This is an overview and some highlights from the 3rd day of the San Antonio Breast Cancer Symposium, more of which we’ll post later, including analysis of the plenary session on epigenetics, environment, and epidemiology.
By Karuna Jaggar, Executive Director
GeparTrio Trial from Germany: “Neoadjuvant Chemotherapy adapted by interim response improves overall survival of primary breast cancer patients”
With this sessions, researchers presented a study that looked at whether there is greater benefit if neoadjuvant (which is to say, pre-operative) chemotherapy is adjusted based on tumor response. This is called response-guided therapy.
Three years after initial data from this study was presented, the investigators presented five year survival data. Because the initial results were negative, today’s positive results were a surprise for many. And, we should be cautious not to overly rely on pathological free response as predictive of overall survival.
So, what did this practice-changing study find?
The study looked at patients who had received two cycles of TAC and evaluated the tumor response after 6 weeks. (Note: the trial occurred before Herceptin was widely available for HER2+ tumors.) Tumor response was considered a 50% reduction in tumor size.
If the tumor responded, TAC was continued and the patients were randomly assigned to the standard 4 additional cycles or (on the theory that more is better) to 6 additional cycles.
If the tumor did not respond after 2 cycles of TAC, patients were randomly assigned 4 more cycles of TAC (which is the standard of care) or NX for 4 cycles.
The researchers found that after 62 months of follow up—despite prior data that there was no benefit to pathological free response—there is benefit for patients with this response-guided therapy when it comes to both recurrence and death. This modified chemo treatment, based on tumor response, resulted in 30% reduction in recurrence and 20% reduction in deaths.
Subgroup analysis showed that almost all of this benefit was seen in hormone positive tumors, where HER2+ and triple negative tumors did not benefit from response-guided treatment.
Furthermore, the study found that pCR is highly prognostic fro HER2+ and triple negative tumors.
The feeling is that the somewhat surprising results of this trial will encourage more pre-operative/ neoadjuvant chemotherapy, especially in hormone positive cancers for women who will benefit from chemotherapy.
The BOLERO-2 Phase III Trial: “Everolimus for postmenopausal women with advanced breast cancer: updated results of the BOLERO-2 Phase III trial”
This trial addressed the issue of resistance to endocrine therapies. The standard of care for metastatic hormone receptive breast cancer is to sequentially give single agent therapies, switching when the disease progresses. Each subsequent therapy typically has a shorter window of efficacy and the goal of this study is to overcome resistance to endocrine therapy.
In the trial were 724 post menopausal women with advanced breast cancer which had recurred or progressed. All patients had received a non-steroidal aromatase inhibitor (AI). More than ½ of the patients had received three or more previous endocrine therapies.
All study patients received the steroidal AI Exemestane (Aromasin) in the trial, some were given Everolimus in addition to the Aromasin, while the rest were given a placebo and no Aromasin.
The researchers found that progression free survival and response improved by adding Everolimus, which was thought to inhibit other pathways when a tumor became resistant to endocrine therapies.
There was a high rate of patients discontinuing treatment, the majority because of disease progression. Side effects of Everolimus include stomatitis, rash, fatigue, diarrhea, decreased appetite, nausea and hyperglycemia.
The question remains whether these are better than chemotherapy side effects as the alternative to hormone therapy is chemotherapy for metastatic disease.
The presenter concluded saying that Everolimus is the first agent to increase the efficacy of hormone therapy in patients with ER+, HER2- metastatic breast cancer.
FDA approval will likely be sought as a way to overcome endocrine resistance and delay chemotherapy. I have to note that this is a very expensive drug.
GEPARQUINTO: “Neoadjuvant chemotherapy of pacitaxel with or without RAD001: results of the non-responder part of the GEPARQUINTO study (GBG 44)
The question these researchers considered was, looking at a group not responding that well to chemo, if they add in an antiogenesis inhibitor (blocking the growth of new blood vessels), will it help the chemo?
The answer was no–this was a negative study, meaning it did not have statistically significant results.
While the study looked at HER2+ and HER2- tumors, only the HER2- results were presented today. Patients received 4 cycles of EC and were randomized to get Avastin (bevacizumab). The study had a negative result looking at pathologically complete response at surgery, such that adding Avastin did not increase the efficacy of chemotherapy after 4 cycles. Looking at the GeparTrio study from earlier in the same session, we are reminded of the dangers of focusing only on pathologically complete response and further study is needed to learn the impact on overall survival.
“Risk of contralateral breast cancer in BRCA 1 and 2 carriers compared to non-BRCA 1 and 2 carriers in consecutive patient series”
This study from the Netherlands draws on a huge data set and anonymous tissue bank.
The study aimed to understand the risk of a 2nd breast cancer for women with the BRCA 1 or 2 mutation and a history of beast cancer. Women who have had one diagnosis of breast cancer have a higher risk of cancer of the other breast (called contralateral breast cancer), than the general population and this study aimed to understand the risks of that for BRCA mutation carriers specifically.
The researchers examined almost 5,000 tissue samples and tested for the BRCA 1 and 2 mutations, identifying 4% of the population as BRCA carriers (about 3% BRCA 1 and 1% BRCA 2).
- Women with the BRCA 1 mutation have approximately a 20% risk of conralateral breast cancer in a 10 year period
- Women with the BRCA 2 mutation have approximately an 11% risk of contralateral breast cancer in a 10 year period
- Noncarriers (with no BRCA mutation) have approximately a 6% risk of contralateral breast cancer in a 10 year period
The data identified subgoups of BRCA carriers with different statistics:
- The BRCA mutation carriers with the highest risk were patients with a first breast cancer diagnosed under age 41, with a 26% risk of a 2nd breast cancer
- Patients with a triple negative breast cancer diagnosed between the ages of 41-50 also were higher risk with a 15% chance of a 2nd breast cancer
- On the other end of the spectrum, non triple negative patients with a first breast cancer diagnosed between ages 41-50 had a 3.5% risk of a 2nd breast cancer.
Relevance of this study to patients and their doctors includes improving personal surveillance after breast cancer and personalized treatment choices. If confirmed in other studies, age and receptor-status of the first breast tumor may be guidelines for prophylactic measures and screening for BRCA mutation carriers.
“Next generation sequencing reveals co-activating events in the MAPK and P13K/AKT pathways in metastatic triple negative breast cancers”
This study highlights the way that research is evolving. While it is not a trial, it seeks to establish proof of concept of a direction for future research on personalized treatment.
The investigators worked with a small sample of 14 patients with triple negative metastatic breast cancer to sequence the genes of these tumors. The urgency and need is that about 1/3 of triple negative breast cancers will metastasize and the median survival is just one year. All tumors have a lot of mutations and the objective of this study is to identify mutations that can be clinically targeted. That is, by looking at every gene and pathways that are up-regulated (increased) and down-regulated (decreased), identify treatments that target these pathways. Twelve pathways have been sequenced to date — half are in African American women, the other half in White women. I was pleased to hear this because so often women of color are not included enough in trials, which impacts their ability to get effective treatment down the line.
It was striking that this is the only presentation so far to show photographs of actual women’s bodies—and the human toll of this disease hit home, seeing the age of each woman and thinking about what might be happening in her life outside of breast cancer. I couldn’t help but think of my own loved ones and what the ages that flashed on the screen marked in their lives and wonder about these 14 women. Does breast cancer coincide with a professional promotion, birth of children, completion of a higher degree, settling down with a partner…
“Results of a randomized, double-blind, multicenter, placebo-controlled study of adjuvant lapatinib in women with early-stage erbB2-overexpressing breast cancer”
Worldwide many patients don’t have access to Herceptin for Her2+ breast cancer and this trial addresses the question of whether Lapatinib is effective for HER2+ breast cancers.
It is worth noting that the design of trial is unusual in that women were eligible to participate at any time period after their initial diagnosis. The median time from diagnosis to randomization was 2.7 years and a majority had been diagnosed within 4 years.
- HER2+ tumors (confirmed locally)
- No prior Herceptin
- All had neoadjuvant chemo and age-appropriate hormone therapy
The study tested the efficacy of Lapatinib vs placebo with the primary objectives of disease free survival and, second, overall survival. Initial examination of the data showed that there was no statistically significant benefit in disease-free survival for Lapatinib.
However when the investigators went back to restain the tissue and validate the local lab’s HER2 status, only 79% were found to truly be HER2+, highlighting again the need for patients to be able to get second opinions about what’s going on in their bodies—down with gene patents!
Getting back to the study, looking at this group, there was a significant benefit in disease free survival with Lapatinib. Overall survival was the same for both groups. Less than 6% of patients died in both arms of the trial. Because Lapatinib crosses the blood/brain barrier (which Herceptin does not), an additional finding was a reduction of relapse of metastasis to the brain.
Issues of safety/toxicity:
- Increased treatment discontinuation and interruption of treatment to readjust
- No serious adverse events
- Diarrhea, rash, nausea, fatigue—all reversible and none fatal
Because of the widespread use of Herceptin in the United States today, there is no clinical use for this study in the U.S. An additional take-away from the study is the fact that HER2+ patients remain at ongoing risk of recurrence. The natural history of HER2+ which was demonstrated by the placebo arm showed a natural recurrence about 3% per annum.
“AVEREL, a randomized Phase III trial to evaluate bevacizumab (BEV) in combo with tratuzumab (H) and docetaxel (DOC) as first line therapy for HER2+ locally recurrant/metastatic breast cancer”
On Thursday afternoon the results of AVEREL were presented. AVAREL is a randomized Phase 3 trial to evaluate bevacizumab (Avastin) in combination with tratuzumab (Hercptin) and docetaxil for metastatic HER2+ breast cancer. Bevacuzumab (Avastin) is an anti-angiogenic drug that received accelerated approval by the FDA based on initial results. Since 2007, BCAction has actively opposed FDA approval of Avastin for metastatic breast cancer because of its failure to improve overall survival and its severe negative side effects.
Based on preclinical data, this trial sponsored by Roche sought to investigate the combination of Avastin with Herceptin and Docetaxel for metastatic HER2+ breast cancer. Avastin blocks antiogenesis, and recently the FDA revoked approval to use Avastin for breast cancer due to severe side effects and little impact on overall survival. Investigators are still trying to determine if there is a subset of women who do benefit from the drug. AVAREL is the first randomized trial of Avastin in Her2+ breast cancer, which is an aggressive form of the disease. This trial studied first-line treatment in 424 patients enrolled in the study between Sept 2006-Feb 2010 who had not received prior treatment for metastasis. Participants were randomly assigned to two arms:
- Trastuzumab (Herceptin) + docetaxel
- Trastuzumab (Herceptin) + docetaxel + bevacizumab (Avastin)
Investigator analysis after an average of 26 months found no statistically significant reduction in progression free survival, though there was a not statisticall significant 18% reduction of disease progression or death in the Avastin arm. Subgroup analysis found benefit for women over 65 years at time of entry but these were very small numbers and not statistically significant. There was no difference in response for estrogen receptor positive and negative disease.
However an independent review committee found a statistically significant small improvement (2.9 months) in progression free survival where the investigators didn’t.
There were a high rate of adverse events, with almost everyone experiencing some adverse event. More than 2/3 (68%) experienced grade 3-5 adverse events, with few deaths. 38% of patients on the Avastin arm discontinued due to adverse events compared with 28% on the control arm. Significant issues of concern are Avastin’s effect on heart health, in particular left ventrical dysfunction, cardiac failure, etc.
The presenter suggested that this study represents proof of concept for Avastin and presented some data on their work to identify an appropriate biomarker that indicates which patients may benefit. In particular, there was some data presented that may indicate that levels of VEGF-A plasma—which corresponds to HER2 over-expression—may provide a way of distinguishing a subgroup of patients who may benefit from Avastin.
Exploratory study of biomarkers suggests that levels of VEGF-A appear to correlate with how well Avastin works, suggesting the possibility of identifying a subgroup with high VEGF levels who may benefit from Avastin. Looking at safety and toxicity, almost everyone in the trial had an adverse event (nearly 98%). While there were few deaths , 68% experienced grade 3-5 adverse events (compared to 63% without Avastin). Overall 38% of patients in the Avastin arm discontinued the drug due to adverse effects compared to 28% in the Herceptin and chemo arm. Serious toxicity included left ventrical dysfunction, cardiac failure, and acute pulmonary edema.
In the mentor session I mentioned above, a patient advocate in the audience asked about the adverse side effects of the drug. One of the panelists responded somewhat dismissively, to which the advocate replied, “But what about the deaths from Avastin in the clinical trials?” The panelist responded, “Everything can cause death. Life causes death.”
Update of International Breast Cancer Study Group trial 23-01 to compare axillary dissection versus no axillary dissection in patients with clinically node negative breast cancer and micrometastases in the sentinel node
This trial looked at the question of axillary dissection with minimal sentinel micrometastases. Like previous study, this trial found no benefit of axillary dissection even if the sentinel node is positive.
Eligibility criteria was relaxed as the trial went on, relaxed from 3mm to 5mm later on. Patients were randomized to receive no dissection or axillary dissection. The primary endpoint was disease free survival with secondary endpoints of overall survival, disease free site, surgical complications, etc.
934 patients were enrolled between 2001 and 2010 with a median follow up of 57 months. At which time, there was no difference between the two arms. Overall survival was high: 98% for no dissection and 97.6% with dissection.
There are two reasons to do axillary dissection:
1. prevent disease in the axilla—which must be weighed against the side effects
2. determine treatment plan—and this is becoming less relevant as other methods take precedence
Given the serious side effects of axillary dissection—including lymphedema and neuropathy—standard of care should be not to do axillary dissection with minimal sentinel node involvement.
Often the presentors at SABCS do not lay out a clear conclusion about how their research impacts patient care and clinical practice. Thankfully, in the Q&A after this presentation, Dr. Laura Esserman of UCSF did the concluding for the audience, appealing to all attendees to stop doing axilliary node dissectiom when the sentinel node is minimally involved.
“Clarifying the risk of breast cancer in women with atypical breast lesions”
This is a retrospective study from a Boston group using a computer to classify and analyze a large data set. The primary investigator did not report as she’d had a baby 3 weeks ago.
The goal of the study is to clarify the risk of breast cancer for women with atypical breast lesions, with an analysis of the specific diagnosis and related risk. Additionally, the study sought to evaluate the efficacy of chemoprevention with regard to breast lesions.
Atypical breast lesion diagnoses (in ranked order from lowest to maximum diagnosis) were:
- Atypical ductal hyperplasia
- Atypical lobular hyperplasia
- Lobular carcinoma in situ
- Borderline DCIS
The study looked back at 76,333 breast pathology reports, and found almost 3,000 women with atypical breast lesions.
There was no difference found in types of atypia (cell abnormality) in the natural progression of these lesions. That is, excluding women who had chemoprevention, all diagnoses had similar increased rates of breast cancer after 10 years. I want to note the subjective nature of atypia — four reputable labs can look at the same sample and give four different diagnoses. Talk about a difference of opinion!
Looking at chemoprevention after 1999, 19% (466 women) were treated with chemoprevention compared to 1472 not treated. Chemoprevention reduced the risk of developing breast cancer for women with atypia:
- 5 year drop in breast cancer by half
- At 10 years, the decrease was more significant, with a 66% reduction in breast cancer diagnoses
There was a drop in rates of cancer with chemoprevention regardless of type of atypical lesion. While this retrospective study is not adequate to prove the benefit of chemoprevention, it has already been demonstrated in a separate random control trial. No side effect data was presented.
In the advocate briefing that evening, there was discussion about the need to know when to treat DCIS, and when to leave it alone. Dr. Susan Love noted that, without a way to image how much DCIS a woman has, “watchful waiting is difficult because there’s no way to know when to get nervous.”