What is the optimal neoadjuvant chemotherapy regimen? When should it be used?

OVERVIEW: While neoadjuvant systemic therapy downstages tumors and improves the chance for breast conservation, disease-free and overall survival appears to be comparable with postoperative therapy. The next generation of studies is evaluating a variety of strategies such as the taxanes, dose intensive chemotherapy, new systemic agents and predictors of tumor response, including DNA microarray analysis.

A 43-year-old woman with a breast tumor is referred to you for possible neoadjuvant systemic therapy. She has C cup size breasts and wishes to have breast-conserving therapy, if possible, which would be suboptimal if she went for surgery at the present time. What would be your usual preoperative systemic therapy?

CASE 1

TUMOR SIZE/STATUS		ACT FAC AC FEC PACLITAXEL NONE UNDECIDED 10% 5% 40% 5% 5% 30% 5%
2.8 cm ER+ HER2 -neg
		TAMOXIFEN ANASTROZOLE LETROZOLE OVARIAN ABLATION NONE 25% 15% 5% 5% 50%

CASE 2

TUMOR SIZE/STATUS		ACT FAC AC FEC PACLITAXEL NONE 15% 5% 35% 10% 5% 30%
2.2 cm ER-neg HER2+ (IHC 3+)
		TAMOXIFEN ANASTROZOLE LETROZOLE OVARIAN ABLATION NONE 10% 0% 10% 5% 75%
		TRASTUZUMAB NONE 35% 65%

What would be your usual preoperative systemic therapy if she were 43 years old with a 6.5 cm tumor?

CASE 3

STATUS		ACT FAC AC PACLITAXEL 30% 20% 40% 10%
ER+ HER2-neg
		TAMOXIFEN ANASTROZOLE LETROZOLE OVARIAN ABLATION NONE 20% 25% 10% 5% 40%

CASE 4

STATUS		ACT FAC AC DOXORUBICIN PACLITAXEL GEMCITABINE 35% 15% 35% 5% 5% 5%
ER-neg, HER2+ (IHC 3+)
		TAMOXIFEN ANASTROZOLE LETROZOLE OVARIAN ABLATION NONE 10% 0% 10% 5% 75%
		TRASTUZUMAB NONE 60% 40%

What would be your usual preoperative systemic therapy if she were 43 years old with inflammatory breast cancer?

CASE 5

STATUS		ACT FAC AC PACLITAXEL 30% 30% 30% 10%
ER+, HER2-neg
		TAMOXIFEN ANASTROZOLE LETROZOLE OVARIAN ABLATION NONE 20% 30% 5% 5% 40%

CASE 6

STATUS		ACT FAC AC PACLITAXEL GEMCITABINE 35% 15% 25% 20% 5%
ER-neg, HER2+ (IHC 3+)
		TAMOXIFEN LETROZOLE OVARIAN ABLATION NONE 10% 10% 5% 75%
		TRASTUZUMAB NONE 65% 35%

A 43-year-old woman presents with a 4.6 cm suspicious breast mass, which on core biopsy proves to be ER-positive invasive breast cancer. What would be your most likely current management?

CASE 7

STATUS		REFER PT. TO ONCOLOGIST FOR CONSIDERATION OF PRE-OP SYSTEMIC THERAPY SURGICAL MGMT. OTHER 40% 45% 15%
ER+ invasive breast cancer

A 43-year-old woman presents with a 2.8 cm suspicious breast mass, which on core biopsy proves to be ER-positive invasive breast cancer. What would be your most likely current management?

STATUS		REFER PT. TO ONCOLOGIST FOR CONSIDERATION OF PRE-OP SYSTEMIC THERAPY SURGICAL MGMT. OTHER 10% 80% 10%
ER+ invasive breast cancer

What would be your likely current management if she had inflammatory breast cancer?

STATUS		REFER PT. TO ONCOLOGIST FOR CONSIDERATION OF PRE-OP SYSTEMIC THERAPY SURGICAL MGMT. OTHER 80% 10% 10%
Inflammatory breast cancer

A 65-year-old woman presents with with a 2.8 cm suspicious breast mass, which on core biopsy proves to be ER-positive invasive breast cancer.

CASE 9

STATUS		REFER PT. TO ONCOLOGIST FOR CONSIDERATION OF PRE-OP SYSTEMIC THERAPY SURGICAL MGMT. OTHER 0% 95% 5%
ER+ invasive breast cancer

What would be your likely current management if she had inflammatory breast cancer?

STATUS		REFER PT. TO ONCOLOGIST FOR CONSIDERATION OF PRE-OP SYSTEMIC THERAPY SURGICAL MGMT. OTHER 85% 5% 10%
ER+ invasive breast cancer

NEOADJUVANT CHEMOTHERAPY

I view induction chemotherapy as a positive trend, because you do not lose anything, and there is a higher likelihood of being able to do a lumpectomy with a much better cosmetic result. It also provides an in vivo chemosensitivity assay. This trend will also allow us to start looking at minimally invasive surgery to the primary tumor. I predict that in the next decade we will move away from axillary node dissection, and sentinel node biopsy may be a transition maneuver in this regard, because people do not yet feel totally comfortable giving up the nodal status information. But once we start using systemic therapy first, the remaining question relates to treatment of what’s left of the primary tumor. The research question then would be, “Do you need to take the patient to the operating room at all?”

— Eva Singletary, MD

EFFECT ON PRIMARY TUMOR RESPONSE FROM THE ADDITION OF SEQUENTIAL DOCETAXEL TO AC

In NSABP B-18 survival was equal for preoperative and postoperative adjuvant chemotherapy, thus allowing preoperative therapy to be used safely to make breast conservation treatment feasible. In addition, the breast tumor response was a powerful predictor of both disease-free and overall survival. Based on these results and the very promising data coming out showing the high response rate with taxanes in women with anthracycline-resistant metastatic breast cancer, we embarked on protocol B-27. B-27 showed that the addition of docetaxel to four cycles of preoperative AC did add toxicity, but it significantly increased response rates. The clinical complete response rate was increased by 60%, pathologic complete response rate increased by 87%, and the pathologically negative nodes were increased by 15%. The questions that remain are whether or not this effect on response will translate into an advantage in terms of overall and disease-free survival and whether or not postoperative docetaxel will similarly increase overall and disease-free survival.

—Harry D Bear, MD, PhD
Presentation, 2001 San Antonio Breast Cancer Conference

FUTURE INVESTIGATIONS IN NEOADJUVANT THERAPY

There are a number of questions that remain to be answered in future trials of neoadjuvant therapy. Can we increase the clinical and pathological complete response rate further by the administration of other chemotherapy or biologic agents? Can we avoid breast surgery and/or radiation in patients who have a CR in the breast? Can axillary lymph node dissection be omitted in some or all of these patients, particularly since nodal status is not influenced by subsequent treatment? And perhaps most importantly for the future treatment of women with breast cancer, can the molecular or genetic markers becoming available be used to predict responses to certain drugs?

—Harry D Bear, MD, PhD
Presentation, 2001 San Antonio Breast Cancer Conference

NEOADJUVANT TRASTUZUMAB

A neoadjuvant study of trastuzumab-based therapy would be very interesting. There have been a lot of studies that have shown that neoadjuvant treatment is equivalent to adjuvant treatment, overall, for chemotherapy. However, one interpretation of the study in the metastatic setting of trastuzumab-based treatment is that earlier trastuzumab exposure is better than later trastuzumab exposure. Chemotherapy plus trastuzumab up front was superior to chemotherapy alone, even though two-thirds of the women who got chemotherapy in the metastatic setting without trastuzumab subsequently did receive trastuzumab therapy as part of their treatment.

—Harold J Burstein, MD, PhD

ABERDEEN PREOPERATIVE STUDY

. . . the Aberdeen data provide intriguing support for the view that sequential therapy including docetaxel is superior to maintained therapy with an anthracycline combination as a means of inducing pCR in the neoadjuvant setting. The evidence from this trial is important since it suggests that widespread current practice (which is to continue to give anthracyclines to patients who show an initial response) can be improved upon. It provides support for the general concept of using alternating non-cross-resistant regimens, although the trial does not demonstrate that use of such agents in sequence is superior to their simultaneous use from the outset of neoadjuvant therapy. Although further studies are needed to define the optimal treatment regimen, there is now a case for saying that docetaxel should be considered in the management of all patients receiving primary chemotherapy. Among other unanswered questions is whether inclusion of an anthracycline is an essential component of neoadjuvant regimens.

—Aapro, M. The Oncologist 2001;
6(suppl 3):36-39.

CORRELATION BETWEEN TUMOR RESPONSE AND OUTCOME

After preoperative chemotherapy, the resulting separation of patients into groups according to their tumor response might provide a significant clinical advantage in patient management. Because response to preoperative chemotherapy correlates with DFS and OS, response could be used as an intermediate end point in determining the value of new chemotherapy regimens or new drugs administered after well-established regimens. Because this intermediate end point can be achieved within weeks from the start of preoperative chemotherapy, new regimens could be evaluated promptly and useful conclusions could be drawn without a 5- to 10-year waiting period, as is currently the case after the use of postoperative adjuvant therapy. With the development of several new agents, breast cancer patients might, in the future, be spared from administration of ineffective regimens if these do not translate into prompt tumor response in the preoperative setting.

— Mamounas EP, Fisher B. Seminars in Oncology 2001;
28(4):389-399.

CORRELATION OF BIOMARKERS WITH TUMOR RESPONSE

With primary tumor response as an intermediate end point, the manner in which new tumor markers are developed and evaluated could be changed. Moreover, it might be possible in the future to use such markers in order to identify those patients among the clinical complete responders who have a high likelihood of pathologic complete response and for whom further local therapy in the form of surgical resection and/or breast radiotherapy could be avoided. Furthermore, serial monitoring of tumor marker changes while the tumor is undergoing preoperative chemotherapy might provide biologic insight into the nature and function of such markers.

—Mamounas EP, Fisher B. Seminars in Oncology
2001; 28(4):389-399.

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 CLOSED PROTOCOL

“ Overall, 12% more lumpectomies were performed in the preoperative group; in women with tumors 5.1 cm, there was a 175% increase. … Preoperative therapy reduced the size of most breast tumors and decreased the incidence of positive nodes. The greatest increase in lumpectomy after preoperative thera py occurred in women with tumors ³5 cm, since women with tumors less than 5 cm were already lumpectomy candidates. Preoperative therapy should be considered for the initial management of breast tumors judged too large for lumpectomy.” Fisher B et al. J Clin Oncol 1997;15:2483-2493. Abstract

NSABP B-18: CLINICAL OUTCOME AND NINE-YEAR FOLLOW-UP OF PATIENTS RECEIVING PREOPERATIVE AC VERSUS POSTOPERATIVE AC CHEMOTHERAPY

Pre-op AC Post-op AC Lumpectomy 67% 60% Pathologic Nodal Status     Negative 59% 43%     Positive 41% 57%   S u rv i va l * 69% 70% D F S * 55% 53% I B T R * 10.7% 7.6%

Derived from Fisher B A et al. J Clin Oncol 1997;15:2483-2493. Abstract *Wolmark N et al. J Natl Cancer Inst Monogr 2001;30:96-102. Abstract.

NSABP B-27 TRIAL: PHASE III RANDOMIZED STUDY OF PREOPERATIVE DOXORUBICIN AND CYCLOPHOSPHAMIDE (AC) VERSUS PREOPERATIVE AC FOLLOWED BY DOCETAXEL VERSUS PREOPERATIVE AC AND POSTOPERATIVE DOCETAXEL IN WOMEN WITH OPERABLE CARCINOMA OF THE BREAST CLOSED PROTOCOL

AC=doxorubicin/cyclophosphamide; T=docetaxel; TAM=tamoxifen po x 5 years * Patients undergoing breast-conserving surgery receive radiotherapy.

NCI-00-C-0149 TRIAL: PHASE II PILOT STUDY OF CDNA MICROARRAY AS A MEASURE OF TUMOR RESPONSE TO NEOADJUVANT DOCETAXEL AND CAPECITABINE FOLLOWED BY SURGERY AND ADJUVANT DOXORUBICIN AND CYCLOPHOSPHAMIDE IN PATIENTS WITH STAGE II OR III BREAST CANCER OPEN PROTOCOL

X=capecitabine; T=docetaxel; A C = doxorubicin/cyclophosphamide Patients who undergo lumpectomy and ALND receive standard XRT following the completion of chemotherapy. Patients who undergo a modified radical mastectomy may receive chest wall radiation. ER+ or PR+ patients receive tamoxifen po qd x 5 yrs. Tumor tissue is collected at baseline, day 2 of course 1 of neoadjuvant chemotherapy, prior to course 2 of neoadjuvant chemotherapy, and at surgery. Samples are subjected to reverse transcriptase PCR and cDNA microarray analysis.

STUDY CONTACT: JoAnne Zujewski, Chair, Ph: 301-402-0985 Center for Cancer Research Medicine Branch Bethesda, MD

PRELIMINARY RESULTS OF NSABP B-27: PREOPERATIVE AC DOCETAXEL

THE ADDITION OF DOCETAXEL TO AC ON PRIMARY TUMOR RESPONSE RESULTED IN: Equivalent rates of breast conserving surgery and mastectomy Significantly increased clinical (65% to 40%) and pathological (25.6% to 13.7%) complete response rates A higher percentage of patients with histological negative axillary nodes (59.5% to 51.5%) Additional toxicity (grade 4: 24% to 10%) Note : 2,411 patients randomized , with an average time on study of approximately 40 months

Derived from NSABP Presentation, 2001 San Antonio Breast Cancer Symposium; Abstract

PHASE II STUDY OF PREOPER ATIVE TRASTUZUMAB (HERCEPTIN) AND PACLITAXEL (TAXOL) IN STAGE II/III HER2 OVEREXPRESSING (IHC 2+/3+) BREAST CANCER

PROTOCOL: H + T -> DEFINITIVE SURGERY AC Objective Response (CR + PR) 29/40 (73%) Pathological Complete Response 7/40 (18%)

H = t rastuzumab; T = paclitaxel Derived from Burstein HJ et al. Breast Cancer Res Treat 2001; Abstract 507.

STUDY OF NEOADJUVANT TRASTUZUMAB (HERCEPTIN), DOCETAXEL (TAXOTERE) AND CISPLATIN IN LOCALLY ADVANCED AND INFLAMMATORY HER2 OVEREXPRESSING (IHC 2+/3+) BREAST CANCER

PROTOCOL: H + T + C -> SURGERY AC + XRT + TAMOXIFEN PROJECTED ACCRUAL:

Small series of patients: Stage IIB (n=5), Stage IIIA (n=14), Stage IIIB (n=5) and Stage IV ( n=1) 10 of 16 pati ents (63%) who have undergone surg e r y were node negative

H = t rastuzumab; T=paclitaxel; C=cisplatin Derived from Hurley JE et al. Breast Cancer Res Treat 2001; Abstract 516.

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