Pathologic complete response to presurgery chemo improves survival for triple-negative breast cancer

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Published: 9 Dec 2015
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Dr William Sikov - Women & Infants Hospital of Rhode Island, Providence, USA

Dr Sikov presents, at a press conference at SABCS 2015 about the results from the randomised phase II CALGB/Alliance 40603 clinical trial.

The results showed that patients with stage 2 or stage 3 triple-negative breast cancer who had a pathologic complete response after presurgery chemotherapy had increased event- free and overall survival compared with those who had more than minimal residual invasive disease at surgery following presurgery chemotherapy.

Read the press release here

CALGB 40603 was a factorial two by two randomised phase II study designed to determine whether the addition of either carboplatin or bevacizumab would increase pathologic complete response rates in patients with stage 2 and 3 triple negative breast cancer receiving standard neoadjuvant chemotherapy. As presented two years ago and published earlier this year in the JCO, the study met its primary endpoint, that is the addition of carboplatin increased pCR rates in both the breast and the breast and axilla in a significant fashion. The addition of bevacizumab increased the pCR rate in the breast and had a borderline increase in the pCR in the breast and axilla.

These are the definitions of the endpoints that we’re going to be describing today. These are the long-term endpoints for the study. Event free survival is defined as the time from study entry to ipsilateral invasive breast or other local regional recurrence, distant recurrence or death from any cause, and overall survival the time from study entry to death from any cause. This analysis was performed when patients had reached a median of 39 months from study entry and we had seen a total of 110 events and 77 deaths.

These are the overall results for the study. At 39 months event free survival was 74% and overall survival was 83%. Given the aggressive biology of triple negative breast cancer we suspect that these curves are reaching their plateaux in the near future.

The first question is what was the impact of pathologic response on event free survival and overall survival. You can see from this table that whether we define pCR as pCR breast only, which was the primary endpoint of the study, or pCR breast and axilla, there was a highly statistically significant improvement in both event free and overall survival for patients who achieved a pCR compared to those who did not. There was a 70% improvement in event free survival and an 80% improvement in overall survival for patients achieving pCR breast and axilla. But the amount of residual invasive disease may also be important. A significant fraction of patients treated on our study, actually 13% of the overall study population, achieved minimal residual invasive disease defined as residual cancer burden class 1 by Simmons and colleagues. In the right column you see what happens when we add these patients to our pCR breast and axilla patients. What we see is really there is no reduction in the prognostic significance of achieving a pathologic complete response by adding these patients with minimal residual invasive disease. 

These are the curves for event free survival and overall survival by achievement of pathCR in the breast and axilla compared to not. For comparison this is the curve for pCR versus not from the FDA meta-analysis published by Cortazar and colleagues. If you add in our data you can see that our curves are nearly identical to those achieved in the meta-analysis, despite the fact that we had a significant increase in the pCR rate compared to the studies that were included in the meta-analysis. This is an enumeration of the event free survival and overall survival events seen in our study divided by response. You can see that patients who achieved pathCR had significant reductions in ipsilateral breast recurrences, other local regional recurrences, distant recurrences and breast cancer attributed deaths.

Turning now to the effect of the addition of carboplatin and bevacizumab. As you can see from this table, there were no statistically significant differences in event free survival or overall survival with the addition of carboplatin or bevacizumab compared to patients who did not receive those agents. The hazard ratio, 95% confidence intervals all overlap one. These are figures looking at event free survival for these two comparisons. I ask you not to over-interpret the minute separation between the two curves as statistical analysis tells us this could be the result of chance.

So we had improvements in pathCR and yet we don’t see significant improvements in event free survival. In a large part, of course, this may be due to the fact that the study was not powered to detect these differences but this curve may also help to explain this. This was a model created by two of our co-authors, Don Barry and Cliff Hudis, based on data from the Cortazar meta-analysis. What this curve shows is that as you increase the pathCR rate from a controlled regimen to an experimental regimen you can expect to see an improvement in event free survival that is a lower hazard ratio for event free survival. The greater the increase, the greater the reduction in events. Now, we’ve put on this curve the point estimates and confidence intervals for the 8% increase in pathCR seen with bevacizumab and the 13% increase seen with carboplatin. You can see that while the point estimates conform fairly well to the model, the 95% confidence intervals indicated by the dashed lines are wide and overlap one. What the model tells us is that to show with statistical validity that the addition of a new agent, let’s say, to a standard agent, to a standard regimen, increases event free survival you’re going to need to see a much larger increase in pathologic complete response rate or use a much, much larger study which would have much narrower confidence intervals.

It also suggests that the better your standard regimen is, as in our case our standard regimen was better than we expected, is going to make it all the more difficult to show this improvement in event free survival.

So in conclusion, the study showed that achievement of a pathologic complete response with weekly paclitaxel followed by dose dense AC with or without carboplatin and bevacizumab, is associated with significant improvements in event free survival and overall survival. And that the addition of patients with minimal residual disease, RCB class one, does not diminish the prognostic significance associated with achieving a pathCR. Significant reductions were seen in both local regional recurrences and in distant recurrences and in data that I’ll present later but did not present here you can pick out groups that have particularly poor outcomes, those patients with clinical stage 3 disease who failed to achieve a pathCR and those who have clinically node positive disease at baseline who have persistently positive nodes at surgery. Our results are consistent with the FDA requested meta-analysis. Our study was underpowered to determine whether the addition of carboplatin or bevacizumab would improve event free survival, despite the increases in the pathCR rates. Now, previous studies with bevacizumab have failed to demonstrate improvements in long-term outcomes with the addition of bevacizumab to a control regimen in stage 1-3 triple negative breast cancer and results from other completed studies and ongoing studies, including the GeparSixto results which will be presented today as well, should help to clarify whether the addition of carboplatin benefits patients with early stage triple negative breast cancer. Thank you.