Anna Azvolinsky, PhD

Twenty-five years ago, breast cancer clinical trials examined whether neoadjuvant therapy—prior to surgery&mdash;was as safe as adjuvant therapy. “There was a lot of concern that if the patient progressed on therapy, you would lose the opportunity to operate,” says Kelly K. Hunt,  professor of surgical oncology at the MD Anderson Cancer Center in Houston, Texas.

Hunt discussed the management of the axilla after neoadjuvant chemotherapy at the 32nd Annual Miami Breast Cancer Conference. Hunt says breast cancer interventions have progressed in the adjuvant and neoadjuvant setting, as well as the evolving role of sentinel lymph node dissection (SLND) in the neoadjuvant setting.

Earlier trials, which did not distinguish between the breast cancer subtypes—estrogen-receptor positive, triple-negative, and HER2-positive&mdash;established that neoadjuvant chemotherapy allows for more patients to undergo breast-conserving surgery rather than mastectomies. Meta-analyses that compared adjuvant to neoadjuvant systemic therapies showed no difference in disease progression, distant disease recurrence, or death from breast cancer, and also showed that neoadjuvant chemotherapy had fewer side effects.

Subsequent studies examined whether a pathological complete response (pCR) following neoadjuvant therapy is a valid surrogate endpoint for longer-term outcomes, such as disease-free survival (DFS) and overall survival (OS). Many of these trials provided evidence that pCR does translate to better OS, but meta-analyses could not confirm that pCR translated into improved OS. “Partly, this is because we now understand that when breast cancers are divided into subtypes, patients with ER-negative and HER-positive disease are more likely to have a pCR from neoadjuvant therapy compared with those with ER-positive disease,” says Hunt.

The National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocols B-18 and B-27 have demonstrated that stacking two chemotherapies in the neoadjuvant setting in women with operable breast cancer results in DFS and OS similar to adjuvant chemotherapy. Now, neoadjuvant studies have moved beyond the neoadjuvant-versus-adjuvant-therapy question to ask which neoadjuvant regimens are optimal for each breast cancer subtype to improve pCR, according to Hunt.

“We have learned that not only are we getting more patients to breast conservation, but that we’re getting more patients to node-negative disease following surgery, even when patients started with biopsy-proven node-positive disease,” Hunt says. She mentioned that this holds true for all breast cancer subtypes, but particularly for women with HER2-positive disease, as a result of available HER2-directed therapies.

One study conducted at MD Anderson of 109 patients with HER2-positive node-positive disease demonstrated a 74 percent axillary pCR after Herceptin (trastuzumab)-containing neoadjuvant chemotherapy followed by breast surgery and complete axillary lymph node dissection.

“This was a single-institution study, but others and also the NSABP B-27 and B-18 studies have shown that when you compare patients that were treated with neoadjuvant and adjuvant systemic therapies, there are fewer node-positive patients in the neoadjuvant compared to the adjuvant groups.”

The National Comprehensive Cancer Network guidelines currently list appropriate neoadjuvant therapy options for women with breast cancer based on subtype. “Neoadjuvant therapy is considered for those patients that have at least T2 disease or node-positive disease,” says Hunt. “Some physicians also consider neoadjuvant therapy for small HER2-positive tumors between 1 and 2 centimeters in size.”

“Neoadjuvant therapy is a powerful way to assess response and to help clinicians understand a patient’s prognosis based on residual tumor burden and disease in the lymph nodes,” says Hunt. “The most proven benefit of neoadjuvant systemic therapy is less subsequent surgery.” The neoadjuvant approach has been established; the question now emerging is whether a targeted axillary node dissection, rather than a full axillary dissection, is as accurate and whether it leads to similar outcomes.

Axillary node dissection removes the entire axillary fat pad, which contains between 15 and 20 lymph nodes in the arm pit. These nodes are then assessed by a pathologist. Sentinel lymph node dissection removes one to three lymph nodes and is the standard way to stage breast cancer in patients with clinically lymph node—negative disease. Typically, women are assessed for lymph node disease at diagnosis with a physical examination and ultrasound.

The American College of Surgeons Oncology Group Z0011 trial from 2011 showed that axillary dissection did not result in survival benefit compared with sentinel node dissection alone in women with metastatic disease confined to one or two sentinel nodes. Avoiding a full axillary node dissection is favored, particularly in early-stage disease, because this results in less lymphedema, shoulder pain, and dysfunction for patients, according to Hunt.

Results from this study led to the question of whether a subgroup of patients with breast cancer and biopsy-confirmed node-positive disease who are undergoing neoadjuvant systemic therapy may also opt out of axillary dissection and receive sentinel node dissection instead. “The majority of people agree that sentinel node [dissection] after chemotherapy is favored in clinically node-negative patients. It’s the biopsy-proven, node-positive patients where the false-negative rates for sentinel node surgery have been higher,” Hunt says.

“There are trials ongoing now to understand if we can eliminate axillary dissection and whether we need to replace it with radiation therapy,” says Hunt. The Alliance for Clinical Trials in Oncology A11202 trial is randomizing almost 3000 patients with stage 2 or 3 breast cancer who have received neoadjuvant chemotherapy and remain node positive following surgery. The trial is testing whether or not axillary node dissection plus radiation therapy improves breast cancer recurrence rate compared with sentinel node dissection alone plus radiation therapy in patients with a positive sentinel node after neoadjuvant chemotherapy.

A second ongoing trial, the NSABP B-51/RTOG 1304 phase III study, is randomizing over 1600 women with stage 2 or 3 breast cancer who have received neoadjuvant therapy to either regional radiotherapy or no radiotherapy following surgery. The trial is studying whether or not regional radiotherapy improves invasive breast cancer recurrence-free rates in patients who present with node-positive disease who subsequently convert to node-negative disease at the time of surgery after neoadjuvant chemotherapy.

“The question now is whether we can reduce the extent of surgery we are doing and whether radiation therapy is needed, because both of these [interventions] have long-term morbidities,” says Hunt. “As the cure rates for women with earlier-stage breast cancers are improving, there is no reason why these patients have to live with long-term negative side effects of these treatments and interventions, if they are not necessary.”

Researchers are also trying different techniques to improve the accuracy of lymph node staging following chemotherapy. According to Hunt, the current optimal sentinel-node-surgery approach is the combination of the blue dye, lymphazurin, with a radioisotope tracer, because sometimes a positive node can be missed with either of the individual techniques. Hunt also suggests that if a biopsy at initial diagnosis finds a positive lymph node, that node should be marked in order to target the node for removal after therapy.

“Sentinel node surgery after chemotherapy can be hard, because patients may develop fibrosis. Marking the node improves accuracy and allows the surgeon to pay close attention to how many lymph nodes are removed during the dissection.”

Articles

Surgical oncologist Kelly K. Hunt, of MD Anderson Cancer Center, discusses how breast cancer interventions have progressed in the adjuvant and neoadjuvant setting and the role of sentinel lymph node dissection in the neoadjuvant setting.

Evolving Role of Lymph Node Biopsies After Neoadjuvant Therapy for Breast Cancer

	Treating patients with triple-negative breast cancer (TNBC) remains a challenge because these tumors do not rely on hormone receptors or HER2 amplification for tumor growth. TNBC is a heterogeneous disease that is not defined by a specific biology; therefore, the standard of care remains cytotoxic chemotherapy rather than targeted therapy. A single chemotherapeutic agent is commonly used, with combination chemotherapy reserved for those patients with TNBC who have particularly symptomatic or rapidly progressing visceral disease.

	Lisa A. Carey, professor at the University of North Carolina (UNC) Chapel Hill and researcher at the UNC Breast Center, discussed the management of TNBC at the Miami Breast Cancer Conference. Carey spoke about recent developments for patients with triple-negative disease.

	“What’s new in chemotherapy treatment options is results from a study called the Triple Negative Breast Cancer Trial or TNT reported this past December at the San Antonio Breast Cancer Symposium [SABCS],” said Carey. “This study is the first hint that we could, and should, make different choices of chemotherapy regimens based on the type of triple-negative breast cancer.”

	The United Kingdom-based, randomized, head-to-head TNT investigated whether patients with previously untreated metastatic TNBC respond better to a taxane, the current standard of care, or a platinum-based chemotherapy regimen. Prior to the study, data on whether or not certain patients with TNBC respond better to a platinum-based chemotherapy were lacking.

	“Typically, platinum-based chemotherapies are used later in treatment, but the TNT study showed that either docetaxel or carboplatin worked well as first-line therapy, which is helpful for those of us treating patients, as it provides more options in the front-line setting,” said Carey. Neither the response rate nor progression-free survival (PFS) or overall survival (OS) was different between the two treatment arms. A prespecified subset analysis showed that patients with a germline BRCA1 or BRCA2 mutation had a higher proportion of objective responses and greater PFS when treated with carboplatin compared with docetaxel. The median PFS for patients with BRCA1/2 mutations was 6.8 months in the carboplatin arm compared with 4.8 months in the docetaxel arm. Prior small studies had hinted that BRCA-mutated tumors may respond better to platinum-based chemotherapy, but this is the first trial to formally address this question, according to Carey.

	Additionally, non—basal-like tumors appeared to have a higher response to docetaxel compared with carboplatin, but the number of patients with basal-like tumors was too small to draw conclusions, Carey noted.

	“Based on this study, carboplatin is now on my list of first-line options for sporadic triple-negative breast cancer,” said Carey. “I generally chose between a taxane and platinum chemotherapy based on toxicities. Platinum chemotherapies result in less neuropathy compared to taxanes, but platinum-based regimens are also accompanied by more nausea and myelosuppression and can be harder on the kidneys compared to taxanes. Platinum-based chemotherapy is not a low-toxicity regimen, but rather, has different toxicities and may be more suitable for some patients.” In TNT, the docetaxel arm had a higher frequency of febrile neutropenia and neuropathy compared with the carboplatin arm.

	A type of immunotherapy known as checkpoint inhibition has proven effective in melanoma, renal cell carcinoma and lung cancer. While not historically an immune-responsive cancer type, a recent phase 1 trial, also reported at the 2014 SABCS, showed that the anti-programmed cell death protein-1 (PD-1) antibody, Keytruda (pembrolizumab), has activity in TNBC. Keytruda was recently approved for treatment of metastatic melanoma. The phase 1b TNBC study is the first to show responses to a PD-1 antibody in breast cancer.

	The study recruited 32 women with PD-L1—positive, recurrent, metastatic TNBC. Patients were treated with 10 mg/kg Keytruda every 2 weeks until progression or unacceptable toxicity. Patients on the trial had a median age of 51.9 years, and most patients had received and progressed on at least two lines of chemotherapy for metastatic disease.

	Among the 27 patients who could be evaluated for response, 18.5 percent had an objective response including one complete response and four partial responses. Seven patients had stable disease. The median time to response was 9.9 months. Three of the five responders have been on treatment for at least 11 months.

	Five patients had at least one drug-related serious adverse event (AE). One of these AEs, disseminated intravascular coagulation (DIC) with thrombocytopenia and decreased blood fibrinogen, resulted in death. The safety profile was acceptable in this relatively heavily pretreated cohort, the study authors concluded.

	“While the study is small, the responses seen were really durable,” said Carey. A phase 2 study of Keytruda in TNBC is being planned to start in 2015.

	Another immune checkpoint inhibitor, MPDL3280A, an anti— PD-L1 antibody, against the ligand of PD-1, is also being investigated for TNBC as part of a phase 1 solid tumor clinical trial. Early phase 1 data on patients with TNBC were also reported at the 2014 SABCS. Of nine patients with PD-L1–positive tumors evaluated thus far, three responded, including one complete response. The trial is still recruiting patients with both PD-L1– positive and PD-L1–negative TNBC and other tumor types.

	“There are lots of [sequencing] data already on subclasses within TNBC, and there will be more of those kinds of studies,” said Carey. “How that is going to help treat patients is still an unwritten chapter.”

	Many TNBC primary tumors have been sequenced, but sequencing of primary tumors thus far has not been helpful because these tumors have few actionable mutations. New efforts are focusing on sequencing metastatic TNBC tumors. In estrogen-receptor—positive tumors, sequencing metastatic tumors may be relevant to treatment as new, clinically relevant mutations not seen in the primary tumor have been identified post treatment, according to Carey. “Whether that is true in triple-negative breast cancer remains to be seen.”

	According to Carey, DNA sequencing of tumors may be less helpful compared with RNA expression levels, epigenetics, and protein levels. The Breast Cancer Research Fund is funding the AURORA US and AURORA EU studies to evaluate metastatic breast cancer samples to better understand the molecular biology of metastatic tumors and to develop clinical trials based on these findings. Academic centers including UNC Lineberger Comprehensive Cancer Center are collaborating to analyze metastatic tumors retrospectively and then conduct prospective studies focused on metastatic TNBC tissue. The goals are to identify metastatic-specific molecular and genetic markers of breast cancer and to track these changes in individual patients over time as a response to treatment.

Treating patients with triple-negative breast cancer (TNBC) remains a challenge because these tumors do not rely on hormone receptors or HER2 amplification for tumor growth.

Anna Azvolinsky, PhD

Evolving Role of Lymph Node Biopsies After Neoadjuvant Therapy for Breast Cancer

Views on Evolving Chemotherapy Options—and Beyond—in TNBC

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Anna Azvolinsky, PhD

Evolving Role of Lymph Node Biopsies After Neoadjuvant Therapy for Breast Cancer

Views on Evolving Chemotherapy Options&mdash;and Beyond&mdash;in TNBC

Latest News

Views on Evolving Chemotherapy Options—and Beyond—in TNBC