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Preoperative Chemotherapy for Operable Breast Cancer Improves Surgical Outcomes in the Community Hospital Setting

Preoperative Chemotherapy for Operable Breast Cancer Improves Surgical Outcomes in the Community... Downloaded from https://academic.oup.com/oncolo/article/16/6/752/6401054 by DeepDyve user on 01 February 2022 The Oncologist Breast Cancer Preoperative Chemotherapy for Operable Breast Cancer Improves Surgical Outcomes in the Community Hospital Setting a,b a b,c d IAN K. KOMENAKA, MICHAEL L. HIBBARD, CHIU-HSIEH HSU, BOO GHEE LOW, e a f JASON A. SALGANICK, MARCIA E. BOUTON, CHANDRA JHA a b Maricopa Medical Center, Department of Surgery, Phoenix, Arizona, USA; Arizona Cancer Center, University of Arizona, Tucson, Arizona, USA; Mel and Enid Zuckerman Arizona College of Public Health, University of Arizona, Tucson, Arizona, USA; Southwest Hematology Oncology, Phoenix, Arizona, USA; e f US Oncology, Arizona Oncology Associates, Phoenix, Arizona, USA; Maricopa Medical Center, Department of Medicine, Phoenix, Arizona, USA Key Words. Preoperative chemotherapy  Surgical outcome  Breast cancer  Disparities  Minority  Underinsured  Margin status  Re-excision Disclosures: Ian K. Komenaka: None; Michael L. Hibbard: None; Chiu-Hsieh Hsu: None; Boo Ghee Low: None; Jason A. Salganick: None; Marcia E. Bouton: None; Chandra Jha: None. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors or independent peer reviewers. ABSTRACT Background. Preoperative chemotherapy (PC) for oper- cal response and 25% had a pathologic complete able breast cancer has demonstrated significant benefits response. For clinical stage T2 and stage T3 tumors, in clinical trials. Many patients are treated in the com- the PC group underwent lumpectomy more often munity setting and some may question the applicability than patients in the adjuvant chemotherapy (AC) of PC outside the university setting. The potential ben- group (78% versus 50%; p  .016 and 60% versus efits of PC in terms of surgical outcomes in a community 29%; p  .015, respectively). The rate of close or pos- practice were examined. itive margins in the PC group was half the rate in the Methods. A retrospective review was performed of AC group (23% versus 46%; p  .04) and this re- stage II and stage IIIA breast cancer patients from Jan- sulted in fewer re-excisions (p  .01). The volume of uary 1, 2002 to July 31, 2009. Surgical outcomes of mar- tissue removed was also smaller in the PC group 3 3 gin status, volume of lumpectomy, rate of lumpectomy, (143.6 cm versus 273.9 cm ; p  .003). and re-excision lumpectomy were evaluated. Conclusions. PC for operable breast cancer can sig- Results. There were 212 patients included. Seventy- nificantly improve surgical outcomes in community- nine percent of patients who underwent PC had a clini- based practice. The Oncologist 2011;16:752–759 INTRODUCTION treated with adjuvant chemotherapy (AC) in the prospec- Patients treated with preoperative chemotherapy (PC) for tive, randomized clinical trials National Surgical Adjuvant operable breast cancer had similar survival benefits to those Breast and Bowel Project (NSABP) B18 and NSABP B27 Correspondence: Ian K. Komenaka, M.D., Hogan Building, 2nd Floor, 2601 E Roosevelt Street, Phoenix, Arizona 85008, USA. Tele- phone: 602-344-5368; Fax: 602-344-1299; e-mail: Komenaka@hotmail.com Received August 10, 2010; accepted for publication Feb- ruary 22, 2011; first published online in The Oncologist Express on May 9, 2011. ©AlphaMed Press 1083-7159/2011/$30.00/0 doi: 10.1634/theoncologist.2010-0268 The Oncologist 2011;16:752–759 www.TheOncologist.com Downloaded from https://academic.oup.com/oncolo/article/16/6/752/6401054 by DeepDyve user on 01 February 2022 Komenaka, Hibbard, Hsu et al. 753 [1–4]. Although there were no differences in survival out- overall survival is the same whether chemotherapy is given comes, there were significant benefits recognized in pa- preoperatively or in the adjuvant setting, the only clinical tients who received PC. First, PC allows an in vivo test of indication for PC is to give a patient with a large cancer the chemosensitivity of the cancer. Tumor response as mea- possibility of conserving her breast. In modern breast can- sured by the postchemotherapy pathologic tumor burden in cer treatment, with better technology allowing physicians the breast and lymph nodes correlates with overall survival to determine more accurately which patients benefit from [3–5]. In addition, in patients who do not respond to the che- chemotherapy, PC can be applied to a more appropriate and motherapeutic regimen, optimization of therapy can be carefully selected patient population [13–22]. achieved by terminating the current regimen and changing We sought to examine the applicability of PC for oper- to a different regimen or different type of treatment [5, 6]. In able breast cancer in the community setting and the poten- patients undergoing AC, this type of adjustment is not pos- tial benefits to surgical outcomes. sible because there is no reliable clinical marker for moni- toring tumor response in the adjuvant setting once the METHODS primary tumor and lymph nodes have been removed. Maricopa Medical Center is a 679-bed facility that is the Although there is no difference in survival compared county, safety-net hospital in Phoenix, Arizona, and serves with mastectomy, breast-conserving operations are the pre- a patient base that is 34.5% non–English speaking, and the ferred operative management for patients with early-stage majority of the patients treated are underinsured. Underin- breast cancer [7, 8]. In the NSABP B18 and NSABP B27 sured patients were considered to be all patients without studies, PC resulted in a higher rate of breast-conserving commercial insurance. In the state of Arizona, these pa- operations performed and higher rate of pathologically neg- tients are covered by Medicare and the Arizona Health Care ative lymph nodes than in patients who underwent AC [1, Cost Containment System (AHCCCS, Medicaid). Patients 2]. The higher rate of breast-conserving operations was ob- ineligible for AHCCCS were classified as uninsured self- tained without a significantly higher risk for local recur- pay or charity care patients. Institutional review board ap- rence [1–3, 5]. In patients with cancers 3 cm in size, proval was obtained prior to the start of the study. Bonadonna et al. [3] demonstrated a 6.8% risk for local re- A retrospective review was performed of all breast can- currence as a first event at 65 months of follow-up in pa- cer patients treated for their primary breast cancer in Janu- tients who underwent a breast-conserving operation after ary 1, 2002 to July 31, 2009. Only patients who presented PC. Outside the clinical trial setting and away from the with American Joint Committee on Cancer (AJCC) clinical tertiary cancer center, however, surgical intervention re- stage IIA, IIB, or IIIA breast cancer were included in the mains the most common initial treatment for operable study. All patients having their primary operation prior to breast cancer. January 1, 2002 were excluded. Patients presenting with Evaluation of breast cancer operations cannot be limited AJCC clinical stage 0, I, IIIB (T4), or IV cancers were ex- only to assessment of the rate of breast conservation. At- cluded. Other criteria excluded all male patients and all tainment of negative margins is one of the most important patients with a second primary or recurrence who had factors in performing the breast-conserving operation and is their primary breast cancer prior to January 1, 2002. Af- critical to minimizing the risk for local recurrence [9]. The ter exclusions, a total of 212 patients comprised the study goal of attaining a negative margin must be balanced with population. Sociodemographic information, clinical cosmetic outcome. Although removal of a larger volume of characteristics, and surgical outcomes for all patients were tissue may facilitate attainment of negative margins, this re- collected. Patients were offered PC if they satisfied the fol- sults in a poorer cosmetic outcome [10, 11]. For most lowing criteria. First, they had to have been determined to women, breast cancer treatment significantly impacts mul- require chemotherapy as part of their treatment based on tiple facets of their lives and their quality of life [8, 12]. their clinical presentation and diagnostic biopsy results. Therefore, achievement of negative margins by removing Second, they had to be interested in preserving their breast the smallest volume of tissue should be the goal for breast- but the size of the cancer at presentation required a mastec- conserving operations. tomy. Finally, in some patients who were already candi- Perhaps one reason for the lack of use of PC is the ques- dates for breast conservation, PC was offered to allow a tion of its applicability away from the high-volume tertiary smaller, more cosmetically acceptable lumpectomy; if the referral cancer center. Many patients are treated in the com- patient had clinically suspicious lymph nodes (with the munity setting and some physicians may question the ben- hope of avoiding an axillary dissection); or if the patient efits of PC and its applicability in the “nonresearch” patient was interested in personal clinical response to the chemo- care practice. Some practitioners may believe that because therapy. For all patients, the chemotherapeutic regimen was www.TheOncologist.com Downloaded from https://academic.oup.com/oncolo/article/16/6/752/6401054 by DeepDyve user on 01 February 2022 754 Preoperative Chemotherapy for Operable Breast Cancer the choice of the treating oncologist. In the PC group, the dissection was performed at the discretion of the attending regimens included doxorubicin and cyclophosphamide (six surgeon after discussion with the patient. of 57 patients, 11%), doxorubicin and cyclophosphamide followed by paclitaxel (29 of 57 patients, 51%), doxorubi- Statistical Considerations The study population was classified into two groups based cin and cyclophosphamide followed by docetaxel (eight of on whether the patient received PC or was expected to have 57 patients, 14%), docetaxel, doxorubicin, and cyclophos- AC by the treating physician. Differences in sociodemo- phamide (five of 57 patients, 9%), trastuzumab-containing graphic characteristics, clinical measures, and outcomes of regimens (seven of 57 patients, 12%) and other regimens breast cancer care were evaluated in the study population. (two of 57 patients, 4%). For categorical variables, the Fisher’s exact test for inde- pendence was used to determine differences between the Surgical Outcomes two populations. For each continuous variable, for exam- Patients were classified into two groups based on whether ple, age, body mass index, etc., the mean and standard de- they underwent PC (PC group) or AC (AC group). Then, viation were reported. Unpaired (two-sample) t-tests were based on presenting clinical tumor size, the initial operation used to compare means of the two populations. All statisti- performed was reported (mastectomy or breast-conserving cal tests were two-sided and a p-value .05 was considered operation). The preoperative history and physical examina- statistically significant. tion note, operative note, and mammogram report were re- viewed. If a patient had a documented contraindication to RESULTS breast conservation (i.e., multicentric disease, extensive There were 212 patients included in the study period. So- microcalcifications, etc.) and therefore underwent a mas- ciodemographic information is shown in Table 1. Patients tectomy, she was excluded from the analysis. Margin status in the PC group were significantly younger and more likely was evaluated in all patients who underwent a breast-con- to be premenopausal than patients in the AC group. Patients serving operation. Those with microscopic evidence of a in the PC group were more likely to be employed than those transected (tumor touching ink) margin were considered to in the AC group. There was no difference, however, in in- have a positive margin. Those with microscopic evidence surance status between the two groups. Most patients in of a tumor within 1 mm of an inked margin were considered both groups were Hispanic and insured by AHCCCS (Med- to have a close margin. The number of patients who under- icaid) or uninsured. Very few patients in either group had went a re-excision lumpectomy was recorded. The volume undergone a screening mammogram within 2 years of di- of breast tissue removed was determined by the product of agnosis (Table 1). the anterior–posterior, medial–lateral, and inferior–supe- The clinical presentation of patients in the PC group was rior diameters listed on the pathology report. more advanced than that of patients in the AC group. Pa- Pathologic nodal status was the nodal status determined tients in the PC group presented with a larger mean tumor at operation. The sentinel node procedure at our institution size (4.6 cm versus 3.3 cm) and later clinical stage (Table has been described previously [23]. In brief, the sentinel 2). The histopathologic factors were similar with respect to node procedure was performed using the combination tech- predominant histology, histologic grade, estrogen receptor nique of blue dye and radioactive isotope. The radiocolloid status, progesterone receptor status, and rate of triple-neg- injection was performed in the nuclear medicine suite ap- ative disease. There was a high rate of poorly differentiated proximately 1–7 hours prior to the operation in an intrader- tumors in both groups. Patients in the PC group were more mal periareolar fashion. Three milliliters to 5 ml of blue dye likely to have human epidermal growth factor receptor (isosulfan or methylene) was injected in the operating room 2/neu overexpressed by immunohistochemistry or ampli- after anesthesia was administered. The blue dye was in- fied by fluorescence in situ hybridization than patients in jected intraparenchymally in a subareolar fashion. All the AC group. nodes that were identified as blue stained or radioactively PC resulted in a clinical response in 79% (45 of 57) of the hottest, and any node with a radioactive count within patients. Of these, 54% (31 of 57) had a clinical complete 10% of the hottest node were considered sentinel nodes. In response and 25% (14 of 57) had a clinical partial response. addition, any node that was palpably abnormal was consid- The remaining 21% (12 of 57) had either stable disease or ered a sentinel node. A level I and level II axillary dissec- disease progression and were classified as nonresponders. tion was performed if any of the sentinel lymph nodes were Overall 25% (14 of 57) of patients had a pathologic com- involved with cancer. If a micrometastasis (2 mm) was plete response. identified in any of the sentinel nodes, a completion axillary For clinical stage T2 (2–5 cm) breast cancers, patients in Downloaded from https://academic.oup.com/oncolo/article/16/6/752/6401054 by DeepDyve user on 01 February 2022 Komenaka, Hibbard, Hsu et al. 755 Table 1. Sociodemographic information and use of screening mammography for stage IIA, IIB, and IIIA patients Adjuvant chemotherapy Preoperative chemotherapy Characteristic (n  155) (n  57) p-value Mean age (SD) 53.6 (14.46) 44.1 (9.96) .0001 50 yrs 70 (45%) 38 (67%) .008 50 yrs 85 (55%) 19 (33%) Menopausal status .003 Pre-/perimenopausal 67 (43%) 38 (67%) Postmenopausal 88 (57%) 19 (33%) Mean BMI (SD), kg/m 29.3 (7.72) 28.5 (6.22) .48 Race/ethnicity .41 White 54 (35%) 16 (28%) African American 10 (6%) 4 (7%) Hispanic 83 (54%) 35 (61%) Other 8 (5%) 2 (4%) Employment status .0001 Employed 27 (17%) 26 (46%) Unemployed 94 (61%) 27 (47%) Retired/disabled 34 (22%) 4 (7%) Insurance .44 Commercial 2 (1%) 3 (5%) Medicare 32 (21%) 6 (11%) Medicaid 58 (37%) 23 (40%) None 63 (41%) 25 (44%) Screening mammogram in the 2 yrs 14/128 (11%) 2/35 (6%) .52 prior to diagnosis (age, 40 yrs) Current smoker 41 (26%) 11 (19%) .37 Derived from a Fisher’s exact test for categorical variables and a two-sample t-test for continuous variables. Abbreviations: BMI, body mass index; SD, standard deviation. the PC group initially underwent a breast-conserving oper- tients) (p  .04). This resulted in significantly fewer re- ation significantly more often than those in the AC group— excision lumpectomies in the PC group (18%, seven of 38 78% (21 of 27 patients) versus 50% (56 of 111 patients), patients) than in the AC group (41%, 28 of 68 patients) (p respectively (p .016) (Table 3). For clinical stage T3 (5 .01). The volume of tissue removed was also significantly cm) breast cancers, patients in the PC group initially under- smaller in the PC group (143.6 cm ) than in the AC group went a breast-conserving operation more often than those in (273.9 cm )(p  .003). For those who underwent a second the AC group—60% (18 of 30 patients) versus 29% (12 of operation for close or positive margins, more patients un- 41 patients), respectively (p  .01). Some patients in both derwent a mastectomy in the AC group (six patients) than in the AC group and the PC group chose to have a mastectomy the PC group (one patient). The final surgical procedure for despite being considered a candidate for breast conserva- those presenting with clinical stage T2 breast cancers was tion. When these patients were excluded from the analysis, more often a breast-conserving operation in the PC group the results changed little—for stage T2 disease: PC group, (74%, 20 of 27 patients) than in the AC group (45%, 51 of 91% (21 of 23 patients) versus AC group, 58% (56 of 97 114 patients) (p  .006). Similarly, in patients who pre- patients) (p  .003); for stage T3 disease: PC group, 69% sented with clinical stage T3 breast cancers, the final oper- (18 of 26 patients) versus AC group, 32% (12 of 38 pa- ation was a breast-conserving procedure more often in the tients) (p  .005). For those patients who did undergo a PC group (60%, 18 of 30 patients) than in the AC group breast-conserving operation, the rate of close (1 mm) or (27%, 11 of 43 patients) (p  .007). The rate of pathologi- positive margins in the PC group was half the rate in the AC cally positive nodes was lower in patients in the PC group; group—23% (nine of 38 patients) versus 46% (31 of 68 pa- however, this difference was not statistically significant. www.TheOncologist.com Downloaded from https://academic.oup.com/oncolo/article/16/6/752/6401054 by DeepDyve user on 01 February 2022 756 Preoperative Chemotherapy for Operable Breast Cancer Table 2. Clinical and tumor characteristics of stage IIA, IIB, and IIIA patients Adjuvant chemotherapy Preoperative chemotherapy Characteristic (n  155) (n  57) p-value Mean clinical tumor size (SD), cm 3.3 (1.68) 4.6 (1.62) .0001 Tumor stage T2 114 (74%) 27 (47%) .0005 T3 41 (26%) 30 (53%) Clinical stage at presentation .0001 IIA 113 (73%) 20 (35%) IIB 36 (23%) 29 (51%) IIIA 6 (4%) 8 (14%) Predominant histology .80 Ductal 140 (90%) 51 (89%) Lobular 8 (5%) 5 (9%) Other 7 (5%) 1 (2%) Histologic grade .86 Well differentiated 14 (10%) 3 (6%) Moderately differentiated 34 (23%) 13 (25%) Poorly differentiated 98 (67%) 36 (69%) Estrogen receptor .34 Positive 101 (66%) 33 (58%) Negative 53 (34%) 24 (42%) Progesterone receptor .54 Positive 86 (56%) 29 (51%) Negative 68 (44%) 28 (49%) HER-2/neu status (IHC 3 or FISH) .05 Yes 23 (15%) 16 (39%) No 127 (85%) 41 (61%) Triple negative 38/150 (25%) 16/57 (28%) .72 Derived from a Fisher’s exact test for categorical variables and a two-sample t-test for continuous variables. Nine patients in the adjuvant chemotherapy group and five patients in the preoperative chemotherapy group did not have histologic grade assigned either because it was an infiltrating lobular carcinoma or it was not done. One patient in the adjuvant chemotherapy group did not have estrogen receptor or progesterone receptor testing performed. Five patients did not have HER-2/neu testing performed. Hormone receptor and HER-2/neu not expressed/not amplified. Abbreviations: FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; SD, standard deviation. There was no significant difference in the ipsilateral breast Several prospective, randomized clinical trials have tumor recurrence rate between the AC group (one of 62 pa- shown that patients treated with PC have a similar overall tients, 2%) and the PC group (three of 38 patients, 8%) (p survival duration as patients treated with AC [1–3]. Evalu- .15); however, the mean follow-up was relatively short, at ation of breast cancer care, with its long history of patient 37 months. advocacy, however, cannot be evaluated simply by out- comes as limited as overall survival. For most women, DISCUSSION breast cancer treatment significantly impacts multiple fac- PC led to significantly better breast cancer surgical out- ets of their lives and their quality of life [8, 12]. Despite a comes in this community-based practice of underinsured larger clinical tumor size at presentation, patients who un- county hospital patients. Patients who underwent PC had a derwent PC were significantly more likely to undergo a higher rate of breast-conserving operations, a lower rate of breast-conserving operation for both stage T2 and stage T3 close or positive margins, smaller lumpectomies, fewer re- cancers (Table 3). This finding of a higher rate of breast excisions, and a lower rate of histologically positive nodes preservation was similar to the significant benefit demon- despite presentation at a more advanced clinical stage. strated in the NSABP B18 study for stage T2 (71% for PC Downloaded from https://academic.oup.com/oncolo/article/16/6/752/6401054 by DeepDyve user on 01 February 2022 Komenaka, Hibbard, Hsu et al. 757 Table 3. Surgical outcomes of stage IIA, IIB, and IIIA patients Adjuvant chemotherapy Preoperative chemotherapy Outcome (n  155) (n  57) p-value Initial operation for stage T2 .016 Breast conservation 56 (50%) 21 (78%) Mastectomy 55 (50%) 6 (22%) Initial operation for stage T2 .003 Breast conservation 56 (58%) 21 (91%) Mastectomy 41 (42%) 2 (9%) Initial operation for stage T3 .015 Breast conservation 12 (29%) 18 (60%) Mastectomy 29 (71%) 12 (40%) Initial operation for stage T3 .005 Breast conservation 12 (32%) 18 (69%) Mastectomy 26 (68%) 8 (31%) Lumpectomy margins .04 Positive/close (1 mm) 31/68 (46%) 9/38 (23%) Re-excision lumpectomy 28/68 (41%) 7/38 (18%) .01 Breast conservation .003 Volume of specimen, cm 273.9 143.6 Final operation for stage T2 .006 Breast conservation 51 (45%) 20 (74%) Mastectomy 63 (55%) 7 (26%) Final operation for stage T3 .007 Breast conservation 11 (27%) 18 (60%) Mastectomy 30 (73%) 12 (40%) Clinical stage II IDC .46 Pathologic node positive 44/110 (40%) 6/20 (30%) Clinical stage IIB/III IDC .35 Pathologic node positive 25/39 (64%) 19/37(51%) Derived from a Fisher’s exact test for categorical variables and a two-sample t-test for continuous variables. Excluding patients who elected mastectomy over breast conservation. Abbreviation: IDC, infiltrating ductal carcinoma. versus 63% for AC) and stage T3 (22% for PC versus 8% Evaluation of the breast-conserving operation cannot be for AC) cancers [24]. Although the 22% rate of breast con- limited only to its rate of performance because there are servation appears low, more recent and subsequent data other factors that determine the success of the surgical pro- have found higher rates of breast conservation for patients cedure. Margin status is perhaps the most important imme- with stage T3 tumors after PC. The prospective study re- diate outcome of breast-conserving operations because ported by Bonadonna et al. [3] showed rates of breast con- inadequate margins are one of the strongest predictors of lo- servation of 89% for stage T2 tumors and 62% for stage T3 cal failure [9]. The achievement of negative margins is also tumors. Boughey et al. [6] found that, in patients with stage of importance because a higher number of operations to ob- T2 and stage T3 tumors, those who underwent PC in pro- tain negative margins results in a greater volume of tissue spective randomized trials at MD Anderson Cancer Center excised and a poorer cosmetic result [9, 10, 26, 27]. In some experienced a nonsignificantly higher lumpectomy rate series, the re-excision rate to obtain negative margins can (44% versus 33%) than patients who underwent AC. be as high as 69% [28]. In the current study, patients in the Christy et al. [25] found a statistically significant higher AC group had a rate of close (1 mm) or positive margins breast-conserving operation rate (64% versus 45%; p  double that of those who underwent PC (46% versus 23%; .05) in patients with stage T2 cancers. p .04) (Table 3). This resulted in a statistically significant www.TheOncologist.com Downloaded from https://academic.oup.com/oncolo/article/16/6/752/6401054 by DeepDyve user on 01 February 2022 758 Preoperative Chemotherapy for Operable Breast Cancer higher rate of re-excision lumpectomy in the AC group than node dissection vary greatly, data from the largest pub- in the PC group (41% versus 18%; p .01). In patients who lished prospective, randomized clinical trial to date com- underwent a second operation because of involved margins, paring axillary lymph node dissection with sentinel node more patients underwent a mastectomy in the AC group biopsy, reported by Veronesi et al. [33], demonstrated that than in the PC group (Table 3). Similarly, data from the 91% and 85% of patients experienced pain and numbness, University of Michigan showed that the re-excision rate in respectively, for 6 months after an axillary dissection. That patients who underwent PC was almost half that of those was compared with only 16% and 2% in the sentinel node who did not undergo PC (59% versus 31%; p 0.001) [29]. group. This difference in morbidity should not be underes- Data from Yale University [25] for stage T2 cancers also timated because 6 months is a long time to suffer through an showed a statistically significant lower rate of positive mar- iatrogenic problem. gins (32% versus 10%; p  .01) and need for re-excision This study has several limitations. Retrospective studies lumpectomy (37% versus 6%; p  .01). In the current are subject to inherent limitations and biases. Data from study, the significantly better margin status and lumpec- prospective studies involving minority patients, however, tomy rate cannot be explained by a larger lumpectomy are very difficult to obtain even in a disease as common as specimen volume in the PC group because the volume of breast cancer. Most patients who participate in clinical tri- the lumpectomy specimens in the PC group was nearly half als are non-Hispanic whites and insured, making prospec- 3 3 that of the AC group (143 cm versus 273 cm ; p  .003). tive study of the racial/ethnic minority and underinsured Therefore, not only did the PC group have a lower rate of populations extremely difficult. This study was relatively close and positive margins, those patients also had sig- small and performed at one institution with one patient pop- nificantly less tissue removed in breast-conserving oper- ulation. The small size of the study, however, demonstrates ations. The lower lumpectomy volume in those undergoing that the benefits of PC can apply even to a low-volume com- PC was also demonstrated in a combined analysis of pro- munity-based practice. The applicability to other patient spective, randomized data from the MD Anderson Cancer populations, however, does need to be considered. Finally, Center. A similar statistically significant lower resected follow-up was limited in this study and continued evalua- 3 3 volume was found (113 cm versus 213 cm ; p  .004), tion of patients will be necessary to determine whether with no difference in local recurrence at 33 months of fol- these better surgical outcomes will translate into better low-up [6]. These findings of a smaller lumpectomy vol- long-term outcomes. ume in the PC groups alleviate concerns about diffuse Breast cancer is a heterogeneous disease and patient residual tumor burden dispersed throughout the original tu- populations are equally diverse. In certain populations, al- mor volume. though overall survival is similar in patients undergoing AC The benefits in the PC group were also seen in the lymph and PC, patients undergoing PC may experience benefits in node status. Proportionally, 25% fewer patients who pre- terms of surgical outcomes over the same treatment given in sented with clinical stage IIA disease and 20% fewer stage the adjuvant setting. The surgical benefits of PC demon- IIB/IIIA patients were node positive in the PC group. Data strated in prospective, randomized studies and at large ter- from the NSABP B18 study demonstrated that PC resulted tiary cancer centers can be realized even in a lower volume in a 30%–40% lower rate of lymph node positivity. When community-based practice. the results of the NSABP B18 trial were reported in 1997, the difference in lymph node status affected the postchemo- ACKNOWLEDGMENT therapy stage of the patients [1]. In 2010, however, addi- Chandra Jha is deceased; we appreciate his unending com- tional benefits could be realized. PC was initially mitment to patient care and his significant contributions to considered a contraindication to the sentinel node proce- this manuscript. dure. Subsequent data from the NSABP B27 study reported by Mamounas et al. [30] as well as data from a meta-anal- ysis [31] demonstrated that the sentinel node procedure is as AUTHOR CONTRIBUTIONS accurate after PC as it is without prior chemotherapy. These Conception/Design: Ian K. Komenaka, Michael Hibbard, Chandra Jha, Boo Ghee Low data have resulted in national guidelines stating the accept- Provision of study material or patients: Ian K. Komenaka, Chandra Jha, Boo Ghee Low, Jason Salganick, Marcia Bouton ability of the sentinel node procedure after PC [32]. There- Collection and/or assembly of data: Ian K. Komenaka, Chiu-Hsieh Hsu, fore, because a significant proportion of patients can have Marcia Bouton Data analysis and interpretation: Chiu-Hsieh Hsu their lymph nodes downstaged, PC could save many pa- Manuscript writing: Ian K. Komenaka, Michael Hibbard, Chiu-Hsieh Hsu, Boo Ghee Low, Jason Salganick, Marcia Bouton tients the morbidity of an axillary lymph node dissection. Final approval of manuscript: Ian K. Komenaka, Michael Hibbard, Chandra Although reported morbidity rates related to axillary lymph Jha, Chiu-Hsieh Hsu, Boo Ghee Low, Jason Salganick, Marcia Bouton Downloaded from https://academic.oup.com/oncolo/article/16/6/752/6401054 by DeepDyve user on 01 February 2022 Komenaka, Hibbard, Hsu et al. 759 therapeutic response of the basal-like breast cancer to neoadjuvant chemo- REFERENCES therapy. Breast Cancer Res Treat 2010;123:691–699. 1 Fisher B, Brown A, Mamounas E et al. Effect of preoperative chemother- 17 Hugh J, Hanson J, Cheang MC et al. Breast cancer subtypes and response to apy on local-regional disease in women with operable breast cancer: Find- docetaxel in node-positive breast cancer: Use of an immunohistochemical ings from National Surgical Adjuvant Breast and Bowel Project B-18. definition in the BCIRG 001 trial. J Clin Oncol 2009;27:1168–1176. J Clin Oncol 1997;15:2483–2493. 18 Romond EH, Perez EA, Bryant J et al. 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Meta-analysis of sentinel lymph node biopsy positive breast cancer on chemotherapy: A retrospective analysis of a ran- after preoperative chemotherapy in patients with breast cancer. Br J Surg domised trial. Lancet Oncol 2010;11:55–65. 2006;93:539–546. 14 Paik S, Tang G, Shak S et al. Gene expression and benefit of chemotherapy 32 Buchholz TA, Lehman CD, Harris JR et al. Statement of the science con- in women with node-negative, estrogen receptor-positive breast cancer. cerning locoregional treatments after preoperative chemotherapy for breast J Clin Oncol 2006;24:3726–3734. cancer: A National Cancer Institute conference. J Clin Oncol 2008;26:791– 15 Straver ME, Glas AM, Hannemann J et al. The 70-gene signature as a re- sponse predictor for neoadjuvant chemotherapy in breast cancer. Breast 33 Veronesi U, Paganelli G, Viale G et al. A randomized comparison of sen- Cancer Res Treat 2010;119:551–558. tinel-node biopsy with routine axillary dissection in breast cancer. N Engl 16 Lin Y, Lin S, Watson M et al. A gene expression signature that predicts the J Med 2003;349:546–553. www.TheOncologist.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Oncologist Oxford University Press

Preoperative Chemotherapy for Operable Breast Cancer Improves Surgical Outcomes in the Community Hospital Setting

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10.1634/theoncologist.2010-0268
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Downloaded from https://academic.oup.com/oncolo/article/16/6/752/6401054 by DeepDyve user on 01 February 2022 The Oncologist Breast Cancer Preoperative Chemotherapy for Operable Breast Cancer Improves Surgical Outcomes in the Community Hospital Setting a,b a b,c d IAN K. KOMENAKA, MICHAEL L. HIBBARD, CHIU-HSIEH HSU, BOO GHEE LOW, e a f JASON A. SALGANICK, MARCIA E. BOUTON, CHANDRA JHA a b Maricopa Medical Center, Department of Surgery, Phoenix, Arizona, USA; Arizona Cancer Center, University of Arizona, Tucson, Arizona, USA; Mel and Enid Zuckerman Arizona College of Public Health, University of Arizona, Tucson, Arizona, USA; Southwest Hematology Oncology, Phoenix, Arizona, USA; e f US Oncology, Arizona Oncology Associates, Phoenix, Arizona, USA; Maricopa Medical Center, Department of Medicine, Phoenix, Arizona, USA Key Words. Preoperative chemotherapy  Surgical outcome  Breast cancer  Disparities  Minority  Underinsured  Margin status  Re-excision Disclosures: Ian K. Komenaka: None; Michael L. Hibbard: None; Chiu-Hsieh Hsu: None; Boo Ghee Low: None; Jason A. Salganick: None; Marcia E. Bouton: None; Chandra Jha: None. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors or independent peer reviewers. ABSTRACT Background. Preoperative chemotherapy (PC) for oper- cal response and 25% had a pathologic complete able breast cancer has demonstrated significant benefits response. For clinical stage T2 and stage T3 tumors, in clinical trials. Many patients are treated in the com- the PC group underwent lumpectomy more often munity setting and some may question the applicability than patients in the adjuvant chemotherapy (AC) of PC outside the university setting. The potential ben- group (78% versus 50%; p  .016 and 60% versus efits of PC in terms of surgical outcomes in a community 29%; p  .015, respectively). The rate of close or pos- practice were examined. itive margins in the PC group was half the rate in the Methods. A retrospective review was performed of AC group (23% versus 46%; p  .04) and this re- stage II and stage IIIA breast cancer patients from Jan- sulted in fewer re-excisions (p  .01). The volume of uary 1, 2002 to July 31, 2009. Surgical outcomes of mar- tissue removed was also smaller in the PC group 3 3 gin status, volume of lumpectomy, rate of lumpectomy, (143.6 cm versus 273.9 cm ; p  .003). and re-excision lumpectomy were evaluated. Conclusions. PC for operable breast cancer can sig- Results. There were 212 patients included. Seventy- nificantly improve surgical outcomes in community- nine percent of patients who underwent PC had a clini- based practice. The Oncologist 2011;16:752–759 INTRODUCTION treated with adjuvant chemotherapy (AC) in the prospec- Patients treated with preoperative chemotherapy (PC) for tive, randomized clinical trials National Surgical Adjuvant operable breast cancer had similar survival benefits to those Breast and Bowel Project (NSABP) B18 and NSABP B27 Correspondence: Ian K. Komenaka, M.D., Hogan Building, 2nd Floor, 2601 E Roosevelt Street, Phoenix, Arizona 85008, USA. Tele- phone: 602-344-5368; Fax: 602-344-1299; e-mail: Komenaka@hotmail.com Received August 10, 2010; accepted for publication Feb- ruary 22, 2011; first published online in The Oncologist Express on May 9, 2011. ©AlphaMed Press 1083-7159/2011/$30.00/0 doi: 10.1634/theoncologist.2010-0268 The Oncologist 2011;16:752–759 www.TheOncologist.com Downloaded from https://academic.oup.com/oncolo/article/16/6/752/6401054 by DeepDyve user on 01 February 2022 Komenaka, Hibbard, Hsu et al. 753 [1–4]. Although there were no differences in survival out- overall survival is the same whether chemotherapy is given comes, there were significant benefits recognized in pa- preoperatively or in the adjuvant setting, the only clinical tients who received PC. First, PC allows an in vivo test of indication for PC is to give a patient with a large cancer the chemosensitivity of the cancer. Tumor response as mea- possibility of conserving her breast. In modern breast can- sured by the postchemotherapy pathologic tumor burden in cer treatment, with better technology allowing physicians the breast and lymph nodes correlates with overall survival to determine more accurately which patients benefit from [3–5]. In addition, in patients who do not respond to the che- chemotherapy, PC can be applied to a more appropriate and motherapeutic regimen, optimization of therapy can be carefully selected patient population [13–22]. achieved by terminating the current regimen and changing We sought to examine the applicability of PC for oper- to a different regimen or different type of treatment [5, 6]. In able breast cancer in the community setting and the poten- patients undergoing AC, this type of adjustment is not pos- tial benefits to surgical outcomes. sible because there is no reliable clinical marker for moni- toring tumor response in the adjuvant setting once the METHODS primary tumor and lymph nodes have been removed. Maricopa Medical Center is a 679-bed facility that is the Although there is no difference in survival compared county, safety-net hospital in Phoenix, Arizona, and serves with mastectomy, breast-conserving operations are the pre- a patient base that is 34.5% non–English speaking, and the ferred operative management for patients with early-stage majority of the patients treated are underinsured. Underin- breast cancer [7, 8]. In the NSABP B18 and NSABP B27 sured patients were considered to be all patients without studies, PC resulted in a higher rate of breast-conserving commercial insurance. In the state of Arizona, these pa- operations performed and higher rate of pathologically neg- tients are covered by Medicare and the Arizona Health Care ative lymph nodes than in patients who underwent AC [1, Cost Containment System (AHCCCS, Medicaid). Patients 2]. The higher rate of breast-conserving operations was ob- ineligible for AHCCCS were classified as uninsured self- tained without a significantly higher risk for local recur- pay or charity care patients. Institutional review board ap- rence [1–3, 5]. In patients with cancers 3 cm in size, proval was obtained prior to the start of the study. Bonadonna et al. [3] demonstrated a 6.8% risk for local re- A retrospective review was performed of all breast can- currence as a first event at 65 months of follow-up in pa- cer patients treated for their primary breast cancer in Janu- tients who underwent a breast-conserving operation after ary 1, 2002 to July 31, 2009. Only patients who presented PC. Outside the clinical trial setting and away from the with American Joint Committee on Cancer (AJCC) clinical tertiary cancer center, however, surgical intervention re- stage IIA, IIB, or IIIA breast cancer were included in the mains the most common initial treatment for operable study. All patients having their primary operation prior to breast cancer. January 1, 2002 were excluded. Patients presenting with Evaluation of breast cancer operations cannot be limited AJCC clinical stage 0, I, IIIB (T4), or IV cancers were ex- only to assessment of the rate of breast conservation. At- cluded. Other criteria excluded all male patients and all tainment of negative margins is one of the most important patients with a second primary or recurrence who had factors in performing the breast-conserving operation and is their primary breast cancer prior to January 1, 2002. Af- critical to minimizing the risk for local recurrence [9]. The ter exclusions, a total of 212 patients comprised the study goal of attaining a negative margin must be balanced with population. Sociodemographic information, clinical cosmetic outcome. Although removal of a larger volume of characteristics, and surgical outcomes for all patients were tissue may facilitate attainment of negative margins, this re- collected. Patients were offered PC if they satisfied the fol- sults in a poorer cosmetic outcome [10, 11]. For most lowing criteria. First, they had to have been determined to women, breast cancer treatment significantly impacts mul- require chemotherapy as part of their treatment based on tiple facets of their lives and their quality of life [8, 12]. their clinical presentation and diagnostic biopsy results. Therefore, achievement of negative margins by removing Second, they had to be interested in preserving their breast the smallest volume of tissue should be the goal for breast- but the size of the cancer at presentation required a mastec- conserving operations. tomy. Finally, in some patients who were already candi- Perhaps one reason for the lack of use of PC is the ques- dates for breast conservation, PC was offered to allow a tion of its applicability away from the high-volume tertiary smaller, more cosmetically acceptable lumpectomy; if the referral cancer center. Many patients are treated in the com- patient had clinically suspicious lymph nodes (with the munity setting and some physicians may question the ben- hope of avoiding an axillary dissection); or if the patient efits of PC and its applicability in the “nonresearch” patient was interested in personal clinical response to the chemo- care practice. Some practitioners may believe that because therapy. For all patients, the chemotherapeutic regimen was www.TheOncologist.com Downloaded from https://academic.oup.com/oncolo/article/16/6/752/6401054 by DeepDyve user on 01 February 2022 754 Preoperative Chemotherapy for Operable Breast Cancer the choice of the treating oncologist. In the PC group, the dissection was performed at the discretion of the attending regimens included doxorubicin and cyclophosphamide (six surgeon after discussion with the patient. of 57 patients, 11%), doxorubicin and cyclophosphamide followed by paclitaxel (29 of 57 patients, 51%), doxorubi- Statistical Considerations The study population was classified into two groups based cin and cyclophosphamide followed by docetaxel (eight of on whether the patient received PC or was expected to have 57 patients, 14%), docetaxel, doxorubicin, and cyclophos- AC by the treating physician. Differences in sociodemo- phamide (five of 57 patients, 9%), trastuzumab-containing graphic characteristics, clinical measures, and outcomes of regimens (seven of 57 patients, 12%) and other regimens breast cancer care were evaluated in the study population. (two of 57 patients, 4%). For categorical variables, the Fisher’s exact test for inde- pendence was used to determine differences between the Surgical Outcomes two populations. For each continuous variable, for exam- Patients were classified into two groups based on whether ple, age, body mass index, etc., the mean and standard de- they underwent PC (PC group) or AC (AC group). Then, viation were reported. Unpaired (two-sample) t-tests were based on presenting clinical tumor size, the initial operation used to compare means of the two populations. All statisti- performed was reported (mastectomy or breast-conserving cal tests were two-sided and a p-value .05 was considered operation). The preoperative history and physical examina- statistically significant. tion note, operative note, and mammogram report were re- viewed. If a patient had a documented contraindication to RESULTS breast conservation (i.e., multicentric disease, extensive There were 212 patients included in the study period. So- microcalcifications, etc.) and therefore underwent a mas- ciodemographic information is shown in Table 1. Patients tectomy, she was excluded from the analysis. Margin status in the PC group were significantly younger and more likely was evaluated in all patients who underwent a breast-con- to be premenopausal than patients in the AC group. Patients serving operation. Those with microscopic evidence of a in the PC group were more likely to be employed than those transected (tumor touching ink) margin were considered to in the AC group. There was no difference, however, in in- have a positive margin. Those with microscopic evidence surance status between the two groups. Most patients in of a tumor within 1 mm of an inked margin were considered both groups were Hispanic and insured by AHCCCS (Med- to have a close margin. The number of patients who under- icaid) or uninsured. Very few patients in either group had went a re-excision lumpectomy was recorded. The volume undergone a screening mammogram within 2 years of di- of breast tissue removed was determined by the product of agnosis (Table 1). the anterior–posterior, medial–lateral, and inferior–supe- The clinical presentation of patients in the PC group was rior diameters listed on the pathology report. more advanced than that of patients in the AC group. Pa- Pathologic nodal status was the nodal status determined tients in the PC group presented with a larger mean tumor at operation. The sentinel node procedure at our institution size (4.6 cm versus 3.3 cm) and later clinical stage (Table has been described previously [23]. In brief, the sentinel 2). The histopathologic factors were similar with respect to node procedure was performed using the combination tech- predominant histology, histologic grade, estrogen receptor nique of blue dye and radioactive isotope. The radiocolloid status, progesterone receptor status, and rate of triple-neg- injection was performed in the nuclear medicine suite ap- ative disease. There was a high rate of poorly differentiated proximately 1–7 hours prior to the operation in an intrader- tumors in both groups. Patients in the PC group were more mal periareolar fashion. Three milliliters to 5 ml of blue dye likely to have human epidermal growth factor receptor (isosulfan or methylene) was injected in the operating room 2/neu overexpressed by immunohistochemistry or ampli- after anesthesia was administered. The blue dye was in- fied by fluorescence in situ hybridization than patients in jected intraparenchymally in a subareolar fashion. All the AC group. nodes that were identified as blue stained or radioactively PC resulted in a clinical response in 79% (45 of 57) of the hottest, and any node with a radioactive count within patients. Of these, 54% (31 of 57) had a clinical complete 10% of the hottest node were considered sentinel nodes. In response and 25% (14 of 57) had a clinical partial response. addition, any node that was palpably abnormal was consid- The remaining 21% (12 of 57) had either stable disease or ered a sentinel node. A level I and level II axillary dissec- disease progression and were classified as nonresponders. tion was performed if any of the sentinel lymph nodes were Overall 25% (14 of 57) of patients had a pathologic com- involved with cancer. If a micrometastasis (2 mm) was plete response. identified in any of the sentinel nodes, a completion axillary For clinical stage T2 (2–5 cm) breast cancers, patients in Downloaded from https://academic.oup.com/oncolo/article/16/6/752/6401054 by DeepDyve user on 01 February 2022 Komenaka, Hibbard, Hsu et al. 755 Table 1. Sociodemographic information and use of screening mammography for stage IIA, IIB, and IIIA patients Adjuvant chemotherapy Preoperative chemotherapy Characteristic (n  155) (n  57) p-value Mean age (SD) 53.6 (14.46) 44.1 (9.96) .0001 50 yrs 70 (45%) 38 (67%) .008 50 yrs 85 (55%) 19 (33%) Menopausal status .003 Pre-/perimenopausal 67 (43%) 38 (67%) Postmenopausal 88 (57%) 19 (33%) Mean BMI (SD), kg/m 29.3 (7.72) 28.5 (6.22) .48 Race/ethnicity .41 White 54 (35%) 16 (28%) African American 10 (6%) 4 (7%) Hispanic 83 (54%) 35 (61%) Other 8 (5%) 2 (4%) Employment status .0001 Employed 27 (17%) 26 (46%) Unemployed 94 (61%) 27 (47%) Retired/disabled 34 (22%) 4 (7%) Insurance .44 Commercial 2 (1%) 3 (5%) Medicare 32 (21%) 6 (11%) Medicaid 58 (37%) 23 (40%) None 63 (41%) 25 (44%) Screening mammogram in the 2 yrs 14/128 (11%) 2/35 (6%) .52 prior to diagnosis (age, 40 yrs) Current smoker 41 (26%) 11 (19%) .37 Derived from a Fisher’s exact test for categorical variables and a two-sample t-test for continuous variables. Abbreviations: BMI, body mass index; SD, standard deviation. the PC group initially underwent a breast-conserving oper- tients) (p  .04). This resulted in significantly fewer re- ation significantly more often than those in the AC group— excision lumpectomies in the PC group (18%, seven of 38 78% (21 of 27 patients) versus 50% (56 of 111 patients), patients) than in the AC group (41%, 28 of 68 patients) (p respectively (p .016) (Table 3). For clinical stage T3 (5 .01). The volume of tissue removed was also significantly cm) breast cancers, patients in the PC group initially under- smaller in the PC group (143.6 cm ) than in the AC group went a breast-conserving operation more often than those in (273.9 cm )(p  .003). For those who underwent a second the AC group—60% (18 of 30 patients) versus 29% (12 of operation for close or positive margins, more patients un- 41 patients), respectively (p  .01). Some patients in both derwent a mastectomy in the AC group (six patients) than in the AC group and the PC group chose to have a mastectomy the PC group (one patient). The final surgical procedure for despite being considered a candidate for breast conserva- those presenting with clinical stage T2 breast cancers was tion. When these patients were excluded from the analysis, more often a breast-conserving operation in the PC group the results changed little—for stage T2 disease: PC group, (74%, 20 of 27 patients) than in the AC group (45%, 51 of 91% (21 of 23 patients) versus AC group, 58% (56 of 97 114 patients) (p  .006). Similarly, in patients who pre- patients) (p  .003); for stage T3 disease: PC group, 69% sented with clinical stage T3 breast cancers, the final oper- (18 of 26 patients) versus AC group, 32% (12 of 38 pa- ation was a breast-conserving procedure more often in the tients) (p  .005). For those patients who did undergo a PC group (60%, 18 of 30 patients) than in the AC group breast-conserving operation, the rate of close (1 mm) or (27%, 11 of 43 patients) (p  .007). The rate of pathologi- positive margins in the PC group was half the rate in the AC cally positive nodes was lower in patients in the PC group; group—23% (nine of 38 patients) versus 46% (31 of 68 pa- however, this difference was not statistically significant. www.TheOncologist.com Downloaded from https://academic.oup.com/oncolo/article/16/6/752/6401054 by DeepDyve user on 01 February 2022 756 Preoperative Chemotherapy for Operable Breast Cancer Table 2. Clinical and tumor characteristics of stage IIA, IIB, and IIIA patients Adjuvant chemotherapy Preoperative chemotherapy Characteristic (n  155) (n  57) p-value Mean clinical tumor size (SD), cm 3.3 (1.68) 4.6 (1.62) .0001 Tumor stage T2 114 (74%) 27 (47%) .0005 T3 41 (26%) 30 (53%) Clinical stage at presentation .0001 IIA 113 (73%) 20 (35%) IIB 36 (23%) 29 (51%) IIIA 6 (4%) 8 (14%) Predominant histology .80 Ductal 140 (90%) 51 (89%) Lobular 8 (5%) 5 (9%) Other 7 (5%) 1 (2%) Histologic grade .86 Well differentiated 14 (10%) 3 (6%) Moderately differentiated 34 (23%) 13 (25%) Poorly differentiated 98 (67%) 36 (69%) Estrogen receptor .34 Positive 101 (66%) 33 (58%) Negative 53 (34%) 24 (42%) Progesterone receptor .54 Positive 86 (56%) 29 (51%) Negative 68 (44%) 28 (49%) HER-2/neu status (IHC 3 or FISH) .05 Yes 23 (15%) 16 (39%) No 127 (85%) 41 (61%) Triple negative 38/150 (25%) 16/57 (28%) .72 Derived from a Fisher’s exact test for categorical variables and a two-sample t-test for continuous variables. Nine patients in the adjuvant chemotherapy group and five patients in the preoperative chemotherapy group did not have histologic grade assigned either because it was an infiltrating lobular carcinoma or it was not done. One patient in the adjuvant chemotherapy group did not have estrogen receptor or progesterone receptor testing performed. Five patients did not have HER-2/neu testing performed. Hormone receptor and HER-2/neu not expressed/not amplified. Abbreviations: FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; SD, standard deviation. There was no significant difference in the ipsilateral breast Several prospective, randomized clinical trials have tumor recurrence rate between the AC group (one of 62 pa- shown that patients treated with PC have a similar overall tients, 2%) and the PC group (three of 38 patients, 8%) (p survival duration as patients treated with AC [1–3]. Evalu- .15); however, the mean follow-up was relatively short, at ation of breast cancer care, with its long history of patient 37 months. advocacy, however, cannot be evaluated simply by out- comes as limited as overall survival. For most women, DISCUSSION breast cancer treatment significantly impacts multiple fac- PC led to significantly better breast cancer surgical out- ets of their lives and their quality of life [8, 12]. Despite a comes in this community-based practice of underinsured larger clinical tumor size at presentation, patients who un- county hospital patients. Patients who underwent PC had a derwent PC were significantly more likely to undergo a higher rate of breast-conserving operations, a lower rate of breast-conserving operation for both stage T2 and stage T3 close or positive margins, smaller lumpectomies, fewer re- cancers (Table 3). This finding of a higher rate of breast excisions, and a lower rate of histologically positive nodes preservation was similar to the significant benefit demon- despite presentation at a more advanced clinical stage. strated in the NSABP B18 study for stage T2 (71% for PC Downloaded from https://academic.oup.com/oncolo/article/16/6/752/6401054 by DeepDyve user on 01 February 2022 Komenaka, Hibbard, Hsu et al. 757 Table 3. Surgical outcomes of stage IIA, IIB, and IIIA patients Adjuvant chemotherapy Preoperative chemotherapy Outcome (n  155) (n  57) p-value Initial operation for stage T2 .016 Breast conservation 56 (50%) 21 (78%) Mastectomy 55 (50%) 6 (22%) Initial operation for stage T2 .003 Breast conservation 56 (58%) 21 (91%) Mastectomy 41 (42%) 2 (9%) Initial operation for stage T3 .015 Breast conservation 12 (29%) 18 (60%) Mastectomy 29 (71%) 12 (40%) Initial operation for stage T3 .005 Breast conservation 12 (32%) 18 (69%) Mastectomy 26 (68%) 8 (31%) Lumpectomy margins .04 Positive/close (1 mm) 31/68 (46%) 9/38 (23%) Re-excision lumpectomy 28/68 (41%) 7/38 (18%) .01 Breast conservation .003 Volume of specimen, cm 273.9 143.6 Final operation for stage T2 .006 Breast conservation 51 (45%) 20 (74%) Mastectomy 63 (55%) 7 (26%) Final operation for stage T3 .007 Breast conservation 11 (27%) 18 (60%) Mastectomy 30 (73%) 12 (40%) Clinical stage II IDC .46 Pathologic node positive 44/110 (40%) 6/20 (30%) Clinical stage IIB/III IDC .35 Pathologic node positive 25/39 (64%) 19/37(51%) Derived from a Fisher’s exact test for categorical variables and a two-sample t-test for continuous variables. Excluding patients who elected mastectomy over breast conservation. Abbreviation: IDC, infiltrating ductal carcinoma. versus 63% for AC) and stage T3 (22% for PC versus 8% Evaluation of the breast-conserving operation cannot be for AC) cancers [24]. Although the 22% rate of breast con- limited only to its rate of performance because there are servation appears low, more recent and subsequent data other factors that determine the success of the surgical pro- have found higher rates of breast conservation for patients cedure. Margin status is perhaps the most important imme- with stage T3 tumors after PC. The prospective study re- diate outcome of breast-conserving operations because ported by Bonadonna et al. [3] showed rates of breast con- inadequate margins are one of the strongest predictors of lo- servation of 89% for stage T2 tumors and 62% for stage T3 cal failure [9]. The achievement of negative margins is also tumors. Boughey et al. [6] found that, in patients with stage of importance because a higher number of operations to ob- T2 and stage T3 tumors, those who underwent PC in pro- tain negative margins results in a greater volume of tissue spective randomized trials at MD Anderson Cancer Center excised and a poorer cosmetic result [9, 10, 26, 27]. In some experienced a nonsignificantly higher lumpectomy rate series, the re-excision rate to obtain negative margins can (44% versus 33%) than patients who underwent AC. be as high as 69% [28]. In the current study, patients in the Christy et al. [25] found a statistically significant higher AC group had a rate of close (1 mm) or positive margins breast-conserving operation rate (64% versus 45%; p  double that of those who underwent PC (46% versus 23%; .05) in patients with stage T2 cancers. p .04) (Table 3). This resulted in a statistically significant www.TheOncologist.com Downloaded from https://academic.oup.com/oncolo/article/16/6/752/6401054 by DeepDyve user on 01 February 2022 758 Preoperative Chemotherapy for Operable Breast Cancer higher rate of re-excision lumpectomy in the AC group than node dissection vary greatly, data from the largest pub- in the PC group (41% versus 18%; p .01). In patients who lished prospective, randomized clinical trial to date com- underwent a second operation because of involved margins, paring axillary lymph node dissection with sentinel node more patients underwent a mastectomy in the AC group biopsy, reported by Veronesi et al. [33], demonstrated that than in the PC group (Table 3). Similarly, data from the 91% and 85% of patients experienced pain and numbness, University of Michigan showed that the re-excision rate in respectively, for 6 months after an axillary dissection. That patients who underwent PC was almost half that of those was compared with only 16% and 2% in the sentinel node who did not undergo PC (59% versus 31%; p 0.001) [29]. group. This difference in morbidity should not be underes- Data from Yale University [25] for stage T2 cancers also timated because 6 months is a long time to suffer through an showed a statistically significant lower rate of positive mar- iatrogenic problem. gins (32% versus 10%; p  .01) and need for re-excision This study has several limitations. Retrospective studies lumpectomy (37% versus 6%; p  .01). In the current are subject to inherent limitations and biases. Data from study, the significantly better margin status and lumpec- prospective studies involving minority patients, however, tomy rate cannot be explained by a larger lumpectomy are very difficult to obtain even in a disease as common as specimen volume in the PC group because the volume of breast cancer. Most patients who participate in clinical tri- the lumpectomy specimens in the PC group was nearly half als are non-Hispanic whites and insured, making prospec- 3 3 that of the AC group (143 cm versus 273 cm ; p  .003). tive study of the racial/ethnic minority and underinsured Therefore, not only did the PC group have a lower rate of populations extremely difficult. This study was relatively close and positive margins, those patients also had sig- small and performed at one institution with one patient pop- nificantly less tissue removed in breast-conserving oper- ulation. The small size of the study, however, demonstrates ations. The lower lumpectomy volume in those undergoing that the benefits of PC can apply even to a low-volume com- PC was also demonstrated in a combined analysis of pro- munity-based practice. The applicability to other patient spective, randomized data from the MD Anderson Cancer populations, however, does need to be considered. Finally, Center. A similar statistically significant lower resected follow-up was limited in this study and continued evalua- 3 3 volume was found (113 cm versus 213 cm ; p  .004), tion of patients will be necessary to determine whether with no difference in local recurrence at 33 months of fol- these better surgical outcomes will translate into better low-up [6]. These findings of a smaller lumpectomy vol- long-term outcomes. ume in the PC groups alleviate concerns about diffuse Breast cancer is a heterogeneous disease and patient residual tumor burden dispersed throughout the original tu- populations are equally diverse. In certain populations, al- mor volume. though overall survival is similar in patients undergoing AC The benefits in the PC group were also seen in the lymph and PC, patients undergoing PC may experience benefits in node status. Proportionally, 25% fewer patients who pre- terms of surgical outcomes over the same treatment given in sented with clinical stage IIA disease and 20% fewer stage the adjuvant setting. The surgical benefits of PC demon- IIB/IIIA patients were node positive in the PC group. Data strated in prospective, randomized studies and at large ter- from the NSABP B18 study demonstrated that PC resulted tiary cancer centers can be realized even in a lower volume in a 30%–40% lower rate of lymph node positivity. When community-based practice. the results of the NSABP B18 trial were reported in 1997, the difference in lymph node status affected the postchemo- ACKNOWLEDGMENT therapy stage of the patients [1]. In 2010, however, addi- Chandra Jha is deceased; we appreciate his unending com- tional benefits could be realized. PC was initially mitment to patient care and his significant contributions to considered a contraindication to the sentinel node proce- this manuscript. dure. Subsequent data from the NSABP B27 study reported by Mamounas et al. [30] as well as data from a meta-anal- ysis [31] demonstrated that the sentinel node procedure is as AUTHOR CONTRIBUTIONS accurate after PC as it is without prior chemotherapy. These Conception/Design: Ian K. Komenaka, Michael Hibbard, Chandra Jha, Boo Ghee Low data have resulted in national guidelines stating the accept- Provision of study material or patients: Ian K. Komenaka, Chandra Jha, Boo Ghee Low, Jason Salganick, Marcia Bouton ability of the sentinel node procedure after PC [32]. There- Collection and/or assembly of data: Ian K. Komenaka, Chiu-Hsieh Hsu, fore, because a significant proportion of patients can have Marcia Bouton Data analysis and interpretation: Chiu-Hsieh Hsu their lymph nodes downstaged, PC could save many pa- Manuscript writing: Ian K. Komenaka, Michael Hibbard, Chiu-Hsieh Hsu, Boo Ghee Low, Jason Salganick, Marcia Bouton tients the morbidity of an axillary lymph node dissection. Final approval of manuscript: Ian K. Komenaka, Michael Hibbard, Chandra Although reported morbidity rates related to axillary lymph Jha, Chiu-Hsieh Hsu, Boo Ghee Low, Jason Salganick, Marcia Bouton Downloaded from https://academic.oup.com/oncolo/article/16/6/752/6401054 by DeepDyve user on 01 February 2022 Komenaka, Hibbard, Hsu et al. 759 therapeutic response of the basal-like breast cancer to neoadjuvant chemo- REFERENCES therapy. Breast Cancer Res Treat 2010;123:691–699. 1 Fisher B, Brown A, Mamounas E et al. Effect of preoperative chemother- 17 Hugh J, Hanson J, Cheang MC et al. Breast cancer subtypes and response to apy on local-regional disease in women with operable breast cancer: Find- docetaxel in node-positive breast cancer: Use of an immunohistochemical ings from National Surgical Adjuvant Breast and Bowel Project B-18. definition in the BCIRG 001 trial. J Clin Oncol 2009;27:1168–1176. J Clin Oncol 1997;15:2483–2493. 18 Romond EH, Perez EA, Bryant J et al. 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