Is Breast Cancer Research Geared to Our Patients?

Martine Piccart-Gebhart, MD, PhD, Assesses Progress in HER2-Positive Breast Cancer

Roxanne Nelson, BSN, RN


April 18, 2016

The Quest to Tailor Treatment to Patient Need

Despite these significant advances, Dr Piccart-Gebhart emphasized that one very important component is missing. "The problem is that this research is highly fragmented and occurring in the context of single trials with no intention of putting it into a single platform," she said. "This research has led to many publications, but has this research met the needs of our patients?"

This research has led to many publications, but has this research met the needs of our patients?

From 2000 to 2015, in the quest to tailor treatment for HER2-positive breast cancer, research delved beyond HER2, she noted. "We have looked at other receptors/ligands, transduction pathways and components of the stroma, as well as tumor heterogeneity."

But has this research into biomarkers addressed the needs of patients? Patients with HER2-positive breast cancer have differing concerns about their treatment depending on the stage of their disease. Recognizing these concerns, Dr Piccart-Gebhart reviewed findings of translational research to assess how closely they address patients' top questions regarding their treatment.

Advanced HER2-Positive Disease: Research vs Patient Needs

Patients with advanced-stage HER2-positive breast cancer tend to want answers to the following questions:

  • Can I live for many more years with the disease?

  • Can I be sure that the chosen therapy will truly help me?

  • Can I stay away from therapies with marked side effects for long periods of time?

Efforts in translational research for advanced disease are continuing, and Dr Piccart-Gebhart assessed how well research addresses those concerns.

Prognostic markers. In trials such as CLEOPATRA[1] and EMILIA,[5] the consensus has been that high HER2 mRNA confers a better prognosis. "This was seen across several trials, but it was not a predictive factor," she noted.

In contrast, PIK3CA mutations conferred a worse prognosis, but again they were also not a predictive factor, and a benefit from treatment was still seen even with the presence of these mutations. "In the CLEOPATRA trial, dual blockade worked in both cohorts, but the magnitude of benefit was better in the wild type," explained Dr Piccart-Gebhart. "In the EMILIA trial,[5] T-DM1 worked in both cohorts, but the larger magnitude of benefit was seen in the mutated cohort."

Disappointingly, the ligands, the PIK3CA pathway, and other pathways that were examined in the context of the CLEOPATRA trial did not identify any predictive biomarkers, she pointed out.

Tumor microenvironment. Another translational effort has been research into the tumor microenvironment, where investigators have only recently begun to understand the crucial role that it may play as a prognostic and predictive biomarker. "And in the meantime, we have indirect evidence of its critical importance through the alarming results of some clinical trials," she said.

Trials have shown a loss of survival when trastuzumab is interrupted in the treatment of advanced disease. In the LUX Breast[6] and EGF104900[7] studies, there was a disconnect between progression-free survival, which was very similar between the two treatment arms being compared, and overall survival (OS), which was much worse for the non-trastuzumab-containing arm.

This disconnect could not be explained by differences in the therapies that were given after progression. "I suspect that it might be explained by the microenvironments and the effect that trastuzumab has on the tumor microenvironment," said Dr Piccart-Gebhart. She further explained, "We have become aware that the immune mechanism of action of this drug is far more important than inhibition of signal transduction."

Immune checkpoint blockade may afford even greater manipulation of the tumor environment. The PANACEA trial,[8] which is currently enrolling participants, will add anti-programmed death-1 (PD-1) therapy to trastuzumab. "Clearly our hope is that with just a few doses of anti-PD-1 therapy, long-lasting remissions will be induced, and that will keep patients away from chemotherapy," she added.

Tumor heterogeneity. In researching tumor heterogeneity, Dr Piccart-Gebhart highlighted the ZEPHIR trial,[9] a collaboration between medical oncologists and nuclear medicine in which zirconium 89-labeled trastuzumab was used to measure HER2 expression (extracellular domain) for the entire disease burden—a finding that could potentially identify patients unlikely to benefit from T-DM1 administration.

In the ZEPHIR trial,[9] which is currently ongoing, molecular imaging is used to explore intra-/interpatient heterogeneity in HER2 mapping of metastatic disease. An analysis of 56 patients showed that combining HER2-PET/CT and FDG-PET/CT accurately predicted morphologic response (positive and negative predictive value: 100%) and discriminated patients with a median time to treatment failure (TTF) of only 2.8 months (n = 12) from those with a TTF of 15 months (n = 25).

"Our hope is to close some of the clinical research gaps in advanced HER2-positive breast cancer by examining the cellular and the macromolecular landscape of the so-called HER2-positive and HER2-negative lesions," she said.

To date, how should the three initial questions be answered for patients with advanced HER2-positive disease? Yes to the first, in that patients can live many years; but no to the second, meaning that they cannot be sure that the chosen therapy will help because essential biomarkers are lacking. For the third question, the answer would be "sometimes" because patients may be able to stay away from therapies with marked side effects for long periods of time.

Dr Piccart-Gebhart envisions a way of helping a subset of patients answer the third question more positively, but it will take teamwork. By combining certain imaging patterns with certain molecular profiles, she explained that it may be possible to identify a group of patients who would do extremely well with TDM-1 as first-line therapy, allowing them to stay on this drug for perhaps 3 years. "We know that this drug brings our patients back to an almost normal life," she said.

"To do a better job," concluded Dr Piccart-Gebhart, "we will need to embrace the complexity of the disease, and this can only happen through much more intense interdisciplinary teamwork."

Early HER2-Positive Disease: Research vs Patient Needs

Patients with early HER2-positive breast cancer have a different perspective when it comes to tailoring their treatment. What they want to know is:

  • Can I be sure that my long-term treatment will help me?

  • Can I do as well with a simpler or a shorter treatment?

  • Can I forgo aggressive chemotherapy?

Biomarkers in the adjuvant and neoadjuvant settings. Translational research in early disease is being conducted in both the neoadjuvant and the adjuvant settings, but both have different endpoints. "In the neoadjuvant setting, we usually look for biomarkers predicting pathologic complete response [pCR], and occasionally we look to see if they correlate with event-free survival (EFS) or OS, which are the endpoints that really matter to our patients," she explained. "In the adjuvant setting, we look for biomarkers predicting DFS and OS, and we examine their interaction with treatment."

In early disease, sharp contrasts have been seen in the neoadjuvant and adjuvant settings. In the neoadjuvant setting, high levels of HER2 expression (whether measured by HER2 protein, mRNA, or HER2-enriched PAM50 subtype) are associated with higher pCR' whereas in the adjuvant setting, HER2 levels have not correlated with patient outcomes.

If this is true," said Dr Piccart-Gebhart, "these patients should no longer receive trastuzumab.

"Intriguingly, there has been a suggestion of a lack of benefit of trastuzumab in a subgroup of women whose tumors have a high level of ER expression and low level of HER2 expression," she noted. Investigators in both the NSABP[10] and HERA trials,[11] she said, have made these observations. "If this is true," said Dr Piccart-Gebhart, "these patients should no longer receive trastuzumab."

Dr Piccart-Gebhart pointed out that even though it would be impossible to have a trial to confirm this, "our last chance to validate this potentially important observation will be to re-run the analysis in the context of a meta-analysis of five trials that are looking at shorter vs longer trastuzumab duration."

Transduction pathways. In research examining downstream signaling, two important observations have been made. In the neoadjuvant setting, there is a lower likelihood of pCR with dual HER2 blockade if tumors are estrogen receptor-positive/PIK3CA mutated. However, this did not translate into worse DFS, which was similar between mutated and wild-type tumors.[12]

Dr Piccart-Gebhart posited that it might be too simplistic to examine a single biomarker in a single biologic pathway and expect to find all the answers. She cited Dr Lajos Pusztai's presentation[13] on the whole exome sequencing of pretreatment biopsies in the NeoALTTO trial (a trial that showed the superiority of the combination of lapatinib and trastuzumab in significantly improving rates of pCR) to examine correlations between pCR and OS. When looking at the PIK3CA and RhoA pathways, a subgroup of patients—those with mutated PIK3CA and wild-type RhoA—were found to have a pCR of only 2% with trastuzumab alone, but the pCR was dramatically improved to 43% with the addition of lapatinib.

"Importantly, this translates into improved survival for dual HER2 blockade," noted Dr Piccart-Gebhart. "Those patients who lack mutations in the two pathways (wild-type PIK3CA and wild-type RhoA) have excellent responses to trastuzumab alone and do not benefit from dual blockade," but she added that this finding will require independent validation from other studies.

Tumor microenvironment. In the neoadjuvant setting, tumor infiltrating lymphocytes (TILs) and immune gene expression signatures are subjects of active research, commented Dr Piccart-Gebhart. For example, in NeoALTTO, she reported that she and her colleagues found that a level of TILs greater than 5% was associated with mean higher pCR rates, independent of the treatment group. In addition, TILs retained strong prognostic value for EFS, independent of pCR.[14]

"I was particularly impressed by the good outcome of women whose tumors had baseline TILs of 40% or more, and there were virtually no events," said Dr Piccart-Gebhart. "So if we can provide an independent validation of this observation in the context of a large neoadjuvant trial, we may have a tool to start thinking about 'potential treatment de-escalation.'"

But, Dr Piccart-Gebhart added, immune gene signatures might tell a different story. In the NeoALTTO trial, sequencing showed that in the presence of certain gene signatures, pCR was higher with dual HER2 blockade than with single-agent HER2 blockade.[15] However, pCR was lower in the presence of some stromal signatures. "Clearly," she noted, "it will be interesting to confirm the data obtained with whole exome sequencing with data obtained by RNA sequencing."

Research on the tumor microenvironment in the adjuvant setting has been a little less forthcoming. "In the adjuvant setting, the story is at the beginning, and there are conflicting results, so we need to do more work," said Dr Piccart-Gebhart.

The results of the FinHer study[16] suggest that patients with lymphocyte-predominant breast cancer (LPBC) seem to benefit from the addition of trastuzumab to chemotherapy. But in the N9831 trial,[17] only non-LPBC patients appeared to derive that benefit. She commented that another confounding factor is that the FinHer and N9831 studies used different durations of trastuzumab treatment.

Obviously, said Dr Piccart-Gebhart, there remains a steep learning curve in dissecting the biological complexity of HER2-positive breast cancer; and, despite the huge progress made in targeted therapy, research still has a long way to go to answer patients' needs.

Dr Piccart-Gebhart closed her talk with a plea for greater international collaboration in patient-centered biomarker research, characterized by earlier, more comprehensive data sharing, with the ultimate goal of putting all data on one platform. "I am counting on collaboration from bright young investigators from all around the world to provide a stronger level of evidence for these immune biomarkers, to identify patients who do very well with trastuzumab and chemotherapy, and potentially find patients who can benefit from neoadjuvant approaches and de-escalation."

Dr Piccart-Gebhart is a consultant to Roche-Genentech.


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