no difference in DFS or OS.9 However, as reported by Kuerer et al, patients achieving a pCR after completion of neoadjuvant chemotherapy appeared to have superior survival.4
Many previous trials (including the study reported here) did not exclude patients with human epidermal growth factor receptor 2 (HER2)-positive disease. It is now well established that such patients should be treated with neoadjuvant regimens incorporating HER2-targeted therapy. In fact, an early neoadjuvant study of paclitaxel followed by fluorouracil, epirubicin, and cyclophosphamide with or without 24 weeks of concurrent trastuzumab (Herceptin) in patients with HER2-positive tumors was closed early because patients receiving trastuzumab had a pCR rate of 65%, compared with 26% in those who did not receive it.33 Expanded clinical trials of this approach are in progress.
The selection of capecitabine (Xeloda) and docetaxel in the present trial was based on the hypothesis that the upregulation of thymidine phosphorylase by docetaxel should increase the activity of capecitabine. 34–36 Single-agent docetaxel in the neoadjuvant setting has yielded pCR rates of 7%–20%.6–8 Treatment with docetaxel and capecitabine together has been reported to produce pCR rates of 10%–21%.37–39 The addition of carboplatin was based on studies by Hurley et al at the University of Miami39– 41 suggesting that platinum salts appeared quite active in the neoadjuvant setting, with the combination of docetaxel and cisplatin producing a pCR rate of 20%, with no residual disease in the breast or axilla.40 Other regimens incorporating cisplatin or carboplatin have pCR rates ranging from 16% to 24%.27,42–44
Patients and methods
Study design
In this phase II multicenter study, patients were assigned to receive docetaxel (30 mg/m2 IV) and carboplatin (AUC 2 IV) on days 1, 8, and 15 of each 28-day cycle plus capecitabine (625 mg/m2 PO) twice daily on days 5–18. The capecitabine dose was based on observations that this dose was effective and relatively nontoxic in metastatic breast cancer (C.L. Vogel, empirical observations). Patients were to receive four cycles prior to surgical resection.
Given that this neoadjuvant regimen was under study, all of the patients were scheduled to receive a proven standard postoperative adjuvant chemotherapy regimen, starting 4–6 weeks postoperatively, with doxorubicin (60 mg/m2 IV) and cyclophosphamide (600 mg/m2 IV) every 21 days for 4 cycles. This sequential design was prompted by studies such as the NSABP B-27 and Aberdeen trials.9,32
Radiation therapy after lumpectomy or mastectomy was given according to individual institution guidelines. Patients with hormone receptor–positive tumors received appropriate antihormonal therapy. Tumor measurements were assessed at baseline and on day 1 of each cycle by physical examination with calipers. No breast or other imaging was required during the period of neoadjuvant chemotherapy or immediately preoperatively. Patients were considered evaluable if they proceeded to surgery after all intended cycles of neoadjuvant chemotherapy or if they developed disease progression during neoadjuvant therapy.
Patients
Eligible patients were men and women regardless of menopausal status ≥ 18 years of age with coreneedle biopsy proven locally advanced or inflammatory breast cancer. Breast cancer characteristics such as estrogen receptor (ER), progesterone receptor (PR), or HER2 status were collected but not used for inclusion/exclusion. Eligible tumors were T2 requiring mastectomy; T3N0–2; T4; and any TN2–3 that by calipers was > 2 cm or with fixed or matted axillary or imaging-detected internal mammary nodes. Patients with prior ductal carcinoma in situ (DCIS) were included, as were those with ≤ T2N0M0 breast cancer > 5 years prior.
Other requirements were an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1; life expectancy > 6 months; negative metastatic workup (bone scan and CT chest/abdomen/pelvis); adequate bone marrow, liver, and kidney function; and peripheral neuropathy ≤ grade 1. All patients of child-bearing potential were required to consent to dual methods of contraception during treatment and for 3 months afterward. A negative pregnancy test was required for these women before treatment, and any suspicion of pregnancy had to be reported to the treating physician.
Study endpoints
The primary endpoint of the study was the in-breast pCR after four cycles of platinum-based neoadjuvant chemotherapy. Pathologic complete response was defined as complete disappearance of invasive and in situ disease or invasive disease alone. During the course of this trial, it became generally acceptable to include patients with only residual DCIS as equivalent to pCR.45
The secondary endpoints were pCR in the lymph nodes; clinical response rate; tolerability; breast conservation; time to disease progression (local, regional, and distant); and OS. Also recorded was minimal residual disease (MRD), which we arbitrarily defined as ≤ 1 cm invasive carcinoma at resection. The overall treatment plan included postoperative AC to provide a standard-of-care regimen to maximize curative potential.
Statistical analysis
Data were analyzed on an intentto- treat basis. Although pCR rates with doxorubicin plus either cyclophosphamide or docetaxel have been < 15%, the studies by Smith et al26 and Hurley et al39 with in-breast pCR rates of at least 20% served as comparators (albeit imprecise).
Applying the min/max statistical design, the procedure tests the null hypothesis H0: P ≤ 0.15 against the alternative hypothesis H1: P ≥ 0.30. The overall level of significance and power for this design are 5% and 80%, respectively. The sample size needed for the first stage was 23 evaluable patients. If three or fewer pCR responses were observed, then the study would be terminated and the treatment regimen would not be investigated further. Otherwise, an additional 25 evaluable patients would be accrued for a total of 48 study patients. If 11 or fewer responses were observed, then the study would be terminated. Otherwise, this treatment regimen would be recommended to proceed to phase III for further investigation.
Tolerability assessment
At each visit, toxicities were assessed and graded according to the National Cancer Institute Common Toxicity Criteria, version 2.46 Two dose reductions were allowed for all drugs.
Ethical considerations
The investigational nature of this study was fully disclosed to each patient. In accordance with institutional and federal guidelines, the patients were guided through and subsequently signed the informed consent approved by the appropriate site Institutional Review Board.
Literature review
The terms “neoadjuvant” and “breast” were used in a literature search on PubMed, with filters “English” and “clinical trials.” Abstracts for each of the 398 results were reviewed We used phase II or III trials with at least 30 patients, at least four cycles of chemotherapy, and clearly defined pCR for comparison to this study.
Results Patients
Between June 2003 and December 2006, 50 women with a median age of 49 years (range, 28–75 years) were enrolled. One patient was ineligible due to preceding lumpectomy. The 49 eligible patients were treated with ≥ 1 cycle of neoadjuvant chemotherapy between June 27, 2003, and April 12, 2007.
The baseline characteristics of the 49 eligible patients are summarized in Table 3. Thirty-one patients (63%) were premenopausal. Twenty patients (41%) were positive for either ER or PR and were negative for HER2. Eight patients (16%) had HER2- positive tumors, and 23 (46%) had triple-negative tumors. At baseline, 22 patients (45%) had clinical lymphadenopathy, and 1 patient (2%) had inflammatory breast cancer.
The 41 patients (83%) who completed all four cycles of therapy were evaluable for response; 8 (16%) were inevaluable due to noncompliance (1), grade 3 or 4 toxicity (5), or withdrawal of consent (2). The following efficacy assessments apply to the 41 evaluable patients, whereas the toxicity assessments include the 49 patients who received at least one full cycle of chemotherapy.
Clinical response
At study onset, of the 49 eligible patients, 38 (78%) had a palpable inbreast tumor (median size, 5.5 cm); 22 (45%) had enlarged nodes, and 34 (69%) had confirmed nodal involvement (by biopsy or imaging). A clinical complete response (cCR) rate in the breast was seen in 23 of 41 (56%) evaluable patients. Of 22 patients with baseline lymphadenopathy (by imaging or physical examination), 13 had axillary assessment by physical examination throughout treatment, with 12 (92%) exhibiting a cCR in the axilla.
Pathologic response
After four cycles of chemotherapy, an in-breast pCR (the primary endpoint) was demonstrated in 6 of 41 patients (15%). One of these six patients had residual DCIS and is listed separately. All of these patients had nodal pCR, whereas overall, 20 patients (49%) had negative nodes at resection.
The pathology reports of two patients were read as having invasive tumor within lymphatics and lymphovascular invasion (one each) with no measurable disease, with tumor thus sized as Tx. Neither of these patients had involved lymph nodes. Fourteen patients (34%) had MRD in the breast, and 8 of these 14 patients (57%) had residual nodal disease. Nine patients (22%) had T1c tumors (> 1–2 cm), with five of these nine patients (55%) having nodal disease. Seven patients (17%) had T2 tumors (> 2–5 cm) tumors, with five of these seven patients (71%) having nodal disease. These findings are summarized in Table 4. The correlation between in-breast cCR and pCR was 26%.
Biologic features of responders
Of interest, five of the six patients with a pCR had triple-negative tumors. This translates to a 22% pCR rate (5 of 23) in the triple-negative subset, and a pCR rate of 6% (1 of 18) in patients with ER-positive and/ or PR-positive tumors. The remaining patient with a pCR had ER-, PR-, and HER2-positive disease.
One patient had inflammatory breast cancer at diagnosis, and another developed this during the course of chemotherapy; the latter patient was removed from the study for progressive disease. Interestingly, the patient who presented with inflammatory breast cancer was one of the six patients with a pCR. Both of these inflammatory disease patients had triple-negative tumors.
Conversion to breast conservation
Breast conservation was offered to patients if it was deemed appropriate by the treating surgeon. Preoperative imaging was not mandated and thus was not routinely performed. Mastectomy was ultimately performed in 4 of the 6 patients (67%) with pCR and in 22 of the 35 patients (63%) with less than a pCR. Thus, the choice for breast conservation did not correlate well with response to chemotherapy.
Time to disease progression
At a median follow-up of 48 months (range, 7–63), 36 of 41 patients (88%) remained free of disease (range, 19–63 months). Two patients had progressive disease while they were on study treatment and had T3 tumors on resection. Another three patients were found to have progressive disease at 10, 41, and 50 months from study day 1.
Of the nine patients with T1c disease, only one patient (who had positive nodes at resection) had a recurrence (at 41 months). Overall, the patients who had a recurrence had MRD (one patient), T1c (one patient), T2 (one patient), and T3 (the same two patients whose disease progressed while they were on treatment and continued to progress after surgery).
Disease-free and overall survival
Three patients were lost to followup, with point of last contact at 19, 34, and 59 months. Of the 41 evaluable patients, 5 patients developed progressive disease, with 2 of these patients progressing during the study treatment. Disease-free survival at 12, 24, and 36 months was 89%, 89%, and 78%, respectively. Overall survival at these same time points was 95%, 90%, and 76%. None of the patients with a pCR is known to have recurrent disease. Of the six patients achieving pCR, two were lost to follow-up after 34 and 59 months, and four continued diseasefree at 38, 39, 55, and 62 months.
Adverse events
Five patients were removed from the study secondary to toxicities. Grade 3 and 4 toxicity events are summarized in Table 5. Grade 3 toxicities were anemia (4), diarrhea (2), epigastric pain (1), fatigue (2), hand-foot syndrome (1), infection (1), leukopenia (9), pain (5), and peripheral sensory neuropathy (1). Grade 4 toxicities were depression (1) and leukopenia (4). Toxicities (all grades) occurring in ≥ 10% of the 49 treated patients were anemia (76%), leukopenia (70%), fatigue (67%), nausea (59%), alopecia (49%), thrombocytopenia (47%), diarrhea (47%), constipation (37%), pain (35%), vomiting (31%), epigastric pain (27%), nail changes (22%), epiphora (22%), hand-foot syndrome (20%), infection (18%), edema (16%), rash (16%), anorexia (16%), and depression (10%). In the intent-to-treat population, there were nine dose reductions among nine patients, and 19 dose delays among 15 patients.
Discussion
The combination of agents tested thus far in the neoadjuvant setting consistently produce pCR rates far less than 50% in unselected populations. This study was begun prior to the widespread use of personalized medicine. Most prior published trials had utilized anthracycline-based chemotherapy, with response rates generally ranging between 7% and 36%.6,9–26,28–31,41,42
The idea of thymidine phosphorylase upregulation by the combination of capecitabine and docetaxel upon which this study was largely based34–36 has since been disputed.47 The primary endpoint of this trial of a novel platinum- based regimen was a pCR rate of 15%. It is significant that 83% of the pCRs were in triple-negative tumors. A secondary endpoint of MRD was calculated, as this was in the original design of the study, but ultimately was not relevant to the primary endpoint.
Ultimately, pCR is the more relevant point of discussion for the modern era. The 15% pCR rate seen in this phase II study was within range of those achieved in numerous other phase II/III neoadjuvant chemotherapy trials with ≥ 25 patients, ≥ 3 cycles of chemotherapy, and pCR defined as absence of carcinoma in the breast and axilla. To date, no patient in our study with a pCR has been noted to have recurrent disease. However, a recently published French study found a 22% recurrence rate at 11 years in patients with triple-negative breast cancer achieving pCR, highlighting the importance of longer-term follow- up.48.
The inclusion of patients with HER2-positive disease in neoadjuvant studies without HER2-targeted therapy was standard at the time that this study was conducted, but is no longer appropriate. If we were to exclude the eight HER2-positive patients from analysis, then there would be only 34 patients evaluable for response, with a pCR rate of 18%. Buzdar et al33 demonstrated a 65% pCR rate in women with HER2-positive disease treated with neoadjuvant chemotherapy plus trastuzumab. The improvement in pCR with the addition of trastuzumab is supported by other confirmatory trials. Authors of a single-arm trial of dose-dense epirubicin and cyclophosphamide followed by dosedense docetaxel and trastuzumab in a HER2-positive population reported a pCR rate of 57%.49 The randomized NOAH study50 achieved a pCR rate of 23% in 115 patients treated with trastuzumab-based chemotherapy.
It is interesting to note that five of six patients (83%) achieving a pCR in our study had triple-negative tumors. Investigators at the University of Miami presented a retrospective review of locally advanced triple-negative breast cancer treated with docetaxel and a platinum salt, with 61% of patients also receiving AC. The authors reported a pCR rate of 34% overall and 40% for patients receiving AC.51 A pCR rate of 60% was noted in the triplenegative subset of patients in another study evaluating docetaxel, doxorubicin, and cyclophosphamide with or without vinorelbine/capecitabine (GeparTrio Study).52 Further, a pCR rate of 72% was achieved with singleagent cisplatin in a group of 25 women with BRCA1 mutations, suggesting, if confirmed by others, that this largely triple- negative population may be exquisitely sensitive to platinum salts.43 In contrast, in a previous study of cisplatin in BRCA mutation carriers, Garber et al44 reported a pCR rate of 22%, suggesting that further trials are needed specifically in BRCA carriers and in triple-negative tumors to see whether these specific patient subsets preferentially derive benefit from platinum salts in the neoadjuvant setting.
The results of the current study are consistent with others indicating a low likelihood of pCR in patients with ERpositive tumors. In fact, none of our ER-positive patients had a pCR. Neoadjuvant endocrine therapy in postmenopausal women with ER- and/ or PR-positive disease is a reasonable treatment option for selected patients, but endpoints other than pCR have often been used.53,54 It is therefore difficult to directly compare these two strategies. Currently, investigators are comparing the three aromatase inhibitors head to head in the neoadjuvant setting for postmenopausal women with hormone receptor–positive tumors.55
The historic pCR ceiling appears to be rising, albeit slowly. Where targets such as HER2 overexpression and triple- negative biology are recognized, progress is being made. Patient eligibility criteria for neoadjuvant breast cancer studies at the time of this trial were quite broad, and it is now recognized that specific subsets of breast cancer respond differently to different classes of agents. Furthermore, our knowledge about breast cancer prognostic markers continues to expand. Had this study been designed in 2011, other data points such as Ki67 would have been collected. A recently published study on neoadjuvant triplenegative breast cancer found that only patients with baseline Ki67% expression > 10% achieved pCR.56
Given the long-term implications of not achieving pCR, optimal treatment of patients in the adjuvant setting is critical. Although neoadjuvantly treated patients with ER-positive or HER2-positive disease go on to receive adjuvant agents (antihormonal therapy for ER-positive disease and trastuzumab for HER2-positive disease), patients with triple-negative disease lack long-term therapies of proven efficacy. Perhaps, as we edge closer to defining the optimal neoadjuvant agents for each subset of patients, this will be less of a concern. Many earlyphase neoadjuvant studies have been conducted, with promising reports, yet the results of larger, randomized trials continue to frustrate both investigators and clinicians. These deficits in care can only be answered by carefully planned randomized clinical trials.
Acknowledgment: Funding for this study was provided by sanofi-aventis, U.S.
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ABOUT THE AUTHORS
Aruna Mani, MD; Sandra X. Franco, MD; Grace Wang, MD: Neil Abramson, MD; Lee S. Schwartzberg, MD: James Jakub, MD; Elizabeth Tan-Chiu, MD: Alisha Stein, RNC, BSN, OCN; Alejandra T. Perez, MD; and Charles L Vogel, MD.
Affiliations: Dr. Mani is a breast medical oncologist at Memorial Cancer Institute, Pembroke Pines, FL. Dr. Franco is now Chief of Oncology at the Oncology Center, Clinica del Country, Bogota, Colombia. Dr. Wang is an oncologist at Advanced Medical Specialties, Miami, FL. Dr. Abramson is Clinical Professor of Medicine and Emeritus Director of Education and Research at Baptist Cancer Institute, University of Florida, Jacksonville, FL. Dr. Schwartzberg is Medical Director of The West Clinic, Memphis, TN. Dr. Jakub is now Assistant Professor of Surgery, Division of Gastroenterology and General Surgery, Mayo Clinic, Rochester, MN. Dr. Tan-Chiu is Medical Director of Florida Cancer Care, Davie, FL. Dr. Schwartz is Principal Investigator at Mount Sinai Medical Center, Miami Beach, FL. Ms. Frankel is Director of Oncology Clinical Research and Development at Memorial Cancer Institute, Hollywood, FL. Dr. Krill-Jackson is an oncologist at Mount Sinai Comprehensive Cancer Center, Miami, FL. Ms. Stein is now Oncology Clinical Coordinator at Genentech Inc., Fort Lauderdale, FL. Dr. Perez is Director of the Breast Cancer Center at Memorial Cancer Institute, Hollywood, FL. Dr. Vogel is Professor of Clinical Medicine and Director of the Women’s Center, Sylvester Comprehensive Cancer Center, Deerfield Beach, FL.
Conflicts of interest: Dr. Vogel has served as an advisor and is a member of the speakers’ bureaus of sanofi-aventis U.S. and Roche, as well as many other companies whose products were not part of the current study plan. The other authors have no pertinent conflicts of interest to disclose.
The standard of care for locally advanced breast cancer (LABC) is neoadjuvant chemotherapy,1 with LABC including clinical stages IIA, IIB, and IIIA. The goals of preoperative chemotherapy are to downstage so as to render breast conservation feasible, to eradicate disease in the axillary nodes, and to allow in vivo testing of tumor drug sensitivity, all with the ultimate aim of improving prognosis. Clinical trials have demonstrated that the pathologic in-breast response generally correlates with pathologic response in the lymph nodes. Furthermore, nodal status at the time of surgery correlates with overall survival (OS) and disease-free survival (DFS).2,3 A combined analysis of two large prospective neoadjuvant chemotherapy trials demonstrated significantly higher 5-year OS and DFS in patients achieving in-breast pathologic complete response (pCR), compared with those who did not (OS, 89% vs 64%; DFS, 87% vs 58%, respectively).4
At the start of this trial, the most effective neoad- juvant regimen remained in question. Even now, National Comprehensive Cancer Center guidelines suggest that any recommended adjuvant regimen can be used in the neoadjuvant setting.1 Numerous phase II and III trials have evaluated single-agent5–8 and combination9– 32 chemotherapies, most of which are anthracycline- based, with pCR rates reported between 7% and 36%. In the NSABP-B27 study, patients treated preoperatively with four cycles of doxorubicin and cyclophosphamide (AC) followed by four cycles of docetaxel (Taxotere) had a 26% pCR rate versus a 13% pCR rate in those receiving preoperative AC and postoperative docetaxel. Despite the doubling of pCR with neoadjuvant docetaxel, there was no difference in DFS or OS.9 However, as reported by Kuerer et al, patients achieving a pCR after completion of neoadjuvant chemotherapy appeared to have superior survival.4
Many previous trials (including the study reported here) did not exclude patients with human epidermal growth factor receptor 2 (HER2)-positive disease. It is now well established that such patients should be treated with neoadjuvant regimens incorporating HER2-targeted therapy. In fact, an early neoadjuvant study of paclitaxel followed by fluorouracil, epirubicin, and cyclophosphamide with or without 24 weeks of concurrent trastuzumab (Herceptin) in patients with HER2-positive tumors was closed early because patients receiving trastuzumab had a pCR rate of 65%, compared with 26% in those who did not receive it.33 Expanded clinical trials of this approach are in progress.
The selection of capecitabine (Xeloda) and docetaxel in the present trial was based on the hypothesis that the upregulation of thymidine phosphorylase by docetaxel should increase the activity of capecitabine. 34–36 Single-agent docetaxel in the neoadjuvant setting has yielded pCR rates of 7%–20%.6–8 Treatment with docetaxel and capecitabine together has been reported to produce pCR rates of 10%–21%.37–39 The addition of carboplatin was based on studies by Hurley et al at the University of Miami39– 41 suggesting that platinum salts appeared quite active in the neoadjuvant setting, with the combination of docetaxel and cisplatin producing a pCR rate of 20%, with no residual disease in the breast or axilla.40 Other regimens incorporating cisplatin or carboplatin have pCR rates ranging from 16% to 24%.27,42–44
Patients and methods
Study design
In this phase II multicenter study, patients were assigned to receive docetaxel (30 mg/m2 IV) and carboplatin (AUC 2 IV) on days 1, 8, and 15 of each 28-day cycle plus capecitabine (625 mg/m2 PO) twice daily on days 5–18. The capecitabine dose was based on observations that this dose was effective and relatively nontoxic in metastatic breast cancer (C.L. Vogel, empirical observations). Patients were to receive four cycles prior to surgical resection.
Given that this neoadjuvant regimen was under study, all of the patients were scheduled to receive a proven standard postoperative adjuvant chemotherapy regimen, starting 4–6 weeks postoperatively, with doxorubicin (60 mg/m2 IV) and cyclophosphamide (600 mg/m2 IV) every 21 days for 4 cycles. This sequential design was prompted by studies such as the NSABP B-27 and Aberdeen trials.9,32
Radiation therapy after lumpectomy or mastectomy was given according to individual institution guidelines. Patients with hormone receptor–positive tumors received appropriate antihormonal therapy. Tumor measurements were assessed at baseline and on day 1 of each cycle by physical examination with calipers. No breast or other imaging was required during the period of neoadjuvant chemotherapy or immediately preoperatively. Patients were considered evaluable if they proceeded to surgery after all intended cycles of neoadjuvant chemotherapy or if they developed disease progression during neoadjuvant therapy.
Patients
Eligible patients were men and women regardless of menopausal status ≥ 18 years of age with coreneedle biopsy proven locally advanced or inflammatory breast cancer. Breast cancer characteristics such as estrogen receptor (ER), progesterone receptor (PR), or HER2 status were collected but not used for inclusion/exclusion. Eligible tumors were T2 requiring mastectomy; T3N0–2; T4; and any TN2–3 that by calipers was > 2 cm or with fixed or matted axillary or imaging-detected internal mammary nodes. Patients with prior ductal carcinoma in situ (DCIS) were included, as were those with ≤ T2N0M0 breast cancer > 5 years prior.
Other requirements were an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1; life expectancy > 6 months; negative metastatic workup (bone scan and CT chest/abdomen/pelvis); adequate bone marrow, liver, and kidney function; and peripheral neuropathy ≤ grade 1. All patients of child-bearing potential were required to consent to dual methods of contraception during treatment and for 3 months afterward. A negative pregnancy test was required for these women before treatment, and any suspicion of pregnancy had to be reported to the treating physician.
Study endpoints
The primary endpoint of the study was the in-breast pCR after four cycles of platinum-based neoadjuvant chemotherapy. Pathologic complete response was defined as complete disappearance of invasive and in situ disease or invasive disease alone. During the course of this trial, it became generally acceptable to include patients with only residual DCIS as equivalent to pCR.45
The secondary endpoints were pCR in the lymph nodes; clinical response rate; tolerability; breast conservation; time to disease progression (local, regional, and distant); and OS. Also recorded was minimal residual disease (MRD), which we arbitrarily defined as ≤ 1 cm invasive carcinoma at resection. The overall treatment plan included postoperative AC to provide a standard-of-care regimen to maximize curative potential.
Statistical analysis
Data were analyzed on an intentto- treat basis. Although pCR rates with doxorubicin plus either cyclophosphamide or docetaxel have been < 15%, the studies by Smith et al26 and Hurley et al39 with in-breast pCR rates of at least 20% served as comparators (albeit imprecise).
Applying the min/max statistical design, the procedure tests the null hypothesis H0: P ≤ 0.15 against the alternative hypothesis H1: P ≥ 0.30. The overall level of significance and power for this design are 5% and 80%, respectively. The sample size needed for the first stage was 23 evaluable patients. If three or fewer pCR responses were observed, then the study would be terminated and the treatment regimen would not be investigated further. Otherwise, an additional 25 evaluable patients would be accrued for a total of 48 study patients. If 11 or fewer responses were observed, then the study would be terminated. Otherwise, this treatment regimen would be recommended to proceed to phase III for further investigation.
Tolerability assessment
At each visit, toxicities were assessed and graded according to the National Cancer Institute Common Toxicity Criteria, version 2.46 Two dose reductions were allowed for all drugs.
Ethical considerations
The investigational nature of this study was fully disclosed to each patient. In accordance with institutional and federal guidelines, the patients were guided through and subsequently signed the informed consent approved by the appropriate site Institutional Review Board.
Literature review
The terms “neoadjuvant” and “breast” were used in a literature search on PubMed, with filters “English” and “clinical trials.” Abstracts for each of the 398 results were reviewed We used phase II or III trials with at least 30 patients, at least four cycles of chemotherapy, and clearly defined pCR for comparison to this study.
Results Patients
Between June 2003 and December 2006, 50 women with a median age of 49 years (range, 28–75 years) were enrolled. One patient was ineligible due to preceding lumpectomy. The 49 eligible patients were treated with ≥ 1 cycle of neoadjuvant chemotherapy between June 27, 2003, and April 12, 2007.
The baseline characteristics of the 49 eligible patients are summarized in Table 3. Thirty-one patients (63%) were premenopausal. Twenty patients (41%) were positive for either ER or PR and were negative for HER2. Eight patients (16%) had HER2- positive tumors, and 23 (46%) had triple-negative tumors. At baseline, 22 patients (45%) had clinical lymphadenopathy, and 1 patient (2%) had inflammatory breast cancer.
The 41 patients (83%) who completed all four cycles of therapy were evaluable for response; 8 (16%) were inevaluable due to noncompliance (1), grade 3 or 4 toxicity (5), or withdrawal of consent (2). The following efficacy assessments apply to the 41 evaluable patients, whereas the toxicity assessments include the 49 patients who received at least one full cycle of chemotherapy.
Clinical response
At study onset, of the 49 eligible patients, 38 (78%) had a palpable inbreast tumor (median size, 5.5 cm); 22 (45%) had enlarged nodes, and 34 (69%) had confirmed nodal involvement (by biopsy or imaging). A clinical complete response (cCR) rate in the breast was seen in 23 of 41 (56%) evaluable patients. Of 22 patients with baseline lymphadenopathy (by imaging or physical examination), 13 had axillary assessment by physical examination throughout treatment, with 12 (92%) exhibiting a cCR in the axilla.
Pathologic response
After four cycles of chemotherapy, an in-breast pCR (the primary endpoint) was demonstrated in 6 of 41 patients (15%). One of these six patients had residual DCIS and is listed separately. All of these patients had nodal pCR, whereas overall, 20 patients (49%) had negative nodes at resection.
The pathology reports of two patients were read as having invasive tumor within lymphatics and lymphovascular invasion (one each) with no measurable disease, with tumor thus sized as Tx. Neither of these patients had involved lymph nodes. Fourteen patients (34%) had MRD in the breast, and 8 of these 14 patients (57%) had residual nodal disease. Nine patients (22%) had T1c tumors (> 1–2 cm), with five of these nine patients (55%) having nodal disease. Seven patients (17%) had T2 tumors (> 2–5 cm) tumors, with five of these seven patients (71%) having nodal disease. These findings are summarized in Table 4. The correlation between in-breast cCR and pCR was 26%.
Biologic features of responders
Of interest, five of the six patients with a pCR had triple-negative tumors. This translates to a 22% pCR rate (5 of 23) in the triple-negative subset, and a pCR rate of 6% (1 of 18) in patients with ER-positive and/ or PR-positive tumors. The remaining patient with a pCR had ER-, PR-, and HER2-positive disease.
One patient had inflammatory breast cancer at diagnosis, and another developed this during the course of chemotherapy; the latter patient was removed from the study for progressive disease. Interestingly, the patient who presented with inflammatory breast cancer was one of the six patients with a pCR. Both of these inflammatory disease patients had triple-negative tumors.
Conversion to breast conservation
Breast conservation was offered to patients if it was deemed appropriate by the treating surgeon. Preoperative imaging was not mandated and thus was not routinely performed. Mastectomy was ultimately performed in 4 of the 6 patients (67%) with pCR and in 22 of the 35 patients (63%) with less than a pCR. Thus, the choice for breast conservation did not correlate well with response to chemotherapy.
Time to disease progression
At a median follow-up of 48 months (range, 7–63), 36 of 41 patients (88%) remained free of disease (range, 19–63 months). Two patients had progressive disease while they were on study treatment and had T3 tumors on resection. Another three patients were found to have progressive disease at 10, 41, and 50 months from study day 1.
Of the nine patients with T1c disease, only one patient (who had positive nodes at resection) had a recurrence (at 41 months). Overall, the patients who had a recurrence had MRD (one patient), T1c (one patient), T2 (one patient), and T3 (the same two patients whose disease progressed while they were on treatment and continued to progress after surgery).
Disease-free and overall survival
Three patients were lost to followup, with point of last contact at 19, 34, and 59 months. Of the 41 evaluable patients, 5 patients developed progressive disease, with 2 of these patients progressing during the study treatment. Disease-free survival at 12, 24, and 36 months was 89%, 89%, and 78%, respectively. Overall survival at these same time points was 95%, 90%, and 76%. None of the patients with a pCR is known to have recurrent disease. Of the six patients achieving pCR, two were lost to follow-up after 34 and 59 months, and four continued diseasefree at 38, 39, 55, and 62 months.
Adverse events
Five patients were removed from the study secondary to toxicities. Grade 3 and 4 toxicity events are summarized in Table 5. Grade 3 toxicities were anemia (4), diarrhea (2), epigastric pain (1), fatigue (2), hand-foot syndrome (1), infection (1), leukopenia (9), pain (5), and peripheral sensory neuropathy (1). Grade 4 toxicities were depression (1) and leukopenia (4). Toxicities (all grades) occurring in ≥ 10% of the 49 treated patients were anemia (76%), leukopenia (70%), fatigue (67%), nausea (59%), alopecia (49%), thrombocytopenia (47%), diarrhea (47%), constipation (37%), pain (35%), vomiting (31%), epigastric pain (27%), nail changes (22%), epiphora (22%), hand-foot syndrome (20%), infection (18%), edema (16%), rash (16%), anorexia (16%), and depression (10%). In the intent-to-treat population, there were nine dose reductions among nine patients, and 19 dose delays among 15 patients.
Discussion
The combination of agents tested thus far in the neoadjuvant setting consistently produce pCR rates far less than 50% in unselected populations. This study was begun prior to the widespread use of personalized medicine. Most prior published trials had utilized anthracycline-based chemotherapy, with response rates generally ranging between 7% and 36%.6,9–26,28–31,41,42
The idea of thymidine phosphorylase upregulation by the combination of capecitabine and docetaxel upon which this study was largely based34–36 has since been disputed.47 The primary endpoint of this trial of a novel platinum- based regimen was a pCR rate of 15%. It is significant that 83% of the pCRs were in triple-negative tumors. A secondary endpoint of MRD was calculated, as this was in the original design of the study, but ultimately was not relevant to the primary endpoint.
Ultimately, pCR is the more relevant point of discussion for the modern era. The 15% pCR rate seen in this phase II study was within range of those achieved in numerous other phase II/III neoadjuvant chemotherapy trials with ≥ 25 patients, ≥ 3 cycles of chemotherapy, and pCR defined as absence of carcinoma in the breast and axilla. To date, no patient in our study with a pCR has been noted to have recurrent disease. However, a recently published French study found a 22% recurrence rate at 11 years in patients with triple-negative breast cancer achieving pCR, highlighting the importance of longer-term follow- up.48.
The inclusion of patients with HER2-positive disease in neoadjuvant studies without HER2-targeted therapy was standard at the time that this study was conducted, but is no longer appropriate. If we were to exclude the eight HER2-positive patients from analysis, then there would be only 34 patients evaluable for response, with a pCR rate of 18%. Buzdar et al33 demonstrated a 65% pCR rate in women with HER2-positive disease treated with neoadjuvant chemotherapy plus trastuzumab. The improvement in pCR with the addition of trastuzumab is supported by other confirmatory trials. Authors of a single-arm trial of dose-dense epirubicin and cyclophosphamide followed by dosedense docetaxel and trastuzumab in a HER2-positive population reported a pCR rate of 57%.49 The randomized NOAH study50 achieved a pCR rate of 23% in 115 patients treated with trastuzumab-based chemotherapy.
It is interesting to note that five of six patients (83%) achieving a pCR in our study had triple-negative tumors. Investigators at the University of Miami presented a retrospective review of locally advanced triple-negative breast cancer treated with docetaxel and a platinum salt, with 61% of patients also receiving AC. The authors reported a pCR rate of 34% overall and 40% for patients receiving AC.51 A pCR rate of 60% was noted in the triplenegative subset of patients in another study evaluating docetaxel, doxorubicin, and cyclophosphamide with or without vinorelbine/capecitabine (GeparTrio Study).52 Further, a pCR rate of 72% was achieved with singleagent cisplatin in a group of 25 women with BRCA1 mutations, suggesting, if confirmed by others, that this largely triple- negative population may be exquisitely sensitive to platinum salts.43 In contrast, in a previous study of cisplatin in BRCA mutation carriers, Garber et al44 reported a pCR rate of 22%, suggesting that further trials are needed specifically in BRCA carriers and in triple-negative tumors to see whether these specific patient subsets preferentially derive benefit from platinum salts in the neoadjuvant setting.
The results of the current study are consistent with others indicating a low likelihood of pCR in patients with ERpositive tumors. In fact, none of our ER-positive patients had a pCR. Neoadjuvant endocrine therapy in postmenopausal women with ER- and/ or PR-positive disease is a reasonable treatment option for selected patients, but endpoints other than pCR have often been used.53,54 It is therefore difficult to directly compare these two strategies. Currently, investigators are comparing the three aromatase inhibitors head to head in the neoadjuvant setting for postmenopausal women with hormone receptor–positive tumors.55
The historic pCR ceiling appears to be rising, albeit slowly. Where targets such as HER2 overexpression and triple- negative biology are recognized, progress is being made. Patient eligibility criteria for neoadjuvant breast cancer studies at the time of this trial were quite broad, and it is now recognized that specific subsets of breast cancer respond differently to different classes of agents. Furthermore, our knowledge about breast cancer prognostic markers continues to expand. Had this study been designed in 2011, other data points such as Ki67 would have been collected. A recently published study on neoadjuvant triplenegative breast cancer found that only patients with baseline Ki67% expression > 10% achieved pCR.56
Given the long-term implications of not achieving pCR, optimal treatment of patients in the adjuvant setting is critical. Although neoadjuvantly treated patients with ER-positive or HER2-positive disease go on to receive adjuvant agents (antihormonal therapy for ER-positive disease and trastuzumab for HER2-positive disease), patients with triple-negative disease lack long-term therapies of proven efficacy. Perhaps, as we edge closer to defining the optimal neoadjuvant agents for each subset of patients, this will be less of a concern. Many earlyphase neoadjuvant studies have been conducted, with promising reports, yet the results of larger, randomized trials continue to frustrate both investigators and clinicians. These deficits in care can only be answered by carefully planned randomized clinical trials.
Acknowledgment: Funding for this study was provided by sanofi-aventis, U.S.
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52. Huober J, von Minckwitz G, Denkert C, et al. Effect of neoadjuvant anthracyclinetaxane- based chemotherapy in different biological breast cancer phenotypes: overall results from the GeparTrio study. Breast Cancer Res Treat 2010;124:133–140.
53. Smith IE, Dowsett M, Ebbs SR, et al. Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: the Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) multicenter double-blind randomized trial. J Clin Oncol 2005;23:5108–5116.
54. Mamounas EP. Facilitating breastconserving surgery and preventing recurrence: aromatase inhibitors in the neoadjuvant and adjuvant settings. Ann Surg Oncol 2008;15:691–703.
55. American College of Surgeons, National Cancer Institute, and Cancer and Leukemia Group B. Exemestane, letrozole, or anastrozole in treating postmenopausal women who are undergoing surgery for stage II or stage III breast cancer. ClinicalTrials.gov NCT00265759. http://clinicaltrials.gov. Accessed May 12, 2011.
56. Keam B, Im SA, Lee KH, et al. Ki67 can be used for further classification of triple negative breast cancer into two subtypes with different response and prognosis. Breast Cancer Res 2011 March 2;13(2):R22 (Epub ahead of print).
ABOUT THE AUTHORS
Aruna Mani, MD; Sandra X. Franco, MD; Grace Wang, MD: Neil Abramson, MD; Lee S. Schwartzberg, MD: James Jakub, MD; Elizabeth Tan-Chiu, MD: Alisha Stein, RNC, BSN, OCN; Alejandra T. Perez, MD; and Charles L Vogel, MD.
Affiliations: Dr. Mani is a breast medical oncologist at Memorial Cancer Institute, Pembroke Pines, FL. Dr. Franco is now Chief of Oncology at the Oncology Center, Clinica del Country, Bogota, Colombia. Dr. Wang is an oncologist at Advanced Medical Specialties, Miami, FL. Dr. Abramson is Clinical Professor of Medicine and Emeritus Director of Education and Research at Baptist Cancer Institute, University of Florida, Jacksonville, FL. Dr. Schwartzberg is Medical Director of The West Clinic, Memphis, TN. Dr. Jakub is now Assistant Professor of Surgery, Division of Gastroenterology and General Surgery, Mayo Clinic, Rochester, MN. Dr. Tan-Chiu is Medical Director of Florida Cancer Care, Davie, FL. Dr. Schwartz is Principal Investigator at Mount Sinai Medical Center, Miami Beach, FL. Ms. Frankel is Director of Oncology Clinical Research and Development at Memorial Cancer Institute, Hollywood, FL. Dr. Krill-Jackson is an oncologist at Mount Sinai Comprehensive Cancer Center, Miami, FL. Ms. Stein is now Oncology Clinical Coordinator at Genentech Inc., Fort Lauderdale, FL. Dr. Perez is Director of the Breast Cancer Center at Memorial Cancer Institute, Hollywood, FL. Dr. Vogel is Professor of Clinical Medicine and Director of the Women’s Center, Sylvester Comprehensive Cancer Center, Deerfield Beach, FL.
Conflicts of interest: Dr. Vogel has served as an advisor and is a member of the speakers’ bureaus of sanofi-aventis U.S. and Roche, as well as many other companies whose products were not part of the current study plan. The other authors have no pertinent conflicts of interest to disclose.
The standard of care for locally advanced breast cancer (LABC) is neoadjuvant chemotherapy,1 with LABC including clinical stages IIA, IIB, and IIIA. The goals of preoperative chemotherapy are to downstage so as to render breast conservation feasible, to eradicate disease in the axillary nodes, and to allow in vivo testing of tumor drug sensitivity, all with the ultimate aim of improving prognosis. Clinical trials have demonstrated that the pathologic in-breast response generally correlates with pathologic response in the lymph nodes. Furthermore, nodal status at the time of surgery correlates with overall survival (OS) and disease-free survival (DFS).2,3 A combined analysis of two large prospective neoadjuvant chemotherapy trials demonstrated significantly higher 5-year OS and DFS in patients achieving in-breast pathologic complete response (pCR), compared with those who did not (OS, 89% vs 64%; DFS, 87% vs 58%, respectively).4
At the start of this trial, the most effective neoad- juvant regimen remained in question. Even now, National Comprehensive Cancer Center guidelines suggest that any recommended adjuvant regimen can be used in the neoadjuvant setting.1 Numerous phase II and III trials have evaluated single-agent5–8 and combination9– 32 chemotherapies, most of which are anthracycline- based, with pCR rates reported between 7% and 36%. In the NSABP-B27 study, patients treated preoperatively with four cycles of doxorubicin and cyclophosphamide (AC) followed by four cycles of docetaxel (Taxotere) had a 26% pCR rate versus a 13% pCR rate in those receiving preoperative AC and postoperative docetaxel. Despite the doubling of pCR with neoadjuvant docetaxel, there was no difference in DFS or OS.9 However, as reported by Kuerer et al, patients achieving a pCR after completion of neoadjuvant chemotherapy appeared to have superior survival.4
Many previous trials (including the study reported here) did not exclude patients with human epidermal growth factor receptor 2 (HER2)-positive disease. It is now well established that such patients should be treated with neoadjuvant regimens incorporating HER2-targeted therapy. In fact, an early neoadjuvant study of paclitaxel followed by fluorouracil, epirubicin, and cyclophosphamide with or without 24 weeks of concurrent trastuzumab (Herceptin) in patients with HER2-positive tumors was closed early because patients receiving trastuzumab had a pCR rate of 65%, compared with 26% in those who did not receive it.33 Expanded clinical trials of this approach are in progress.
The selection of capecitabine (Xeloda) and docetaxel in the present trial was based on the hypothesis that the upregulation of thymidine phosphorylase by docetaxel should increase the activity of capecitabine. 34–36 Single-agent docetaxel in the neoadjuvant setting has yielded pCR rates of 7%–20%.6–8 Treatment with docetaxel and capecitabine together has been reported to produce pCR rates of 10%–21%.37–39 The addition of carboplatin was based on studies by Hurley et al at the University of Miami39– 41 suggesting that platinum salts appeared quite active in the neoadjuvant setting, with the combination of docetaxel and cisplatin producing a pCR rate of 20%, with no residual disease in the breast or axilla.40 Other regimens incorporating cisplatin or carboplatin have pCR rates ranging from 16% to 24%.27,42–44
Patients and methods
Study design
In this phase II multicenter study, patients were assigned to receive docetaxel (30 mg/m2 IV) and carboplatin (AUC 2 IV) on days 1, 8, and 15 of each 28-day cycle plus capecitabine (625 mg/m2 PO) twice daily on days 5–18. The capecitabine dose was based on observations that this dose was effective and relatively nontoxic in metastatic breast cancer (C.L. Vogel, empirical observations). Patients were to receive four cycles prior to surgical resection.
Given that this neoadjuvant regimen was under study, all of the patients were scheduled to receive a proven standard postoperative adjuvant chemotherapy regimen, starting 4–6 weeks postoperatively, with doxorubicin (60 mg/m2 IV) and cyclophosphamide (600 mg/m2 IV) every 21 days for 4 cycles. This sequential design was prompted by studies such as the NSABP B-27 and Aberdeen trials.9,32
Radiation therapy after lumpectomy or mastectomy was given according to individual institution guidelines. Patients with hormone receptor–positive tumors received appropriate antihormonal therapy. Tumor measurements were assessed at baseline and on day 1 of each cycle by physical examination with calipers. No breast or other imaging was required during the period of neoadjuvant chemotherapy or immediately preoperatively. Patients were considered evaluable if they proceeded to surgery after all intended cycles of neoadjuvant chemotherapy or if they developed disease progression during neoadjuvant therapy.
Patients
Eligible patients were men and women regardless of menopausal status ≥ 18 years of age with coreneedle biopsy proven locally advanced or inflammatory breast cancer. Breast cancer characteristics such as estrogen receptor (ER), progesterone receptor (PR), or HER2 status were collected but not used for inclusion/exclusion. Eligible tumors were T2 requiring mastectomy; T3N0–2; T4; and any TN2–3 that by calipers was > 2 cm or with fixed or matted axillary or imaging-detected internal mammary nodes. Patients with prior ductal carcinoma in situ (DCIS) were included, as were those with ≤ T2N0M0 breast cancer > 5 years prior.
Other requirements were an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1; life expectancy > 6 months; negative metastatic workup (bone scan and CT chest/abdomen/pelvis); adequate bone marrow, liver, and kidney function; and peripheral neuropathy ≤ grade 1. All patients of child-bearing potential were required to consent to dual methods of contraception during treatment and for 3 months afterward. A negative pregnancy test was required for these women before treatment, and any suspicion of pregnancy had to be reported to the treating physician.
Study endpoints
The primary endpoint of the study was the in-breast pCR after four cycles of platinum-based neoadjuvant chemotherapy. Pathologic complete response was defined as complete disappearance of invasive and in situ disease or invasive disease alone. During the course of this trial, it became generally acceptable to include patients with only residual DCIS as equivalent to pCR.45
The secondary endpoints were pCR in the lymph nodes; clinical response rate; tolerability; breast conservation; time to disease progression (local, regional, and distant); and OS. Also recorded was minimal residual disease (MRD), which we arbitrarily defined as ≤ 1 cm invasive carcinoma at resection. The overall treatment plan included postoperative AC to provide a standard-of-care regimen to maximize curative potential.
Statistical analysis
Data were analyzed on an intentto- treat basis. Although pCR rates with doxorubicin plus either cyclophosphamide or docetaxel have been < 15%, the studies by Smith et al26 and Hurley et al39 with in-breast pCR rates of at least 20% served as comparators (albeit imprecise).
Applying the min/max statistical design, the procedure tests the null hypothesis H0: P ≤ 0.15 against the alternative hypothesis H1: P ≥ 0.30. The overall level of significance and power for this design are 5% and 80%, respectively. The sample size needed for the first stage was 23 evaluable patients. If three or fewer pCR responses were observed, then the study would be terminated and the treatment regimen would not be investigated further. Otherwise, an additional 25 evaluable patients would be accrued for a total of 48 study patients. If 11 or fewer responses were observed, then the study would be terminated. Otherwise, this treatment regimen would be recommended to proceed to phase III for further investigation.
Tolerability assessment
At each visit, toxicities were assessed and graded according to the National Cancer Institute Common Toxicity Criteria, version 2.46 Two dose reductions were allowed for all drugs.
Ethical considerations
The investigational nature of this study was fully disclosed to each patient. In accordance with institutional and federal guidelines, the patients were guided through and subsequently signed the informed consent approved by the appropriate site Institutional Review Board.
Literature review
The terms “neoadjuvant” and “breast” were used in a literature search on PubMed, with filters “English” and “clinical trials.” Abstracts for each of the 398 results were reviewed We used phase II or III trials with at least 30 patients, at least four cycles of chemotherapy, and clearly defined pCR for comparison to this study.
Results Patients
Between June 2003 and December 2006, 50 women with a median age of 49 years (range, 28–75 years) were enrolled. One patient was ineligible due to preceding lumpectomy. The 49 eligible patients were treated with ≥ 1 cycle of neoadjuvant chemotherapy between June 27, 2003, and April 12, 2007.
The baseline characteristics of the 49 eligible patients are summarized in Table 3. Thirty-one patients (63%) were premenopausal. Twenty patients (41%) were positive for either ER or PR and were negative for HER2. Eight patients (16%) had HER2- positive tumors, and 23 (46%) had triple-negative tumors. At baseline, 22 patients (45%) had clinical lymphadenopathy, and 1 patient (2%) had inflammatory breast cancer.
The 41 patients (83%) who completed all four cycles of therapy were evaluable for response; 8 (16%) were inevaluable due to noncompliance (1), grade 3 or 4 toxicity (5), or withdrawal of consent (2). The following efficacy assessments apply to the 41 evaluable patients, whereas the toxicity assessments include the 49 patients who received at least one full cycle of chemotherapy.
Clinical response
At study onset, of the 49 eligible patients, 38 (78%) had a palpable inbreast tumor (median size, 5.5 cm); 22 (45%) had enlarged nodes, and 34 (69%) had confirmed nodal involvement (by biopsy or imaging). A clinical complete response (cCR) rate in the breast was seen in 23 of 41 (56%) evaluable patients. Of 22 patients with baseline lymphadenopathy (by imaging or physical examination), 13 had axillary assessment by physical examination throughout treatment, with 12 (92%) exhibiting a cCR in the axilla.
Pathologic response
After four cycles of chemotherapy, an in-breast pCR (the primary endpoint) was demonstrated in 6 of 41 patients (15%). One of these six patients had residual DCIS and is listed separately. All of these patients had nodal pCR, whereas overall, 20 patients (49%) had negative nodes at resection.
The pathology reports of two patients were read as having invasive tumor within lymphatics and lymphovascular invasion (one each) with no measurable disease, with tumor thus sized as Tx. Neither of these patients had involved lymph nodes. Fourteen patients (34%) had MRD in the breast, and 8 of these 14 patients (57%) had residual nodal disease. Nine patients (22%) had T1c tumors (> 1–2 cm), with five of these nine patients (55%) having nodal disease. Seven patients (17%) had T2 tumors (> 2–5 cm) tumors, with five of these seven patients (71%) having nodal disease. These findings are summarized in Table 4. The correlation between in-breast cCR and pCR was 26%.
Biologic features of responders
Of interest, five of the six patients with a pCR had triple-negative tumors. This translates to a 22% pCR rate (5 of 23) in the triple-negative subset, and a pCR rate of 6% (1 of 18) in patients with ER-positive and/ or PR-positive tumors. The remaining patient with a pCR had ER-, PR-, and HER2-positive disease.
One patient had inflammatory breast cancer at diagnosis, and another developed this during the course of chemotherapy; the latter patient was removed from the study for progressive disease. Interestingly, the patient who presented with inflammatory breast cancer was one of the six patients with a pCR. Both of these inflammatory disease patients had triple-negative tumors.
Conversion to breast conservation
Breast conservation was offered to patients if it was deemed appropriate by the treating surgeon. Preoperative imaging was not mandated and thus was not routinely performed. Mastectomy was ultimately performed in 4 of the 6 patients (67%) with pCR and in 22 of the 35 patients (63%) with less than a pCR. Thus, the choice for breast conservation did not correlate well with response to chemotherapy.
Time to disease progression
At a median follow-up of 48 months (range, 7–63), 36 of 41 patients (88%) remained free of disease (range, 19–63 months). Two patients had progressive disease while they were on study treatment and had T3 tumors on resection. Another three patients were found to have progressive disease at 10, 41, and 50 months from study day 1.
Of the nine patients with T1c disease, only one patient (who had positive nodes at resection) had a recurrence (at 41 months). Overall, the patients who had a recurrence had MRD (one patient), T1c (one patient), T2 (one patient), and T3 (the same two patients whose disease progressed while they were on treatment and continued to progress after surgery).
Disease-free and overall survival
Three patients were lost to followup, with point of last contact at 19, 34, and 59 months. Of the 41 evaluable patients, 5 patients developed progressive disease, with 2 of these patients progressing during the study treatment. Disease-free survival at 12, 24, and 36 months was 89%, 89%, and 78%, respectively. Overall survival at these same time points was 95%, 90%, and 76%. None of the patients with a pCR is known to have recurrent disease. Of the six patients achieving pCR, two were lost to follow-up after 34 and 59 months, and four continued diseasefree at 38, 39, 55, and 62 months.
Adverse events
Five patients were removed from the study secondary to toxicities. Grade 3 and 4 toxicity events are summarized in Table 5. Grade 3 toxicities were anemia (4), diarrhea (2), epigastric pain (1), fatigue (2), hand-foot syndrome (1), infection (1), leukopenia (9), pain (5), and peripheral sensory neuropathy (1). Grade 4 toxicities were depression (1) and leukopenia (4). Toxicities (all grades) occurring in ≥ 10% of the 49 treated patients were anemia (76%), leukopenia (70%), fatigue (67%), nausea (59%), alopecia (49%), thrombocytopenia (47%), diarrhea (47%), constipation (37%), pain (35%), vomiting (31%), epigastric pain (27%), nail changes (22%), epiphora (22%), hand-foot syndrome (20%), infection (18%), edema (16%), rash (16%), anorexia (16%), and depression (10%). In the intent-to-treat population, there were nine dose reductions among nine patients, and 19 dose delays among 15 patients.
Discussion
The combination of agents tested thus far in the neoadjuvant setting consistently produce pCR rates far less than 50% in unselected populations. This study was begun prior to the widespread use of personalized medicine. Most prior published trials had utilized anthracycline-based chemotherapy, with response rates generally ranging between 7% and 36%.6,9–26,28–31,41,42
The idea of thymidine phosphorylase upregulation by the combination of capecitabine and docetaxel upon which this study was largely based34–36 has since been disputed.47 The primary endpoint of this trial of a novel platinum- based regimen was a pCR rate of 15%. It is significant that 83% of the pCRs were in triple-negative tumors. A secondary endpoint of MRD was calculated, as this was in the original design of the study, but ultimately was not relevant to the primary endpoint.
Ultimately, pCR is the more relevant point of discussion for the modern era. The 15% pCR rate seen in this phase II study was within range of those achieved in numerous other phase II/III neoadjuvant chemotherapy trials with ≥ 25 patients, ≥ 3 cycles of chemotherapy, and pCR defined as absence of carcinoma in the breast and axilla. To date, no patient in our study with a pCR has been noted to have recurrent disease. However, a recently published French study found a 22% recurrence rate at 11 years in patients with triple-negative breast cancer achieving pCR, highlighting the importance of longer-term follow- up.48.
The inclusion of patients with HER2-positive disease in neoadjuvant studies without HER2-targeted therapy was standard at the time that this study was conducted, but is no longer appropriate. If we were to exclude the eight HER2-positive patients from analysis, then there would be only 34 patients evaluable for response, with a pCR rate of 18%. Buzdar et al33 demonstrated a 65% pCR rate in women with HER2-positive disease treated with neoadjuvant chemotherapy plus trastuzumab. The improvement in pCR with the addition of trastuzumab is supported by other confirmatory trials. Authors of a single-arm trial of dose-dense epirubicin and cyclophosphamide followed by dosedense docetaxel and trastuzumab in a HER2-positive population reported a pCR rate of 57%.49 The randomized NOAH study50 achieved a pCR rate of 23% in 115 patients treated with trastuzumab-based chemotherapy.
It is interesting to note that five of six patients (83%) achieving a pCR in our study had triple-negative tumors. Investigators at the University of Miami presented a retrospective review of locally advanced triple-negative breast cancer treated with docetaxel and a platinum salt, with 61% of patients also receiving AC. The authors reported a pCR rate of 34% overall and 40% for patients receiving AC.51 A pCR rate of 60% was noted in the triplenegative subset of patients in another study evaluating docetaxel, doxorubicin, and cyclophosphamide with or without vinorelbine/capecitabine (GeparTrio Study).52 Further, a pCR rate of 72% was achieved with singleagent cisplatin in a group of 25 women with BRCA1 mutations, suggesting, if confirmed by others, that this largely triple- negative population may be exquisitely sensitive to platinum salts.43 In contrast, in a previous study of cisplatin in BRCA mutation carriers, Garber et al44 reported a pCR rate of 22%, suggesting that further trials are needed specifically in BRCA carriers and in triple-negative tumors to see whether these specific patient subsets preferentially derive benefit from platinum salts in the neoadjuvant setting.
The results of the current study are consistent with others indicating a low likelihood of pCR in patients with ERpositive tumors. In fact, none of our ER-positive patients had a pCR. Neoadjuvant endocrine therapy in postmenopausal women with ER- and/ or PR-positive disease is a reasonable treatment option for selected patients, but endpoints other than pCR have often been used.53,54 It is therefore difficult to directly compare these two strategies. Currently, investigators are comparing the three aromatase inhibitors head to head in the neoadjuvant setting for postmenopausal women with hormone receptor–positive tumors.55
The historic pCR ceiling appears to be rising, albeit slowly. Where targets such as HER2 overexpression and triple- negative biology are recognized, progress is being made. Patient eligibility criteria for neoadjuvant breast cancer studies at the time of this trial were quite broad, and it is now recognized that specific subsets of breast cancer respond differently to different classes of agents. Furthermore, our knowledge about breast cancer prognostic markers continues to expand. Had this study been designed in 2011, other data points such as Ki67 would have been collected. A recently published study on neoadjuvant triplenegative breast cancer found that only patients with baseline Ki67% expression > 10% achieved pCR.56
Given the long-term implications of not achieving pCR, optimal treatment of patients in the adjuvant setting is critical. Although neoadjuvantly treated patients with ER-positive or HER2-positive disease go on to receive adjuvant agents (antihormonal therapy for ER-positive disease and trastuzumab for HER2-positive disease), patients with triple-negative disease lack long-term therapies of proven efficacy. Perhaps, as we edge closer to defining the optimal neoadjuvant agents for each subset of patients, this will be less of a concern. Many earlyphase neoadjuvant studies have been conducted, with promising reports, yet the results of larger, randomized trials continue to frustrate both investigators and clinicians. These deficits in care can only be answered by carefully planned randomized clinical trials.
Acknowledgment: Funding for this study was provided by sanofi-aventis, U.S.
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ABOUT THE AUTHORS
Aruna Mani, MD; Sandra X. Franco, MD; Grace Wang, MD: Neil Abramson, MD; Lee S. Schwartzberg, MD: James Jakub, MD; Elizabeth Tan-Chiu, MD: Alisha Stein, RNC, BSN, OCN; Alejandra T. Perez, MD; and Charles L Vogel, MD.
Affiliations: Dr. Mani is a breast medical oncologist at Memorial Cancer Institute, Pembroke Pines, FL. Dr. Franco is now Chief of Oncology at the Oncology Center, Clinica del Country, Bogota, Colombia. Dr. Wang is an oncologist at Advanced Medical Specialties, Miami, FL. Dr. Abramson is Clinical Professor of Medicine and Emeritus Director of Education and Research at Baptist Cancer Institute, University of Florida, Jacksonville, FL. Dr. Schwartzberg is Medical Director of The West Clinic, Memphis, TN. Dr. Jakub is now Assistant Professor of Surgery, Division of Gastroenterology and General Surgery, Mayo Clinic, Rochester, MN. Dr. Tan-Chiu is Medical Director of Florida Cancer Care, Davie, FL. Dr. Schwartz is Principal Investigator at Mount Sinai Medical Center, Miami Beach, FL. Ms. Frankel is Director of Oncology Clinical Research and Development at Memorial Cancer Institute, Hollywood, FL. Dr. Krill-Jackson is an oncologist at Mount Sinai Comprehensive Cancer Center, Miami, FL. Ms. Stein is now Oncology Clinical Coordinator at Genentech Inc., Fort Lauderdale, FL. Dr. Perez is Director of the Breast Cancer Center at Memorial Cancer Institute, Hollywood, FL. Dr. Vogel is Professor of Clinical Medicine and Director of the Women’s Center, Sylvester Comprehensive Cancer Center, Deerfield Beach, FL.
Conflicts of interest: Dr. Vogel has served as an advisor and is a member of the speakers’ bureaus of sanofi-aventis U.S. and Roche, as well as many other companies whose products were not part of the current study plan. The other authors have no pertinent conflicts of interest to disclose.