Tom Castles

Patients with metastatic breast cancer who received an oral version of the chemotherapy drug paclitaxel with encequidar (Oral Paclitaxel) saw 14.8% improved response rates and 40% lower rates of peripheral neuropathy compared to those who took the drug intravenously (IV), according to the results of a new phase 3 clinical trial presented at the San Antonio Breast Cancer Symposium (SABCS).

“As an oncologist, it’s been very frustrating to have an effective chemotherapy like paclitaxel that a lot of patients cannot tolerate,” said the study’s lead investigator Dr. Gerardo Antonio Umanzor Funez, of the Centro Oncologico Integral in San Pedro Sula, Honduras, during a press conference at SABCS. “The therapy used in this phase 3 study — oral paclitaxel and encequidar  – was designed to overcome this issue.”

In the pivotal phase 3, open-label, randomized trial, which was conducted at 45 sites in Central and South America, researchers enrolled 402 patients with metastatic breast cancer to evaluate paclitaxel given in combination with encequidar, a novel inhibitor that allows the oral form of the chemotherapy agent to be absorbed into the bloodstream.

Patients were randomly assigned to receive either 205mg/m

of Oral Paclitaxel for three consecutive days a week (taking roughly 11 tablets per day depending on their body size), or 175mg/m

Treatment with Oral Paclitaxel resulted in a significantly improved centrally confirmed response rate of 40.4%, compared with 25.6% with IV paclitaxel representing an absolute improvement of 14.8%. These results were further supported by a significant improvement in overall response with Oral Paclitaxel, with an absolute improvement of 12.4%. Additionally, tumor response in all clinically important subgroups was consistent with the overall confirmed response profiles.

Researchers also measured progression-free survival (PFS), the time from treatment to disease progression or worsening. When it came to PFS, they found a nonsignificant association between oral and IV paclitaxel, meaning the difference was not greater between the groups than what could be expected by chance.

Peripheral neuropathy, a condition that causes weakness, numbness and pain that typically occurs in the hands and feet, is a common side effect of treatment with IV paclitaxel, but rates were greatly reduced in patients who took the oral formulation. In the trial, 57% of patients who took IV paclitaxel were treated for peripheral neuropathy, while only 17% of patients in the oral formulation arm needed treatment.

While the two drugs’ toxicity profiles were similar, there were higher rates of neutropenia infection and gastrointestinal side effects in patients who took Oral Paclitaxel, but these were low grade and manageable, according to the authors.

Oral administration of cancer chemotherapy is important to patients and preferable to intravenous drugs, especially in areas where they have difficulty accessing infusion clinics regularly, Umanzor added. But the fact that the drug must be taken orally and that patients must fast while taking it was a shortcoming of the study. With treatment, Umanzor Funez explained, there is a four-hour fasting period prior to taking the first tablet of encequidar. After the patient waits an hour, they then take oral paclitaxel, followed by an additional hour of fasting afterward.

“I think this is going to be a limitation of this medication,” said Dr Virginia Kaklamani, co-director of SABCS and leader of the breast cancer program at the University of Texas Health in San Antonio. “Many of our patients may not be able to tolerate 11 tablets, but keep in mind it’s only for three days per week. That’s something we’ll take into consideration before we prescribe.”

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Patients with metastatic breast cancer who received an oral version of the chemotherapy drug experienced improved response rates and reductions in peripheral neuropathy compared to those who took the drug intravenously.

Oral Paclitaxel Improves Response, Reduces Peripheral Neuropathy in Metastatic Breast Cancer

Patients with early-stage triple-negative breast cancer (TNBC) who did not have circulating tumor DNA (ctDNA) in their blood experienced superior outcomes, compared to those with the biomarker, after chemotherapy was given as a first step to shrink their tumors before surgery, according to trial results presented at the San Antonio Breast Cancer Symposium (SABCS).

The new data suggested that ctDNA, which is DNA shed from tumors that circulates in the bloodstream, could be a powerful predictor of survival in women with TNBC, a considerably more aggressive form of breast cancer that has not benefitted from recent advancements in hormonal targeted therapies seen in other types of breast cancers, according to Dr. Milan Radovich, associate professor of surgery at the Indiana University School of Medicine.

“We know with TNBC that patients with this cancer have their disease recur at a very high rate, particularly peaking in the first three years after surgery,” Radovich said during a press conference at SABCS, held Dec. 10-14, in San Antonio, Texas. “This causes an untenable situation for our patients, who live in constant fear and uncertainty of their cancers recurring after chemotherapy and surgery, (which is the current standard of care).”

When treated with neoadjuvant chemotherapy followed by surgery, about one in three patients will have a pathologic complete response, an absence of residual disease of the resected breast. In these cases, long-term survival rates are quite high.

But two in three patients have residual disease after chemo and surgery, with very poor long-term survival rates. Radovich and colleagues focused on this residual disease population in their study and harnessed the power of circulating tumor markers like ctDNA and circulating tumor cells (CTC), which are living tumor cells floating in the circulation that can be detected with simple blood draws.

“The question is if we detect the ctDNA and CTCs in patients who have completed neoadjuvant chemotherapy and surgery, are they at high risk of their cancers coming back? Again, these patients after chemotherapy and surgery are disease-free. We don’t detect any cancer, can’t see it, can’t feel it, can’t scan for it. But in a proportion of them, we know that their cancer will come back anyway,” he said.

Radovich and colleagues analyzed samples from the BRE12-158 clinical trial, designed to evaluate genomically-directed therapy compared with physician’s choice of treatment after neoadjuvant chemotherapy in 196 patients with TNBC. ctDNA was sequenced in 142 patients, and two-year disease-free survival was evaluated as a primary endpoint of the study presented at the symposium.

At two years, ctDNA-negative patients demonstrated superior disease-free survival, compared with ctDNA-positive patients (81% vs. 56%).

“The results are absolutely striking,” Radovich said. “Patients who have ctDNA in their circulation after surgery have significantly inferior distant disease-free survival (DDFS) compared to patients who are ctDNA negative.”

Next, Radovich and colleagues sought to find out whether the combination of ctDNA and CTC in the blood could become an even more powerful indicator of two-year DDFS. They observed a stepwise gradation in the outcomes: If patients came up negative for both ctDNA and CTCs, they had exceptionally superior outcomes; if they were positive for one marker or the other, they had intermediate outcomes; and if they were positive for both CTC and ctDNA, they had inferior outcomes.

The two-year disease-free survival for patients who were positive for both ctDNA and CTC was 52%, compared with 89% among those who were negative for both.

“This population that is ctDNA-negative and CTC-negative had a two-year DDFS of 89% even though based on standard clinical parameters, they’re at very high risk of relapse,” Radovich said. “When you look at their detailed clinical data, many of these patients had large tumors greater than 5 centimeters, several had lymph node involvement, yet they were biomarker-negative for both and have now had exceptional long-term outcomes.”

Although the trial is still ongoing, Radovich and colleagues announced that they’d take their findings a step further by launching a new trial, known as PERSEVERE, which will help further stratify patients who have residual disease after standard therapy.

“These results might be applicable to other types of breast cancer,” Radovich said. “But in TNBC, we think this represents the greatest opportunity.”

Patients with early-stage triple-negative breast cancer who did not have circulating tumor DNA in their blood experienced superior outcomes to chemotherapy followed by surgery.
 

Circulating Tumor DNA After Neoadjuvant Chemo May Determine Risk of Recurrence in TNBC

Residual cancer burden, or the amount of cancer cells that remain following treatment with chemotherapy, can help physicians pinpoint accurate long-term predictions about the likelihood that a patient’s breast cancer will return, as well as the likelihood and duration that a patient will survive, according to a large meta-analysis of patients with breast cancer presented at the San Antonio Breast Cancer Symposium (SABCS).

The meta-analysis, which is a study that analyzes the results of several studies on one subject, was led by Dr. W Fraser Symmans, professor and director of research operations in the department of pathology at The University of Texas MD Anderson Cancer Center in Houston.

In the study, Symmans and his colleagues from the I-SPY Clinical Trials Consortium compiled and analyzed data that represented roughly 5,100 patients. They examined associations between residual cancer burden index and event-free survival, which is the length of time after treatment ends that the patient remains free from the complications that the treatment was intended to delay, as well as distant recurrence-free survival, or the amount of time after treatment that a patient’s disease did not return.

In a statement, Symmans explained that residual cancer burden is assessed through several factors. These include size of the primary tumor, percentage of the tumor that spreads or remains in one location and the involvement of lymph nodes. Moreover, to make more accurate predictions, patients with residual cancer burden were classified into three separate groups by severity of their burden: RCB-1 (minimal burden), RCB-2 (moderate burden) and RCB-3 (extensive burden).

“The most interesting result in my opinion is that when you look at the residual cancer burden index scores and you look at that as a function of survival, you can see a log-linear relationship,” Symmans said during a press conference at the symposium, held Dec. 10-14, in San Antonio, Texas. “The implication of this result is that you can take an individual patient’s score of how much residual cancer burden they have and calibrate that to an accurate estimate of their risk over time.”

For patients who were hormone receptor (HR)-positive and HER2-negative, 11% were classified as having a pathologic compete response, meaning they lacked all signs of cancer in tissue samples or biopsy after treatment. For HR-positive, HER2-positive patients, 38% were classified as having a pathologic compete response.

“The measurement of (residual cancer burden) index is strongly prognostic, allowing us to measure risk of recurrence with confidence,” Symmans said in a statement. “This meta-analysis of residual cancer burden provides real-world evidence of how patients are responding to neoadjuvant treatments, and calibration of (residual cancer burden) index to prognostic risk enables us to determine the most appropriate next steps for breast cancer patients.”

In patients who were HR-negative,HER2-positive, 69% were classified as having a pathologic compete response. And for patients who were HR-negative, HER2-negative, 43% were classified as having a pathologic compete response.

Residual cancer burden was also measured in these patients. According to the results, their residual cancer burden levels were as follows at the 10-year follow-up date:

HR-positive, HER2-negative patients: 19% of the pathologic compete response group had a recurrence or died, compared with 14% in RCB-1, 31% in RCB-2, and 48% in RCB-3.

HR-positive, HER2-positive: 9% of the pathologic compete response group had a recurrence or died, compared with 17% in RCB-1, 36% in RCB-2, and 55% in RCB-3.

HR-negative, HER2-positive: 7% of the pathologic compete response group had a recurrence or died, compared with 15% in RCB-1, 37% in RCB-2 and 40% in RCB-3.

HR-negative/HER-2 negative: 14% of the pathologic compete response group had recurrence or died, compared with 25% in RCB-1, 39% in RCB-2, and 75% in RCB-3.

While results suggested that these prognostic indicators could be strong and reliable, the study was limited in that it was based on data from multiple different institutions that used variation in their methods for collecting data.

“Looking ahead, if we can standardize the reporting of residual cancer burden, that will only improve its usefulness in determining long-term prognosis,” Symmans said.

Residual cancer burden can help physicians pinpoint accurate long-term predictions about the likelihood that a patient’s breast cancer will return.

Measuring Residual Cancer Burden Could Help Improve Predictions of Breast Cancer Outcomes 

Women who took estrogen alone as hormone therapy for their menopause experienced decreased rates of breast cancer and death from the disease even after they stopped taking the therapy, while postmenopausal women who took estrogen with progestin experienced increased breast cancer rates, according to long-term follow-up results from two large, randomized, placebo-controlled Women's Health Initiative (WHI) trials.

The new data, presented during a press conference at the San Antonio Breast Cancer Symposium (SABCS), included 27,347 postmenopausal women aged 50 to 79 years with no prior breast cancer, enrolled in one of two randomized clinical trials that took place at 40 different centers in the United States between 1993 and 1998, with follow-up taking place over more than 19 years, through September 2016.

In total, 8,506 postmenopausal women with an intact uterus received conjugated equine estrogens (CEE) with medroxyprogesterone acetate (MPA), while 8,102 women received a placebo treatment. Both groups received their treatment for a median of 5.6 years.

Postmenopausal women who had undergone a hysterectomy received CEE alone (5,310) or placebo (5,429) for a median of 7.2 years.

Among those who only received CEE — the estrogen-only group – 520 cases of breast cancer were diagnosed after 16.1 years of follow-up. These women were 23% less likely to have been diagnosed with breast cancer and 44% less likely to die from the disease when compared with women who had received placebo.

In the group that received both estrogen and progestin (CEE with MPA), there were 1,003 diagnoses of breast cancer after 18.3 years of follow-up, for a 29% increased risk of diagnosis versus those on placebo. This group also saw an increased risk for death from breast cancer in the extended analysis, but this finding did not reach statistical significance.

“Menopausal hormone therapy with estrogen plus progestin (for postmenopausal women with an intact uterus) and estrogen alone (for postmenopausal women with prior hysterectomy) continues to be used by millions of women worldwide,” Dr. Roman Chlebowski, chief of the Division of Medical Oncology and Hematology at Harbor-UCLA Medical Center, and an investigator at The Lundquist Institute, said in a statement. “Nonetheless, after nearly half a century, menopausal hormone therapy influence on breast cancer incidence and mortality remains unsettled, with discordant findings from prospective observational studies compared to findings from randomized clinical trials.”

When asked at the press conference whether the new findings should impact clinical guidelines that doctors use to treat their patients, Chlebowski said he was hopeful that they would, and added that it’s important to consider the weight of his 20-year randomized-controlled trial in a large patient population against a meta-analysis of observational studies, which are not as rigorous.

“Women who are considering estrogen alone should know it’s safer and that there may be a breast cancer benefit associated with its use. I think women considering estrogen plus progestin have a little bit more of a difficult dilemma, because they have to be willing to accept an increased 20-year, and even a lifetime, breast cancer risk,” he said. “Having said that, for a woman with limited symptoms…the absolute risk is very small.”

Women who took estrogen alone as hormone therapy for their menopause experienced decreased rates of breast cancer and death from the disease even after they stopped taking the therapy, when compared to women who took estrogen with progestin.

Author | Tom Castles

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