SABCS Surgical Studies With Practice-Changing Potential Form Basis of Review of Noteworthy Data

J. Michael Dixon, MD, OBE

The value of surgery in some women with metastatic breast cancer was challenged by data from studies presented at the recent San Antonio Breast Cancer Symposium (SABCS).

In an interview, J. Michael Dixon, MD, OBE, discussed the results of studies on that topic and other notable surgical findings presented at SABCS in December 2013 (Table), including a new approach to detecting sentinel lymph nodes and data on avoiding radiotherapy (RT) in elderly patients.

The professor of Surgery, consultant surgeon, and clinical director of the Breakthrough Research Unit at the University of Edinburgh in Scotland shared highlights of that research with attendees at the 31st Annual Miami Breast Cancer Conference in March. Dixon served as one of the program directors for the conference.

Surgery Questioned in Some Metastatic Breast Cancers

There were two randomized studies and one registration study in patients with stage IV breast cancer presented at SABCS, each looking at the value of surgery, Dixon said.

“Two randomized studies looked at surgical removal of primary tumors with or without involved axillary lymph nodes in women with metastatic breast cancer. Despite the literature indicating that surgery appeared advantageous in women with metastatic disease, neither of these studies showed any advantage for surgery,” Dixon said.

One study conducted in India (Abstract S2-02), he said, compared overall survival (OS) in women with metastatic breast cancer who were treated with anthracycline-based chemotherapy, responded, and then were given either locoregional treatment (LRT) or no LRT.

Locoregional treatment consisted of surgery— either breast-conserving surgery or mastectomy plus axillary lymph node dissection—followed by RT. Both groups received standard endocrine therapy after the last cycle of chemotherapy, if indicated. The median follow-up was 17 months, and 218 deaths had been recorded at data cutoff. The authors, Badwe et al, found that median OS in the LRT and no-LRT arms, respectively, was 18.8 and 20.5 months (HR = 1.07; 95% CI, 0.82- 1.40; P = .60), and the corresponding 2-year OS rates were 40.8% and 43.3%, respectively. After adjusting for age, estrogen receptor (ER) status, HER2 receptor status, site of metastases, and number of metastatic lesions in a Cox regression model, there was no significant difference in OS between the two arms (HR = 1.00; 95% CI, 0.76- 1.33; P = .98), the investigators reported. “Locoregional treatment of the primary tumor and axillary nodes has no impact on OS in patients diagnosed with [metastatic breast cancer] at initial presentation who have responded to frontline chemotherapy,” Badwe et al wrote. “We were unable to identify any subgroups that are likely to benefit from [LRT]. Such treatment should be reserved for women who need it for palliative reasons.”

A second study (Abstract S2-03), this one conducted in Turkey, compared immediate LRT at diagnosis against systemic therapy in a group of women with metastatic breast cancer. The extent of metastases was less than in the Indian study, but the findings were the same—that LRT did not improve survival, except in a specific subgroup.

Finally, a US registration study presented by King et al (Abstract P2-18-09) identified a group of women who were found to have metastases within 3 months of surgery who had a more favorable outlook compared with women who had stage IV disease at first presentation. Among the stage IV patients, though, those who had surgery did not seem to have a better outcome. A commentary by an investigator leading the US randomized study questioned whether this study was sufficiently powered to detect small differences in outcome from surgery, yet still concluded that the pendulum had swung away from the belief that surgery in patients with metastatic breast cancer improves OS.

Study Challenges Axillary Lymph Node Dissection in Clinically N0 Patients

Dixon also pointed to notable 10-year follow-up data from NSABP B-32, a prospective, randomized phase III trial (Abstract S2-05) that compared sentinel node resection with or without conventional axillary dissection in clinically node-negative patients. Findings by Julian et al that were presented at SABCS focused on secondary endpoints of that trial, concerning the potential effects of occult metastatic disease on outcomes.

The top-line finding of the follow-up data, Dixon said, is that axillary lymph node dissection is unnecessary in this population, regardless of the presence (diagnosed or not) of occult metastatic disease.

In the study, 5611 women with operable, clinically node-negative, invasive breast cancer were randomized to receive sentinel node resection plus axillary dissection or sentinel node resection alone with axillary dissection only if sentinel nodes were positive. In a blinded review, pathologically negative sentinel nodes were checked by immunohistochemistry (IHC) for occult metastatic disease. The findings of the IHC test were evaluated to determine their effects on patient outcomes, and that data were reported by Julian and colleagues at SABCS.

Dixon explained that, at 10 years, the NSABP B-32 trial showed no significant difference in OS, disease-free survival (DFS), or regional control in patients with clinically node-negative disease treated by sentinel lymph node biopsy, regardless of whether axillary lymph node dissection was conducted. In patients diagnosed via IHC as having micrometastases or isolated tumor cells, he added, there was no significant difference in OS at 10 years when compared with the patients with true node-negative disease. According to the SABCS abstract, the 10-year HR for the difference in OS between the two study groups was 1.09 (P = .35); for the difference in DFS was 1.02 (P = .72); and for the difference in local/regional recurrence was 0.96 (P = .77). Local-regional recurrences were experienced by 4.3% of patients in the group that received both sentinel node resection and axillary dissection, and by 4% of those in the other group. Axillary recurrences occurred in 0.2% and 0.5% of those groups, respectively. Median time on the study was 131.1 months.

Of the total study population, the authors reported, 3989 patients were deemed sentinel node-negative, and 3884 (a nearly equal number from each group) underwent blinded IHC analyses. A total of 616 patients, again nearly evenly divided between the two groups, were found to have sentinel-node occult metastatic disease. There was a nearly significant difference in OS between the occult and nonoccult metastases groups (HR = 1.26; P = .06), and a significant difference in DFS between the two groups (HR = 1.24; P = .01).

However, the authors wrote, local-regional recurrence was not significantly different (HR = 0.8; P = .52). Of a total of 165 local-regional recurrences, occult local-regional recurrences accounted for 32 (19.3%), with just five axillary recurrences in the sentinel node resection-only group related to sentinel-node occult-detected disease. No statistical differences were found between the occult groups with and without axillary dissection for OS (HR = 0.98; P = .91) or DFS (HR = 0.82; P = .2).

“Although occult metastatic disease was detected in [sentinel nodes that had been negative when tested by hematoxylin and eosin staining], its presence had no significant impact on OS, DFS, or local-regional recurrences in the large group of 5611 patients,” the authors concluded. “Specifically, in [the group treated with sentinel-node resection only], the 15.3% of patients with IHC-positive nodes caused no significant impact on axillary failures. IHC use is not routinely recommended.”

Studies on Sentinel Lymph Node Detection, Radiotherapy May Change Practice

There are a variety of new methods for the detection of sentinel lymph nodes, and one that caught Dixon’s attention at SABCS involved the injection of iron followed by the use of a magnetometer and gamma probe to detect the iron particles in the sentinel lymph nodes. The SentiMag study (Abstract P1-01-02) compared the “gold standard” 99mTc, which can detect the location of sentinel lymph nodes within 1 or 2 days, against a new, quicker technique that uses superparamagnetic iron oxide (SPIO) particles to detect sentinel lymph nodes. In the study, the same 150 patients with histologically confirmed breast carcinoma underwent both techniques—99mTc 1 or 2 days prior to sentinel node biopsy, and SPIO 20 minutes prior. Results were similar, but slightly superior, with SPIO, and all pathologically positive lymph nodes detected with 99mTc were also detected with SPIO, the authors found. “The SentiMag provides an easy technique which can be rapidly implemented into daily routine,” they wrote. “Due to the simple handling, preoperative efforts can be reduced to a minimum.

If further and consistent results prove its efficacy, this technique may ultimately replace the standard of care.” Finally, a study about the role of RT in elderly patients, presented in results of the PRIME II trial (S2-01), was of note at SABCS, Dixon said. The trial’s results indicated that patients aged 65 years or older who have ER-rich cancers treated with tamoxifen after wide excision may avoid RT, he said.

In light of falling disease recurrence rates due to effective systemic therapy, the study’s authors sought to determine whether RT could be omitted in carefully defined groups of older patients. They tested 1326 patients over 6 years ending in 2009, randomizing the women 1:1 to receive or not receive RT. The patients were ≥65 years with T1-2 (up to 3 cm), N0, M0, hormone receptor—positive, axillary node-negative cancers with clear excision margins (≥1 mm), and were receiving adjuvant hormone therapy. Patients could have grade 3 tumors or lymphovascular invasion, but not both. The primary endpoint of the trial was ipsilateral breast tumor recurrence (IBTR). At 5 years, the authors found that IBTR was 4.1% without RT (95% CI, 2.4%-5.7%) and 1.3% with RT (95% CI, 0.2%-2.3%).

In patients receiving RT who had IBTR, the HR for IBTR was 4.34 (95% CI, 1.79-10.55; P = .001). Overall actuarial survival at 5 years was 93.8% without RT and 94.2% with RT (P = .24), the authors reported. There were no significant differences in regional recurrence (1.4% no RT vs 0.5% RT), contralateral breast cancer (0.9% no RT vs 1.5% RT), nor distant metastases (1.0% vs 0.3%). Breast cancer-free survival was 94.6% for no RT and 97.3% for those receiving RT (P = .003), and this difference was due to the greater IBTR in the no-RT group, the authors wrote. The majority of deaths were not linked to breast cancer (35 no RT vs 29 RT from a total of 87 deaths), with no influence of omission of RT (P = .27), they wrote. The investigators concluded that, “although RT reduces IBTR significantly, the absolute reduction in this study is very small.” “RT does not reduce the rate of regional recurrence, distant metastases or affect overall survival,” they added. “Omission of postoperative (whole-breast radiation therapy) in this population based on the 5-year rate of IBTR appears safe, especially in the presence of comorbidities.”

Table. Dixon’s List of Notable Surgical Abstracts From SABCS

Abstract Number

Study

Eligible Patients

Investigation Design

Findings

S2-02

Surgical removal of primary tumor and axillary lymph nodes in women with metastatic breast cancer at first presentation: a randomized controlled trial. (Badwe R, Parmar V, Hawaldar R, et al)

Patients with metastatic breast cancer at diagnosis who responded to anthracycline- based chemotherapy (and endocrine therapy, if indicated)

Patients received surgery and radiotherapy, or neither

No difference in OS between arms

S2-03

Early follow up of a randomized trial evaluating resection of the primary breast tumor in women presenting with de novo stage IV breast cancer; Turkish study (protocol MF07-01). (Soran A, Ozmen V, Ozbas S, et al)

Stage IV breast cancer with distant metastases at presentation

Patients received surgery plus radiation or neither, then both groups received systemic therapy

Surgery/radiotherapy did not significantly improve survival except in those with solitary bone metastasis, with a trend toward improvement in patients with bone metastasis only

P2-18-09

TBCRC 013: A prospective analysis of the role of surgery in stage IV breast cancer. (King TA, Lyman JP, Gonen M, et al)

Stage IV breast cancer

Compared 2-year survival in patients who presented with stage IV breast cancer (Arm A) and those who developed metastases within 3 months after primary surgery (Arm B)

Patients in Arm B had improved 2-year OS; in both groups combined, surgery was associated with improved OS; in Arm A patients who responded to chemotherapy, surgery did not improve OS

S2-05

10-y follow-up results of occult detected sentinel node disease: NSABP B-32, a randomized phase III clinical trial to compare sentinel node resection to conventional axillary dissection in clinically node-negative breast cancer patients. (Julian TB, Anderson SJ, Krag DN, et al)

Operable, clinically node-negative, invasive breast cancer

Trial compared sentinel node resection with or without axillary dissection; Julian et al’s follow-up considered whether the presence of occult metastatic disease affected results

Axillary dissection is not necessary in this population, and the presence of occult metastatic disease does not affect outcomes

P1-01-02

The SentiMag study: Sentinel node biopsy with superparamagnetic iron oxide vs radioisotope. (Thill M, Kurylcio A, Blechmann R, et al)

Histologically confirmed breast carcinoma

99mTc compared against superparamagnetic iron oxide particles (SPIO) in the same 150 patients to detect sentinel lymph nodes prior to surgery

SPIO matched effectiveness of 99mTc and worked more quickly

S2-01

The PRIME II trial: Wide local excision and adjuvant hormonal therapy ± postoperative whole breast irradiation in women ≥65 years with early breast cancer managed by breast conservation. (Kunkler IH, Williams LW, Jack W, et al)

Women ≥65 years with T1-2 (up to 3 cm), N0, M0, hormone receptor—positive, axillary node-negative breast cancers with clear excision margins (≥1 mm) who are receiving adjuvant hormone therapy

Patients randomized to receive or not receive radiotherapy

Omission of postoperative whole-breast radiation therapy in this population appears safe

OS indicates overall survival; N0, no cancer in lymph nodes; M0, no distant metastasis. Full abstracts available at: http://www.sabcs.org/resources/