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Breast Conservation After Neoadjuvant Chemotherapy: the MD Anderson Cancer Center Experience

Posted on: Thursday, 17 February 2005, 03:00 CST

Objective:

To determine the patterns of local-regional recurrence (LLR) and ipsilateral breast tumor recurrence (IBTR) in patients treated with neoadj uvant chemotherapy followed by breast conserving therapy (BCT), and to correlate outcomes with clinical and pathologic variables.

Methods:

A retrospective review of medical records identified 401 patients treated with BCT following neoadjuvant chemotherapy, between the years of 1987 and ZOOO. After excluding several cases that had undergone excisional biopsy prior to therapy, had no identifiable tumor, inflammatory changes or systemic disease at presentation, 340 cases in 338 patients served as the primary focus of this study. The clinical stage at diagnosis was I in 4%, II in 58% and HI in 38%. Following biopsy and appropriate staging studies, patients were treated with a variety of doxorubicin based chemotherapy regimens. Indications for neoadjuvant therapy were broad, and 76% of these patients were treated on a variety of clinical protocols. Patients treated off protocol were generally treated with the intention of obtaining a clinical response which would facilitate BCT. Surgery consisted of gross excision of the residual tumor with an attempt to obtain negative margins. Standard level I/II node dissections, with or without sentinel node biopsies, were performed in 81 % of the cases. The final pathologic margin was positive in only 15 (4%) of these patients. The majority of estrogen receptor (ER) + post- menopausal patients received tamoxifien and 77% of patients received additional adjuvant chemotherapy following BCT.

Results:

Disease characteristics following neoaduvant chemotherapy and BCT were as follows:

No residual primary tumor - 24%.

Residual disease morphology:

no residual - 24%;

solitary mass - 54%;

multifocal residual disease - 23%.

Median residual tumor size - 1.0 cm (range 0-6 cm).

Margin status:

negative (78%);

close (16%);

positive (4%);

unknown (2%).

DCIS present - 38%.

Lympho-vascular invasion (LVI) present - 15%.

Nodal status:

negative - .51%;

1-3 positive - 28%;

4-10 positive - 10%;

> positive - 4%;

unknown - 7%.

With a median follow-up time of 6.3 months, 29 patients developed local regional relapse (LRR), resulting in a 5-year local-regional relapse free rate of 91%. Of the 29 LRRs, 16 were ipsilatcral breast relapses, seven of which occurred in the supraclavicular fossa, two in the axilla, two in the infraclavicular fossa and two in the internal mammary nodes. The 5- year rate of ipsilatcral breast tumor relapse was 95%.

Variables that positively correlated with IBTR and LRR were clinical N2 or N3 disease, pathologic residual tumor larger than 2 cm, multifocal pattern of residual disease and lymphovasucular space invasion in the specimen. Initial T-Category (Tl-2 vs. T3-4) correlated with LRR but not IBTR. Of note, patients with a pathologic complete response (CR) had a similar rate of LRR and IBTR as those without a pathologic CR.

Conclusions:

The use of neoadjuvant chemotherapy followed by BCT in appropriately selected patients results in an acceptable rate of LRR and IBTR. Adverse factors associated with a higher rate of LRR include multifocal residual disease, LVI or both. This cohort represents a minority of patients in this series.

Commentary:

This study adds to a growing body of literature suggesting that neoadjuvant chemotherapy can result in significant tumor responses in breast cancer and can ultimately increase the feasibility of breast conserving therapy. While retrospective, their results are impressive and suggest that local relapse rates are quite acceptable using this approach in selected patients. One major drawback of the study is its selection bias and retrospective nature. The authors acknowledge the limitations of the selection biases inherent in this type of analysis, in that they were unable to determine the true proportion of all patients treated with neoadjuvant chemotherapy desiring breast conservation, who subsequently became eligible for this treatment. Having said that, it is clear from this and other studies that a substantial percentage of patients who might otherwise not be eligible candidates for breast conservation, will have a significant response to neoadjuvant chemotherapy and will then have the option of breast conservation. Randomized studies demonstrate no compromise in survival, and the current study by Chen et al. along with several other studies, demonstrate acceptable rates of local-regional control1-3. The increased utilization of neoadjuvant chemotherapy for both locally advanced and earlier stages of breast cancer provides an opportunity for addressing some important and clinically relevant issues, particularly in light of recent technological developments in the management of breast cancer.

One area requiring clarification relates to the optimal pretreatment work-up for these patients. In this regard, the role of breast MRI, as a supplement to mammography and ultrasound, prior to and following neoadjuvant chemotherapy, needs to be defined4. Should MRI of the breast be routinely obtained in patients treated with neoadjuvant chemotherapy? Should patients with diffuse involvement of the breast seen by MRI be excluded from breast conserving approaches? Can the post-neoadjuvant MRI scan be used to better select patients for breast conserving therapy? What is the role of PET and/or CT-PET in this setting? What is the optimal imaging for follow-up in patients treated with neoadjuvant chemotherapy and breast conserving therapy?

In addition to questions regarding imaging, evaluation and management of the axilla is a complicated issue in the neoadjuvant setting. Clearly the role of sentinel lymph node sampling in the neoadjuvant setting requires further investigation5 Is there a role for pre-neoadjuvant sentinel node sampling to assess pretreatment nodal status? Is there a role for post-neoadjuvant sentinel node sampling and how will this information be used?

Since these patients will be routinely receiving radiation therapy to the breast, what is the benefit of axillary dissection in comparison to axillary radiation, following neoadjuvant therapy in the clinically negative axilla.

Finally, what is the role of molecular and genetic markers in the setting of neoadjuvant chemotherapy for breast cancer? Can molecular markers be used to predict response, select optimal chemotherapeutic regimens and ultimately select patients most suitable for this approach? Studies correlating clinical and pathologic response rates, as well as long-term local control rates, to molecular profiles can provide meaningful and potentially clinically applicable data in this regard6.

These are just a sample of clinically relevant issues which need to be further explored. Well designed prospective clinical trials, with companion molecular and imaging studies, addressing these and other issues in patients treated with neoadjuvant chemotherapy, are encouraged. Such studies will provide exciting avenues of investigation, and hopefully advance the treatment and cure of breast cancer for all women.

Further reading:

1. Broet P, Scholl SM, de la Rochefordiere A, et al. Short and long-term effects on survival in breast cancer patients treated by primary chemotherapy: an updated analysis of a randomized trial. Breast Cancer Res Treat 1999;58:151-6

2. 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

3. Powlcs 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

4. Warren RM, Bobrow LG, Earl HM, et al. Can breast MRI help in the management of women with breast cancer treated by neoadjuvant chemotherapy? Br J Cancer 2004:90:1349-60

5. Trocha SD, Giuliano AE. Sentinel node in the era of ncoadjuvant therapy and locally advanced breast cancer. SurgOncol 2003; 12:271-6

6. Haffty BG. Molecular and genetic markers in the localregional management of breast cancer. Semin Radiat Oncoi 2002;12:.329-40

Chen AM, Meric-Bernstam F, Hunt KK, Thames HD, Oswald MJ, Outlaw ED, Strom EA, McNccsc MD, Kuerer HM, Ross MI, Singletary SE, Ames FC, Feig BW, Sahin AA, Perkins GH, Schechter NR, Hortobagyi GN, Buchholz TA. J Clin Oncol 2004;22: 2303-12

Commentary by: Bruce G. Haffty, MD, Dept of Therapeutic Radiology, Yale University School of Medicine, USA

Copyright CRC Press Sep 2004

Source: Women's Oncology Review

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