New Options for Low-Risk, HER2-Positive Tumors Featured in Research Overview

Debu Tripathy, MD

Fresh insights into outcomes for patients with low-risk, HER2-positive breast cancer suggest that adjuvant chemotherapy regimens with or without trastuzumab (Herceptin) should be considered as options for managing this growing population, according to Debu Tripathy, MD.

Two abstracts^1,2 involving patients whose tumors were categorized as node-negative and T1a or T1b are among the highlights of 2013 that Tripathy reviewed during the 31st Annual Miami Breast Cancer Conference in a presentation entitled “ASCO/ San Antonio Update: Medical Oncology.” His reviews have become an annual feature of the conference. Tripathy has identified noteworthy research in several categories from among abstracts presented last year during the 2013 American Association of Clinical Oncology (ASCO) in June and the 2013 San Antonio Breast Cancer Symposium in December. In an interview, Tripathy said research findings on low-risk, HER2-positive disease are significant enough to change practice.

“This is an area that was a blind spot for us,” said Tripathy, who serves as co-leader of the Women’s Cancer Program at the USC Norris Comprehensive Cancer Center and is one of the MBCC directors. “We obviously know that trastuzumab can improve outcomes when added to chemotherapy for HER2-positive breast cancer, but the dilemma has always been about lowrisk tumors that are T1a or T1b, and node negative.”

Tripathy, whose research has contributed to the development of trastuzumab, said one of the challenges facing clinicians treating patients with low-risk, HER2-positive breast cancer is balancing the potential for adverse events (AEs) with the benefits of adjuvant therapy that may only lower their risk of recurrence by 1% to 2%. “There are obviously side effects from both chemotherapy and trastuzumab, including a small chance of cardiomyopathy,” he said.

Patients deemed low risk receive a wide range of treatments—either no adjuvant therapy, a more intensive chemotherapy/trastuzumab regimen, or perhaps hormone therapy with or without trastuzumab if their tumors are hormone receptor (HR)-positive, said Tripathy. He said a recently presented phase II trial suggests that low-risk patients might benefit from a less intensive chemotherapy regimen of trastuzumab plus weekly paclitaxel for 12 cycles. “Now we have this middle road that seems to be effective,” he said.

Treatment Trends Examined

There is much uncertainty about optimal treatments for patients with T1a/T1b N0M0 (≤1 cm) breast cancer even as mammogram screenings contribute to a rise in the incidence of such early-stage cancers, said Ines Maria Vaz Duarte Luis, MD, MSc, of the Dana-Farber Cancer Institute, in a presentation at ASCO.¹ In fact, she said patients with T1a/T1b N0 breast cancer make up approximately 20% of stage I-III disease in the developed world.

Traditionally, such patients have been excluded from clinical trials, resulting in limited data on chemotherapy outcomes for subsets of patients, said Vaz Duarte Luis. In order to gather data on this patient population, researchers analyzed therapy trends and outcomes for women treated for newly diagnosed stage I-III unilateral breast cancer treated from 2000-2009 at eight centers in the National Comprehensive Cancer Network. Survival outcomes at 5 years were analyzed for four subgroups: HR+/ HER2—; HR–/HER2–; HR+/HER2+; and HR–/HER2–. At ASCO, Vaz Duarte Luis and colleagues focused on their findings concerning 4113 patients with T1a/ T1b N0M0 tumors.

Overall, they found that that the use of adjuvant chemotherapy with or without trastuzumab varied widely among subgroups; a high proportion of patients with HER2-positive and HR—/HER2– T1N0 disease received therapy and the percentage of patients with HER2-positive disease receiving therapy increased dramatically over the years (Table 1). The 5-year distant relapse-free survival (DRFS) rates showed most subgroups experienced an improved prognosis with adjuvant therapy compared with those who had not been treated, although there were variations. In the HER2-positive groups, patients who received adjuvant therapy experienced better outcomes.

In the HR+/HER2+ group, the proportion of patients with T1b tumors (N = 199) who received adjuvant chemotherapy with or without trastuzumab rose from 36% in 2003 to 100% in 2009. The 5-year DRFS rate was 91% among those who were not treated as opposed to 95% for those who received adjuvant therapy. Of the patients in this group, 54% received chemotherapy and 36% received trastuzumab.

Table 1. Trends and Outcomes for Patients With T1b Tumors

Subgroups

Patients (N)

Treatment Trends Chemotherapy ± trastuzumb

(% treated)

DRFS Without chemotherapy or trastuzumab

(5-y median rate)

DRFS With chemotherapy and/or trastuzumab

(5-y median rate)

2003

2009

HR+/HER2+

199

36%

100%

91% (n = 89)

95% (n = 110)

HR—/HER2+

105

76%

100%

81% (n = 17)

94% (n = 88)

HR+/HER2—

2246

10%

13%

96% (n = 2005)

95% (n = 241)

HR—/HER2–

264

70%

69%

90% (n = 94)

93% (n = 170)

DRFS indicates distant relapse-free survival.

Vaz Duarte Luis et al. 2013 San Antonio Breast Cancer Symposium. Abstract 1006.

In the HR—/HER2+ group, the proportion of patients with T1b tumors (N = 105) who received adjuvant therapy rose from 76% in 2003 to 100% in 2009. The 5-year DRFS rate was 81% among those who were not treated as opposed to 94% for those who received adjuvant therapy. Of the patients in this group, 84% received chemotherapy and 46% received trastuzumab.

The researchers concluded that certain subgroups, such as those with T1bN0 HR-negative tumors, face a sufficient risk of recurrence to consider chemotherapy, but they noted in their abstract that “careful examination of cutoffs for absolute benefit sufficient to recommend chemotherapy is warranted.” Tripathy said the findings suggest a reduction in the risk of recurrence among HER2-positive patients whose regimens incorporated trastuzumab. However, he noted the data are not from a randomized clinical trial, a limitation that Vaz Duarte Luis also acknowledged.

Strong Showing for Trastuzumab

While the examination of adjuvant therapy trends presented a nuanced picture according to subtype, the phase II Adjuvant Paclitaxel Trastuzuamb (APT) study concluded that the combination of adjuvant paclitaxel plus trastuzumab yielded excellent outcomes for patients with early-stage node-negative, HER2-positive disease.²

Prior randomized trials have shown that adding trastuzumab to chemotherapy reduces the risk of recurrence for patients with HER2-positive breast cancer, but relatively few patients with stage I disease and “virtually no patients with tumors ≤1 cm” have been included in these studies, said Sara M. Tolaney, MD, MPH, of the Dana-Farber Cancer Institute, during her presentation of the study results at ASCO.

Figure. Patient Characteristics in APT Trial

For the study, Tolaney and colleagues recruited 410 patients with HER2-positive disease whose tumors were ≤3 cm and either node negative or with 1 lymph node micrometastasis with a negative axillary dissection.

Of the 406 participants who went on to receive treatment, half of the patients had T1a/T1b tumors (≤0.5 cm to ≤1.0 cm) while the other half of the patients had tumors categorized as T1c/T2 (>1.0 cm to ≤3.0 cm). Sixty-seven percent of the patients were HR-positive and 33% were HR-negative (Figure).

Patients received paclitaxel (80 mg/m2) plus trastuzumab (4 mg/kg loading dose, then 2 mg/kg) for 12 weekly cycles, followed by trastuzumab for 39 weeks (2 mg/kg w or 6 mg/kg q3w).

After a median follow-up of 3.6 years, the participants achieved a 98.7% three-year disease-free survival rate (95% CI, 97.6%-99.8%; P <.0001). Similarly, the 3-year recurrence-free interval (RFI) rate was 99.2% (95% CI, 98.3% to >99.9%). RFI included incidences of invasive local or regional recurrence, distant recurrence, and death from breast cancer (Table 2).

The most common AEs were grade 2/3 fatigue, diarrhea, and neuropathy. Two patients (0.5%) experienced symptomatic congestive heart failure (grade 3 left ventricular systolic dysfunction) that reversed upon discontinuing trastuzumab; 13 patients (3.2%) displayed asymptomatic declines in LVEF, 11 of whom were able to resume trastuzumab therapy after a break.

Table 2. Key Results in APT Trial

Outcomes

DFS, 3-y

RFI, 3-y

Rate

98.7%

99.2%

95% CI

97.6%—99.8%

98.3%—>99.9%

P value

<.0001

n/a

CI indicates confidence interval; DFS, disease-free survival; RFI, recurrence-free interval.

Tolaney SM et al. 2013 San Antonio Breast Cancer Symposium. Abstract S1-04.

“They used a lower side effect regimen that had previously not been tested,” said Tripathy. “While there isn’t a comparator arm that did not get trastuzumab therapy, I think the results of this study along with the safety profile are such that we can probably add this as a potential regimen for patients with very low-risk disease.”

He said patients in this population could receive standard doxorubicin/cyclophosphamide, paclitaxel plus trastuzumab, or docetaxel/carboplatin/trastuzumab if their risks were higher, but that the side effects many not be worth the very small benefit for lower risk tumors. “Weekly paclitaxel with trastuzumab is yet another option for such cancer,” Tripathy said. “I believe that this finding could represent a practice-changing option.”

Future Considerations

Although tools for assessing risk stratification for patients with early-stage, HR-positive breast cancer have been in development, more work must be done to help guide therapies for those who are HER2- positive, said Tripathy. New therapies such as pertuzumab (Perjeta) and ado-trastuzumab emtansine (T-DM1; Kadcyla), as well as multiple-therapy regimens that are being tested in the adjuvant setting, will present new challenges in managing patients with lower risk disease.

“In the future, we will develop molecular and protein assays to help us discern which patients may benefit more from trastuzumab or not benefit,” Tripathy said. “As we start adding more HER2-based targeted therapies, we are definitely going to need them to help us guide patients.

“I suspect what’s going to happen in the HER2 field is that we’re going to be developing more and more drugs for patients and we’ll probably be overtreating some patients with multiple drugs that they may not need,” said Tripathy. “We’re going to need better risk stratification as we go forward.”

References

1. Vaz Duarte Luis IM, Ottesen RA, Hughes ME, et al. Time trends in the use of adjuvant chemotherapy and outcomes in women with T1N0 breast cancer in the National Comprehensive Cancer Network. J Clin Oncol. 2013;31(suppl; abstr 1006).
2. Tolaney SM, Barry WT, Dang CT, et al. A phase II study of adjuvant paclitaxel and trastuzumab (APT trial) for node-negative HER2-positive breast cancer. Presented at: 2013 San Antonio Breast Cancer Symposium; December 10-14, 2013; San Antonio, TX. Abstract S1-04.