Decision Making in the Surgical Management of Invasive Breast Cancer-Part 2: Expanded Applications for Breast-Conserving Surgery

Treatment of early-stage invasive breast cancer with breast-conserving surgery plus radiation therapy (RT) yields overall survival outcomes equivalent to those achieved with mastectomy. Further, breast-conserving surgery is endorsed by the National Comprehensive Cancer Network as being supported by the highest-level, category 1 evidence. Advances in pathologic evaluation, management of multiple tumors, oncoplastic lumpectomy techniques, neoadjuvant chemotherapy, and hypofractionated RT can expand the pool of patients eligible for breast-conserving surgery. Selected patients (for example, patients older than 70 years of age with hormone receptor–positive T1 tumors who are willing to commit to receiving adjuvant endocrine therapy) may be able to forgo RT completely. This article will detail current management approaches to achieving breast conservation in patients with invasive breast cancer, including cases of bulky tumors and/or multiple tumors.

Introduction

The most recent breast cancer guidelines released by the National Comprehensive Cancer Network (NCCN) continue to rate breast-conserving surgery for early-stage invasive disease as being supported by the highest-level-category 1-evidence (ie, based upon data from prospective randomized clinical trials).[1] Several management strategies may be employed to expand the number of patients who are deemed eligible for breast-conserving surgery. These include reversal of conventional primary surgery/systemic therapy treatment sequence by delivery of neoadjuvant chemotherapy; broadened applications of lumpectomy to patients with multiple breast tumors; omission/modification of breast irradiation after lumpectomy; and newer approaches to oncoplastic breast reconstruction for lumpectomy patients.

Neoadjuvant Systemic Therapy

The benefits of neoadjuvant chemotherapy in women with unresectable breast cancer became apparent several decades ago. In this scenario neoadjuvant chemotherapy was shown to improve operability, and successfully downstaged patients from this era routinely underwent modified radical mastectomy. The neoadjuvant treatment plan also offers the following advantages[2,3]:

• It enables clinicians to monitor disease chemosensitivity, since breast tumor downstaging by neoadjuvant chemotherapy is a surrogate marker for the effectiveness of chemotherapy in sterilizing micrometastases.

• It increases the possibility of downstaging axillary disease, so that patients are more likely to be node-negative after primary chemotherapy-which then potentially increases the likelihood that axillary lymph node dissection will not be necessary. A comprehensive discussion of axillary surgical management in neoadjuvant chemotherapy is beyond the scope of this review. Many patients receiving neoadjuvant chemotherapy who present with node-positive breast cancer will require axillary lymph node dissection for definitive staging and regional control of disease. However, NCCN guidelines[1] support the option of omitting axillary lymph node dissection in patients with needle biopsy–proven nodal disease whose axilla has been proven to be downstaged following neoadjuvant chemotherapy through a targeted axillary dissection involving dual-agent (blue dye and radiotracer) lymphatic mapping, resection of more than two sentinel nodes, and radiographic confirmation that the original biopsied/clip-marked lymph node has been removed.

• It may provide patients with an additional window of time during which they can seek genetic counseling/testing, as well as contemplate their individual preferences regarding lumpectomy vs mastectomy.

Several international studies have confirmed the safety of reversing the conventional breast cancer treatment sequence, so that chemotherapy precedes surgery (Table 1). Overall survival is the same within each study for the two randomization arms, definitively demonstrating that survival is not compromised by modest delays in performing surgery while chemotherapy is delivered preoperatively. These studies also confirm that the neoadjuvant approach increases the volume of patients who are eligible for breast-conserving surgery.

Candidates for neoadjuvant chemotherapy must be carefully vetted to ensure that all necessary cancer-related information is available to the care team prior to initiating treatment. A radio-opaque clip must be left in place within the tumor bed for subsequent lumpectomy targeting. Mammograms showing microcalcifications may be used as inherent tumor localization markers. Patients who are fortunate enough to achieve a complete clinical response but who have neither marker clips nor calcifications to identify the tumor bed must undergo mastectomy after receiving neoadjuvant chemotherapy. Patients who have diffuse microcalcifications or multiple widely spaced tumors at the time of diagnosis should be informed that they must undergo mastectomy regardless of how well they respond to neoadjuvant chemotherapy. Patients with several tumors should have multiple biopsies to completely characterize biomarker expression, since this information will determine individual eligibility for endocrine therapy and targeted therapy with anti–human epidermal growth factor receptor 2 (HER2) agents.

Breast imaging should be repeated after completion of neoadjuvant chemotherapy, to assess the patient’s response to treatment and facilitate surgical planning. Occasionally, patients will have unmasking of previously obscured microcalcifications that might influence their eligibility for lumpectomy. The standard of care at this time is for patients receiving neoadjuvant chemotherapy to routinely undergo definitive breast surgery; ongoing research and clinical trials (including the NRG Oncology trial NRG-BR005) will explore the prospect of avoiding surgery in the subset of patients appearing to be “exceptional responders”-that is, cases in which clinical evaluation, postchemotherapy core needle biopsies, and breast imaging are consistent with a complete pathologic response.

Bulky cancers that are hormone receptor (HR)-positive and HER2-negative are less likely to have a brisk response to neoadjuvant chemotherapy and are generally triaged toward primary surgery unless they are associated with biopsy-proven nodal disease or are unresectable. Neoadjuvant endocrine therapy is an alternative option for this phenotype, but clinical response tends to be relatively slow and complete pathologic responses are uncommon.[4-7] Improved eligibility for lumpectomy is therefore less well documented compared with neoadjuvant chemotherapy delivered for triple-negative breast cancer (ie, tumors that are estrogen receptor–negative, progesterone receptor–negative, and HER2–negative) or cancers that overexpress the HER2 protein.

Lumpectomy for Multiple Breast Tumors

Cases of multiple breast tumors are often categorized as multifocal (more than one tumor within a single quadrant) vs multicentric (multiple tumors across at least two quadrants). Since distinct tumors can be situated in close proximity to each other while technically residing in separate quadrants, these imprecise definitions do not reflect the extent of affected breast tissue. The reported prevalence of multifocal/multicentric breast cancer therefore varies substantially in the medical literature, from 13% to 75%.[8] Early studies of breast-conserving surgery for patients with multiple tumors revealed rates of local recurrence exceeding 20%, leading to this feature being considered a contraindication to breast-conserving therapy.[9-11] However, more recent studies with closer attention to margin control have demonstrated improved outcomes with this less invasive treatment approach, compared with earlier evaluations (Table 2). The generally accepted approach is that breast-conserving therapy can be attempted in these cases as long as the tumors can be encompassed within a single margin-negative lumpectomy specimen, and with a cosmetically acceptable volume of residual breast tissue. The Alliance Z11102 trial (ClinicalTrials.gov identifier: NCT01556243), a phase II trial by the Alliance for Clinical Trials in Oncology, is currently evaluating the safety of breast-conserving surgery in women with multiple ipsilateral primary breast cancers resected via either single or multiple margin-negative lumpectomy specimens.

Neoadjuvant chemotherapy can be offered to appropriately selected patients with multiple tumors. As demonstrated by Ataseven et al,[12] breast conservation in these patients is associated with local control comparable to that achieved in patients with unifocal disease managed by neoadjuvant chemotherapy. If preoperative chemotherapy is considered, then it is critical for all tumor sites to be biopsied and marked with radio-opaque clips prior to treatment, to confirm biomarker status and ensure that all tumor sites can be identified and resected when the patient is ready for surgical planning.

Lumpectomy With vs Without Whole-Breast Radiation Therapy (WBRT)

Conventional WBRT following lumpectomy is delivered in fractions of 1.8 Gy to 2.0 Gy daily over a period of several weeks, to reach a cumulative dose of 6,000 rads (60 Gy), and is planned with CT guidance (three-dimensional conformal RT) to optimize coverage of the breast while minimizing toxicity to adjacent organs. Standard WBRT therefore involves a commitment to Monday-through-Friday daily radiation treatments for 5 to 6 weeks, and breaks in care are strongly discouraged. While each RT session is relatively brief, the treatment frequency mandates that the patients have readily available transportation access as well as proximity to the radiation oncology facility. These requirements can present significant logistical barriers to receiving breast-conserving therapy for patients residing in geographically remote areas, patients with mobility/disability challenges, and patients with socioeconomic disadvantages that limit reliable transportation options.

While the landmark prospective randomized clinical trials that established the safety of breast-conserving surgery typically utilized standard WBRT, the logistical disadvantages have motivated the development of alternative approaches, such as partial-breast irradiation, hypofractionated RT, or complete omission of radiation. Intensity-modulated RT is a modification that incorporates the advantages of CT guidance to enhance the precision of radiation field planning; this approach can be applied to both WBRT and partial-breast RT planning. Data regarding effectiveness of conventional WBRT remain the most robust, but studies of the other strategies are compelling. The various approaches to delivery of RT are comprehensively reviewed by Shah et al,[13] and are summarized below.

Accelerated whole-breast irradiation (commonly called “hypofractionated” RT) allows for treatment completion in 3 to 5 weeks by reducing the number of fractions used to treat the entire breast, while increasing the radiation dose delivered per fraction. This approach became popular following publication of a Canadian trial that randomized 1,234 patients to either standard WBRT or accelerated treatments delivered as 42.5 Gy in 16 fractions.[14] Local control, toxicity, and cosmesis were all comparable at 10-year follow-up. The UK Standardisation of Breast Radiotherapy (START) trials A and B evaluated different fractionation schedules (both delivered over shorter timeframes compared with standard WBRT), and have reported acceptable results.[15,16] There has been widespread adoption of hypofractionated RT since it offers patients the convenience of a reduced RT treatment schedule, and this strategy is endorsed by the NCCN. Appropriate patient selection is important, however; the safety and effectiveness of this strategy is less well documented among patients younger than 50 years of age, patients with large breasts, and patients receiving neoadjuvant chemotherapy.

Accelerated partial-breast irradiation, or APBI, represents an alternative strategy for reducing the time commitment necessary for delivery of adjuvant radiation with breast conservation for patients with early-stage breast cancer. Treatment can be completed in 1 to 3 weeks and involves higher doses of radiation per fraction delivered to a smaller area of breast tissue. The APBI approach focuses on the post-lumpectomy tumor bed, which is the site for the majority of true local recurrences. Partial-breast irradiation can also be delivered as interstitial brachytherapy, as applicator-based/balloon-catheter brachytherapy, or with external beam techniques. Early results from prospective randomized clinical trials of partial-breast irradiation are promising, but data on the optimal technique, and long-term oncologic and cosmetic results, continue to evolve.[13,17]

Intraoperative RT (IORT) is a mechanism that strives to facilitate breast conservation by delivering partial-breast radiation treatment to the lumpectomy bed at the time of surgery. This approach requires a significant start-up investment in specialized surgical equipment and is not widely available. Other concerns regarding this approach include the potential compromise of definitive margin control, and more limited visualization/image guidance of the treatment field. While early outcome results from prospective clinical trials such as TARGIT-A and ELIOT[18,19] suggest that IORT can be delivered safely and effectively, the ELIOT trial reported rates of local recurrence following IORT that were significantly higher compared with those observed following standard WBRT (albeit within the prespecified equivalence margin).

Complete omission of RT with breast-conserving surgery for early-stage breast cancer represents the ultimate strategy for minimizing the inconvenience of adjuvant local therapy in this setting. The National Surgical Adjuvant Breast and Bowel Project B-06 clinical trial confirmed that adjuvant RT after lumpectomy contributes substantially to local control of disease (with 20-year rates of local recurrence at 14% with adjuvant RT vs 39% without it), without significantly altering overall survival.[20] Furthermore, it is well documented that selected clinicopathologic features such as advanced age, smaller tumor size, and HR positivity (coupled with a commitment by the patient to complete adjuvant endocrine therapy) identify subsets of patients at lower risk for local recurrence following breast-conserving surgery. These observations have motivated prospective randomized clinical trials specifically designed to assess the safety of omitting adjuvant breast RT following lumpectomy for predefined categories of low-risk breast cancer.

The Cancer and Leukemia Group B (CALGB) 9343 clinical trial randomized 636 women (accrued from 1994 to 1999), 70 years of age and older, with clinical stage I breast cancer (either estrogen receptor–positive or indeterminate status), to receive either breast irradiation along with 5 years of adjuvant tamoxifen therapy or adjuvant tamoxifen alone. All participants had an initial margin-negative lumpectomy (defined as no tumor cells on the inked surface). Of note, participants had to be clinically node-negative, but approximately two-thirds of participants had no histopathologic/surgical confirmation of nodal status. With a median follow-up of 12.6 years, overall survival rates of patients in the two study arms were nearly identical (67% for patients treated with tamoxifen plus radiation and 66% for patients treated with tamoxifen alone).[21] While the rates of local recurrence have remained relatively low for both study arms over time, a progressively widening gap has been observed, favoring improved local control for the patients treated with both tamoxifen and radiation. At 5 years, the rates of locoregional recurrence for the tamoxifen-only vs the tamoxifen-plus-radiation arms were 4% and 1%, respectively (P < .001)[22]; at 10 years these rates were 10% and 2%, respectively (P < .001).[21]

The PRIME II study accrued 1,326 participants 65 years of age and older with HR-positive tumors no larger than 3 cm; all patients underwent a margin-negative lumpectomy (margin at least 1 mm in thickness).[23] Unlike the CALGB trial, PRIME II accrued during the era of lymphatic mapping and sentinel lymph node biopsy for breast cancer staging, and so all participants were required to be histopathologically node-negative. The randomization arms compared WBRT along with adjuvant endocrine therapy vs endocrine therapy alone. With a median follow-up of 5 years, ipsilateral breast tumor recurrences have been reported in 1.3% of patients receiving endocrine therapy plus radiation vs 4.1% of patients receiving endocrine therapy only (P = .0002); the overall survival rate has been exactly the same, at 93.9%.

The CALGB and PRIME studies indeed represent exciting, thoughtful approaches to streamlining breast cancer treatment for older patients, while minimizing both cost and toxicity. Potential concerns about extrapolating the existing trial-based data to real-world practice include the need for patients to commit to several years of endocrine therapy at the time of diagnosis (when the patient cannot necessarily predict her tolerance of the prescribed treatment), and the lack of information regarding outcomes in patients treated with RT only (since some patients will prefer to focus on local control by completing a few weeks of adjuvant RT rather than several years of endocrine therapy). Future efforts to more precisely identify lumpectomy patients who can safely avoid breast irradiation and/or endocrine therapy may incorporate gene expression studies and breast MRI.

Oncoplastic Breast-Conserving Surgery

A variety of breast reshaping and reduction mammoplasty techniques have been developed as strategies to enable larger volumes of tumor tissue to be removed during lumpectomies, with minimal resulting breast deformities.[24] While these approaches are promising, they may limit subsequent options for re-excision lumpectomy if margins are inadequate; inappropriate attention to specific margin surfaces can be more challenging if breast tissue surrounding the lumpectomy cavity has been reconfigured. Also, systematic review of outcomes suggests that further research into the oncologic safety of these newer techniques is warranted.[25]

Summary and Conclusions

In terms of overall survival outcomes, breast-conserving surgery and mastectomy are equal treatments for patients with invasive breast cancer. Advances in pathologic evaluation, management of multiple tumors, neoadjuvant chemotherapy, and hypofractionated RT techniques have the potential to render more patients eligible for breast-conserving surgery.

Financial Disclosure:The author has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

References:

1. Gradishar WJ, Anderson BO, Balassanian R, et al. Invasive breast cancer version 1.2016, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2016;14:324-54.

2. Mamounas EP. Impact of neoadjuvant chemotherapy on locoregional surgical treatment of breast cancer. Ann Surg Oncol. 2015;22:1425-33.

3. King TA, Morrow M. Surgical issues in patients with breast cancer receiving neoadjuvant chemotherapy. Nat Rev Clin Oncol. 2015;12:335-43.

4. Loibl S, Denkert C, von Minckwitz G. Neoadjuvant treatment of breast cancer: clinical and research perspective. Breast. 2015;24(suppl 2):S73-S77.

5. Spring LM, Gupta A, Reynolds KL, et al. Neoadjuvant endocrine therapy for estrogen receptor-positive breast cancer: a systematic review and meta-analysis. JAMA Oncol. 2016;2:1477-86.

6. Haddad TC, Goetz MP. Landscape of neoadjuvant therapy for breast cancer. Ann Surg Oncol. 2015;22:1408-15.

7. Agrawal LS, Mayer IA. Optimizing the use of neoadjuvant endocrine therapy. Curr Oncol Rep. 2015;17:33.

8. Bendifallah S, Werkoff G, Borie-Moutafoff C, et al. Multiple synchronous (multifocal and multicentric) breast cancer: clinical implications. Surg Oncol. 2010;19:e115-e123.

9. Kurtz JM, Jacquemier J, Amalric R, et al. Breast-conserving therapy for macroscopically multiple cancers. Ann Surg. 1990;212:38-44.

10. Leopold KA, Recht A, Schnitt SJ, et al. Results of conservative surgery and radiation therapy for multiple synchronous cancers of one breast. Int J Radiat Oncol Biol Phys. 1989;16:11-6.

11. Wilson LD, Beinfield M, McKhann CF, Haffty BG. Conservative surgery and radiation in the treatment of synchronous ipsilateral breast cancers. Cancer. 1993;72:137-42.

12. Ataseven B, Lederer B, Blohmer JU, et al. Impact of multifocal or multicentric disease on surgery and locoregional, distant and overall survival of 6,134 breast cancer patients treated with neoadjuvant chemotherapy. Ann Surg Oncol. 2015;22:1118-27.

13. Shah C, Tendulkar R, Smile T, et al. Adjuvant radiotherapy in early-stage breast cancer: evidence-based options. Ann Surg Oncol. 2016;23:3880-90.

14. Whelan TJ, Pignol JP, Levine MN, et al. Long-term results of hypofractionated radiation therapy for breast cancer. N Engl J Med. 2010;362:513-20.

15. Hopwood P, Haviland JS, Sumo G, et al. Comparison of patient-reported breast, arm, and shoulder symptoms and body image after radiotherapy for early breast cancer: 5-year follow-up in the randomised Standardisation of Breast Radiotherapy (START) trials. Lancet Oncol. 2010;11:231-40.

16. Haviland JS, Owen JR, Dewar JA, et al. The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials. Lancet Oncol. 2013;14:1086-94.

17. Vicini F, Shah C, Tendulkar R, et al. Accelerated partial breast irradiation: an update on published level I evidence. Brachytherapy. 2016;15:607-15.

18. Vaidya JS, Wenz F, Bulsara M, et al. Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial. Lancet. 2014;383:603-13.

19. Veronesi U, Orecchia R, Maisonneuve P, et al. Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): a randomised controlled equivalence trial. Lancet Oncol. 2013;14:1269-77.

20. Fisher B, Redmond C, Poisson R, et al. Eight-year results of a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med. 1989;320:822-8.

21. Hughes KS, Schnaper LA, Bellon JR, et al. Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast cancer: long-term follow-up of CALGB 9343. J Clin Oncol. 2013;31:2382-7.

22. Hughes KS, Schnaper LA, Berry D, et al. Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer. N Engl J Med. 2004;351:971-7.

23. Kunkler IH, Williams LJ, Jack WJ, et al. Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial. Lancet Oncol. 2015;16:266-73.

24. Clough KB, Benyahi D, Nos C, et al. Oncoplastic surgery: pushing the limits of breast-conserving surgery. Breast J. 2015;21:140-6.

25. Yiannakopoulou EC, Mathelin C. Oncoplastic breast conserving surgery and oncological outcome: systematic review. Eur J Surg Oncol. 2016;42:625-30.

26. Mauriac L, Durand M, Avril A, Dilhuydy JM. Effects of primary chemotherapy in conservative treatment of breast cancer patients with operable tumors larger than 3 cm: results of a randomized trial in a single centre. Ann Oncol. 1991;2:347-54.

27. Mauriac L, MacGrogan G, Avril A, et al. Neoadjuvant chemotherapy for operable breast carcinoma larger than 3 cm: a unicentre randomized trial with a 124-month median follow-up. Institut Bergonie Bordeaux Groupe Sein (IBBGS). Ann Oncol. 1999;10:47-52.

28. Scholl SM, Asselain B, Palangie T, et al. Neoadjuvant chemotherapy in operable breast cancer. Eur J Cancer. 1991;27:1668-71.

29. Scholl SM, Fourquet A, Asselain B, et al. Neoadjuvant versus adjuvant chemotherapy in premenopausal patients with tumours considered too large for breast conserving surgery: preliminary results of a randomised trial: S6. Eur J Cancer. 1994;30A:645-52.

30. Scholl SM, Pierga JY, Asselain B, et al. Breast tumour response to primary chemotherapy predicts local and distant control as well as survival. Eur J Cancer. 1995;31A:1969-75.

31. Powles TJ, Hickish TF, Makris A, et al. Randomized trial of chemoendocrine therapy started before or after surgery for treatment of primary breast cancer. J Clin Oncol. 1995;13:547-52.

32. Makris A, Powles TJ, Ashley SE, et al. A reduction in the requirements for mastectomy in a randomized trial of neoadjuvant chemoendocrine therapy in primary breast cancer. Ann Oncol. 1998;9:1179-84.

33. Makris A, Powles TJ, Dowsett M, et al. Prediction of response to neoadjuvant chemoendocrine therapy in primary breast carcinomas. Clin Cancer Res. 1997;3:593-600.

34. Cleator SJ, Makris A, Ashley SE, et al. Good clinical response of breast cancers to neoadjuvant chemoendocrine therapy is associated with improved overall survival. Ann Oncol. 2005;16:267-72.

35. Fisher B, Brown A, Mamounas E, et al. Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol. 1997;15:2483-93.

36. Fisher B, Bryant J, Wolmark N, et al. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol. 1998;16:2672-85.

37. Wolmark N, Wang J, Mamounas E, et al. Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18. J Natl Cancer Inst Monogr. 2001;(30):96-102.

38. Rastogi P, Anderson SJ, Bear HD, et al. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol. 2008;26:778-85.

39. van der Hage JA, van de Velde CJ, Julien JP, et al. Preoperative chemotherapy in primary operable breast cancer: results from the European Organization for Research and Treatment of Cancer trial 10902. J Clin Oncol. 2001;19:4224-37.

40. Gianni L, Baselga J, Eiermann W, et al. First report of the European Cooperative Trial in Operable Breast Cancer (ECTO): effects of primary systemic therapy (PST) on local-regional disease. Proc Am Soc Clin Oncol. 2002;21:34a, abstr 132.

41. Gianni L, Baselga J, Eiermann W, et al. Feasibility and tolerability of sequential doxorubicin/paclitaxel followed by cyclophosphamide, methotrexate, and fluorouracil and its effects on tumor response as preoperative therapy. Clin Cancer Res. 2005;11:8715-21.

42. Jakesz R, for the ABCSG. Comparison of pre- vs. postoperative chemotherapy in breast cancer patients: four-year results of Austrian Breast and Colorectal Study Group (ABCSG) trial 7. Proc Am Soc Clin Oncol. 2001;20:32a, abstr 125.

43. Hartsell WF, Recine DC, Griem KL, et al. Should multicentric disease be an absolute contraindication to the use of breast-conserving therapy? Int J Radiat Oncol Biol Phys. 1994;30:49-53.

44. Nos C, Bourgeois D, Darles C, et al. [Conservative treatment of multifocal breast cancer: a comparative study.] Bulletin du Cancer. 1999;86:184-8.

45. Cho LC, Senzer N, Peters GN. Conservative surgery and radiation therapy for macroscopically multiple ipsilateral invasive breast cancers. Am J Surg. 2002;183:650-4.

46. Kaplan J, Giron G, Tartter PI, et al. Breast conservation in patients with multiple ipsilateral synchronous cancers. J Am Coll Surg. 2003;197:726-9.

47. Okumura S, Mitsumori M, Yamauchi C, et al. Feasibility of breast-conserving therapy for macroscopically multiple ipsilateral breast cancer. Int J Radiat Oncol Biol Phys. 2004;59:146-51.

48. Gentilini O, Botteri E, Rotmensz N, et al. Conservative surgery in patients with multifocal/multicentric breast cancer. Breast Cancer Res Treat. 2009;113:577-83.

49. Lim W, Park EH, Choi SL, et al. Breast conserving surgery for multifocal breast cancer. Ann Surg. 2009;249:87-90.

50. Chung AP, Huynh K, Kidner T, et al. Comparison of outcomes of breast conserving therapy in multifocal and unifocal invasive breast cancer. J Am Coll Surg. 2012;215:137-46.

51. Lynch SP, Lei X, Hsu L, et al. Breast cancer multifocality and multicentricity and locoregional recurrence. Oncologist. 2013;18:1167-73.