Point/Counter

Should neoadjuvant carboplatin be used for triple-negative breast cancer?

Click here to read the Cover Story, “Deeper understanding of disease biology may improve outcomes in triple-negative breast cancer.”

POINT

Yes.

Carboplatin is a potentially life-saving treatment option for advanced clinical stage triple-negative breast cancers.

Lajos Pusztai, MD
Lajos Pusztai

Four published randomized trials — GeparSixto, CALGB 40603, Brightness and I-SPY 2 — have shown a significant improvement in pCR rate with inclusion of carboplatin. The pCR rates increased on average from around 30% to 35% with anthracycline taxane to between 50% and 55% when carboplatin is included. Moving these additional patients into the pCR category by a more effective cytotoxic therapy is important because patients who achieve pCR invariably do very well, and their distant metastatic recurrence rates are below 5%.

There is confusion around how to translate improvements in pCR rates into improvements in survival at a clinical trial level. A fundamental truth is that survival can only be improved for patients who are at risk for dying of breast cancer. Many patients with triple-negative breast cancer are cured with surgery alone, which is particularly true for T1 and T2 node-negative tumors. Therefore, not all of the additional patients who achieve pCR with carboplatin will experience increased survival; some will have been cured with surgery alone and a small percentage will relapse despite pCR.

Any given neoadjuvant trial always has a greater power to detect differences in pCR rate than differences in survival. Expected survival improvements in a trial arm that shows higher pCR rate is a function of the baseline prognostic risk of the trial population and the magnitude of improvement in pCR rate. Despite all four of the randomized carboplatin trials being substantially underpowered, by design, to detect improved survival, GeparSixto has shown statistically significant improvement in DFS (HR = 0.55; P = .04) and distant metastasis-free survival (HR = 0.5; P = .01). Every metastasis avoided is a life saved from breast cancer death.

The CALGB 40603 trial also showed a trend toward improved DFS but it has not reached statistical significance. The Brightness trial has not yet reported survival outcomes.

It is also worth remembering that, historically, almost every regimen that has improved pCR rates also improved survival. Even the survival results from the ALTTO trial confirmed the findings of NeoALTTO in terms of better survival with treatment that produced a higher pCR rate (HR = 0.84; P = .048), but missed the ‘magical P value’ for significance set to P < .025 due to the particularities of the trial design.

The only clear deviation from this rule is the experience with bevacizumab (Avastin, Genentech), which has not shown any improvement in survival despite consistent improvements in pCR rates in the neoadjuvant setting. This may relate to the particular mechanism of action for how this drug leads to increased pCR rates.

An additional important point to make is that smaller residual cancer after neoadjuvant chemotherapy allows for smaller surgeries for cancers larger than 2 cm to start with, and this may result in better cosmetic outcome. However, there is a toxicity price to pay for the higher pCR rates with carboplatin, as there are significantly higher hematologic toxicities, particularly grade 3 and grade 4 neutropenia and thrombocytopenia.

The bottom line is that, for patients with triple-negative breast cancer — particularly node-positive larger tumors — carboplatin might turn out to be a proven potentially life-saving regimen after a pooled survival analysis of the neoadjuvant trials will be performed, or when the currently accruing NRG-BR003 adjuvant carboplatin trial finally reports its outcome.

References:

Hatzis C, et al. Clin Can Res. 2016;doi:10.1158/1078-0432.CCR-14-3304.

Pusztai L, et al. Ann Oncol. 2017;doi:10.1093/annonc/mdx215.

Sikov WM, et al. Abstract S2-05. Presented at: San Antonio Breast Cancer Symposium; Dec. 8-12, 2015; San Antonio.

von Minckwitz G, et al. Lancet. 2014;doi:10.1016/S1470-2045(14)70160-3.

von Minckwitz G, et al. N Engl J Med. 2012;doi:10.1056/NEJMoa1111065.

Lajos Pusztai, MD, is codirector of Yale Cancer Center’s genetics and genomics program. He can be reached at lajos.pusztai@yale.edu. Disclosure: Pusztai reports no relevant financial disclosures.

COUNTER

No.

The role of carboplatin as neoadjuvant treatment for triple-negative breast cancer remains unclear.

Vandana G. Abramson, MD
Vandana G. Abramson

We now have a few large studies that have shown an increase in pCR with the addition of carboplatin. The biology of triple-negative breast cancer indicates that a large proportion of this subtype of breast cancer would benefit from the DNA-damaging effects of platinum-based therapy. For example, the CALGB 40603 study showed a pCR increase in the control arm (weekly paclitaxel for 12 weeks, followed by dose-dense doxorubicin and cyclophosphamide for 4 weeks) from 46% to 60% with the addition of carboplatin. Moreover, the GeparSixto study improved the pCR rate in the control arm (weekly paclitaxel with weekly nonpegylated liposomal doxorubicin for 18 weeks, along with bevacizumab every 3 weeks) from 37% to 53% with carboplatin. The Brightness study improved pCR in the control group (paclitaxel weekly for 12 weeks followed by dose-dense adjuvant chemotherapy) from 31% to 57.5% with the addition of carboplatin.

So, it is certainly tempting to want to use carboplatin in the neoadjuvant setting given the impressive improvements in pCR seen in these studies to date, but we have to remember that pCR is not a perfect or even validated surrogate for OS.

Take CALGB 40603, for example, which failed to show a significant improvement in EFS. Also, although the GeparSixto trial did show a 9.7% improvement in 3-year EFS with the addition of carboplatin, we have to remember that the backbone for the control group did not include an alkylating agent, which could theoretically act as the platinum-like agent in other studies by inducing DNA damage. EFS from the Brightness study is still pending.

The toxicities of these platinum agents are significant and, without a definite long-term benefit, routinely using them is difficult to justify. Given these uncertainties, I would not recommend the routine addition of carboplatin as neoadjuvant treatment for triple-negative breast cancer. However, carboplatin can be considered on a case-by-case basis, including for those with BRCA mutations or very high-risk disease (eg, stage IIIb or inflammatory tumors). The ongoing ECOG-ACRIN study E1131 is evaluating adjuvant carboplatin or cisplatin vs. capecitabine for patients with significant residual disease after standard neoadjuvant treatment, and this is an extremely compelling option.

References:

Sikov WM, et al. Abstract S2-05. Presented at: San Antonio Breast Cancer Symposium; Dec. 8-12, 2015; San Antonio.

von Minckwitz G, et al. Lancet Oncol. 2014;doi:10.1016/S1470-2045(14)70160-3.

von Minckwitz G, et al. N Engl J Med. 2012;doi:10.1056/NEJMoa1111065.

Vandana G. Abramson, MD, is associate professor of medicine at Vanderbilt University Medical Center. She can be reached at vandana.abramson@vanderbilt.edu. Disclosures: Abramson reports no relevant financial disclosures.

COUNTER

No.

It remains unclear if the addition of carboplatin to standard cytotoxic chemotherapy in operable triple-negative breast cancer leads to long-term clinical benefit.

Kevin Kalinsky, MD, MS
Kevin Kalinsky

Achieving a pCR after neoadjuvant chemotherapy has important prognostic implications for patients with operable triple-negative breast cancer. Patients with a pCR are at a lower risk for recurrence than patients with residual disease.

In the randomized GeparSixto and CALGB 40603 trials, the pCR rate appeared significantly higher among patients with triple-negative breast cancer who received carboplatin in addition to taxane- and anthracycline-based chemotherapy.

The carboplatin dosing in the GeparSixto trial was weekly, as opposed to every 3 weeks in CALGB 40603. However, it is notable that concomitant use of carboplatin with chemotherapy was associated with higher toxicity, leading to higher rates of treatment reduction and discontinuation than without carboplatin. In addition, the trials differed in terms of the impact of carboplatin on DFS, with an improvement observed in GeparSixto but no improvement observed in CALGB 40603. Notably, neither of the trials were powered to address the impact of carboplatin on DFS or OS.

Although these studies are intriguing in terms of their short-term pathologic benefit, it remains unclear if the addition of carboplatin to standard therapy in operable triple-negative breast cancer leads to long-term clinical benefit.

There are ongoing trials for patients with stage II/stage III triple-negative breast cancer to address the role of platinum therapies. For example, in the randomized ECOG-ACRIN 1131 trial, patients with residual triple-negative breast cancer after neoadjuvant chemotherapy will receive either cisplatin or carboplatin once every 3 weeks for four cycles, or capecitabine once every 2 weeks on and then 1 week off for six cycles. This is the standard of care per the CREATE-X trial.

For the randomized NRG-BR003 trial, patients with high-risk triple-negative breast cancer will receive adjuvant anthracycline-based chemotherapy followed by weekly paclitaxel with or without carboplatin once every 3 weeks.

The primary endpoint of these trials is invasive DFS and, if met, these studies have the potential to change practice in operable triple-negative breast cancer.

There may be clinical situations that may lead a treating physician to consider adding carboplatin to neoadjuvant chemotherapy, such as a young woman with a germline BRCA mutation and locally advanced disease. However, I would argue that — based upon the differences in study designs of currently reported phase 2 trials, and the fact that these trials were underpowered to determine DFS and OS benefit — the addition of a platinum-based therapy remains a research question. Given the potential added toxicity of platinum therapies, it also will be important to potentially identify molecular subsets that associate with platinum therapy sensitivity, so as to limit overtreatment in this population.

Thus, although the GeparSixto and CALGB 40603 trials demonstrate a pCR benefit, larger studies that are powered to address long-term clinical benefit with platinum therapies are necessary prior to this approach being deemed standard of care for operable triple-negative breast cancer.

References:

Masuda N, et al. N Eng J Med. 2017;doi:10.1056;NEJMoa1612645.

von Minckwitz G, et al. Lancet Oncol. 2014;doi:10.1016/S1470-2045(14)70160-3.

Sikov WM, et al. Abstract S2-05. Presented at: San Antonio Breast Cancer Symposium; Dec. 8-12, 2015; San Antonio.

Kevin Kalinsky, MD, MS, is assistant professor of medicine at NewYork-Presbyterian Hospital/Columbia University Medical Center. He can be reached at kk2693@cumc.columbia.edu. Disclosure: Kalinsky reports no relevant financial disclosures.

Click here to read the Cover Story, “Deeper understanding of disease biology may improve outcomes in triple-negative breast cancer.”

POINT

Yes.

Carboplatin is a potentially life-saving treatment option for advanced clinical stage triple-negative breast cancers.

Lajos Pusztai, MD
Lajos Pusztai

Four published randomized trials — GeparSixto, CALGB 40603, Brightness and I-SPY 2 — have shown a significant improvement in pCR rate with inclusion of carboplatin. The pCR rates increased on average from around 30% to 35% with anthracycline taxane to between 50% and 55% when carboplatin is included. Moving these additional patients into the pCR category by a more effective cytotoxic therapy is important because patients who achieve pCR invariably do very well, and their distant metastatic recurrence rates are below 5%.

There is confusion around how to translate improvements in pCR rates into improvements in survival at a clinical trial level. A fundamental truth is that survival can only be improved for patients who are at risk for dying of breast cancer. Many patients with triple-negative breast cancer are cured with surgery alone, which is particularly true for T1 and T2 node-negative tumors. Therefore, not all of the additional patients who achieve pCR with carboplatin will experience increased survival; some will have been cured with surgery alone and a small percentage will relapse despite pCR.

Any given neoadjuvant trial always has a greater power to detect differences in pCR rate than differences in survival. Expected survival improvements in a trial arm that shows higher pCR rate is a function of the baseline prognostic risk of the trial population and the magnitude of improvement in pCR rate. Despite all four of the randomized carboplatin trials being substantially underpowered, by design, to detect improved survival, GeparSixto has shown statistically significant improvement in DFS (HR = 0.55; P = .04) and distant metastasis-free survival (HR = 0.5; P = .01). Every metastasis avoided is a life saved from breast cancer death.

The CALGB 40603 trial also showed a trend toward improved DFS but it has not reached statistical significance. The Brightness trial has not yet reported survival outcomes.

It is also worth remembering that, historically, almost every regimen that has improved pCR rates also improved survival. Even the survival results from the ALTTO trial confirmed the findings of NeoALTTO in terms of better survival with treatment that produced a higher pCR rate (HR = 0.84; P = .048), but missed the ‘magical P value’ for significance set to P < .025 due to the particularities of the trial design.

The only clear deviation from this rule is the experience with bevacizumab (Avastin, Genentech), which has not shown any improvement in survival despite consistent improvements in pCR rates in the neoadjuvant setting. This may relate to the particular mechanism of action for how this drug leads to increased pCR rates.

An additional important point to make is that smaller residual cancer after neoadjuvant chemotherapy allows for smaller surgeries for cancers larger than 2 cm to start with, and this may result in better cosmetic outcome. However, there is a toxicity price to pay for the higher pCR rates with carboplatin, as there are significantly higher hematologic toxicities, particularly grade 3 and grade 4 neutropenia and thrombocytopenia.

The bottom line is that, for patients with triple-negative breast cancer — particularly node-positive larger tumors — carboplatin might turn out to be a proven potentially life-saving regimen after a pooled survival analysis of the neoadjuvant trials will be performed, or when the currently accruing NRG-BR003 adjuvant carboplatin trial finally reports its outcome.

References:

Hatzis C, et al. Clin Can Res. 2016;doi:10.1158/1078-0432.CCR-14-3304.

Pusztai L, et al. Ann Oncol. 2017;doi:10.1093/annonc/mdx215.

Sikov WM, et al. Abstract S2-05. Presented at: San Antonio Breast Cancer Symposium; Dec. 8-12, 2015; San Antonio.

von Minckwitz G, et al. Lancet. 2014;doi:10.1016/S1470-2045(14)70160-3.

von Minckwitz G, et al. N Engl J Med. 2012;doi:10.1056/NEJMoa1111065.

Lajos Pusztai, MD, is codirector of Yale Cancer Center’s genetics and genomics program. He can be reached at lajos.pusztai@yale.edu. Disclosure: Pusztai reports no relevant financial disclosures.

PAGE BREAK

COUNTER

No.

The role of carboplatin as neoadjuvant treatment for triple-negative breast cancer remains unclear.

Vandana G. Abramson, MD
Vandana G. Abramson

We now have a few large studies that have shown an increase in pCR with the addition of carboplatin. The biology of triple-negative breast cancer indicates that a large proportion of this subtype of breast cancer would benefit from the DNA-damaging effects of platinum-based therapy. For example, the CALGB 40603 study showed a pCR increase in the control arm (weekly paclitaxel for 12 weeks, followed by dose-dense doxorubicin and cyclophosphamide for 4 weeks) from 46% to 60% with the addition of carboplatin. Moreover, the GeparSixto study improved the pCR rate in the control arm (weekly paclitaxel with weekly nonpegylated liposomal doxorubicin for 18 weeks, along with bevacizumab every 3 weeks) from 37% to 53% with carboplatin. The Brightness study improved pCR in the control group (paclitaxel weekly for 12 weeks followed by dose-dense adjuvant chemotherapy) from 31% to 57.5% with the addition of carboplatin.

So, it is certainly tempting to want to use carboplatin in the neoadjuvant setting given the impressive improvements in pCR seen in these studies to date, but we have to remember that pCR is not a perfect or even validated surrogate for OS.

Take CALGB 40603, for example, which failed to show a significant improvement in EFS. Also, although the GeparSixto trial did show a 9.7% improvement in 3-year EFS with the addition of carboplatin, we have to remember that the backbone for the control group did not include an alkylating agent, which could theoretically act as the platinum-like agent in other studies by inducing DNA damage. EFS from the Brightness study is still pending.

The toxicities of these platinum agents are significant and, without a definite long-term benefit, routinely using them is difficult to justify. Given these uncertainties, I would not recommend the routine addition of carboplatin as neoadjuvant treatment for triple-negative breast cancer. However, carboplatin can be considered on a case-by-case basis, including for those with BRCA mutations or very high-risk disease (eg, stage IIIb or inflammatory tumors). The ongoing ECOG-ACRIN study E1131 is evaluating adjuvant carboplatin or cisplatin vs. capecitabine for patients with significant residual disease after standard neoadjuvant treatment, and this is an extremely compelling option.

References:

Sikov WM, et al. Abstract S2-05. Presented at: San Antonio Breast Cancer Symposium; Dec. 8-12, 2015; San Antonio.

von Minckwitz G, et al. Lancet Oncol. 2014;doi:10.1016/S1470-2045(14)70160-3.

von Minckwitz G, et al. N Engl J Med. 2012;doi:10.1056/NEJMoa1111065.

Vandana G. Abramson, MD, is associate professor of medicine at Vanderbilt University Medical Center. She can be reached at vandana.abramson@vanderbilt.edu. Disclosures: Abramson reports no relevant financial disclosures.

PAGE BREAK

COUNTER

No.

It remains unclear if the addition of carboplatin to standard cytotoxic chemotherapy in operable triple-negative breast cancer leads to long-term clinical benefit.

Kevin Kalinsky, MD, MS
Kevin Kalinsky

Achieving a pCR after neoadjuvant chemotherapy has important prognostic implications for patients with operable triple-negative breast cancer. Patients with a pCR are at a lower risk for recurrence than patients with residual disease.

In the randomized GeparSixto and CALGB 40603 trials, the pCR rate appeared significantly higher among patients with triple-negative breast cancer who received carboplatin in addition to taxane- and anthracycline-based chemotherapy.

The carboplatin dosing in the GeparSixto trial was weekly, as opposed to every 3 weeks in CALGB 40603. However, it is notable that concomitant use of carboplatin with chemotherapy was associated with higher toxicity, leading to higher rates of treatment reduction and discontinuation than without carboplatin. In addition, the trials differed in terms of the impact of carboplatin on DFS, with an improvement observed in GeparSixto but no improvement observed in CALGB 40603. Notably, neither of the trials were powered to address the impact of carboplatin on DFS or OS.

PAGE BREAK

Although these studies are intriguing in terms of their short-term pathologic benefit, it remains unclear if the addition of carboplatin to standard therapy in operable triple-negative breast cancer leads to long-term clinical benefit.

There are ongoing trials for patients with stage II/stage III triple-negative breast cancer to address the role of platinum therapies. For example, in the randomized ECOG-ACRIN 1131 trial, patients with residual triple-negative breast cancer after neoadjuvant chemotherapy will receive either cisplatin or carboplatin once every 3 weeks for four cycles, or capecitabine once every 2 weeks on and then 1 week off for six cycles. This is the standard of care per the CREATE-X trial.

For the randomized NRG-BR003 trial, patients with high-risk triple-negative breast cancer will receive adjuvant anthracycline-based chemotherapy followed by weekly paclitaxel with or without carboplatin once every 3 weeks.

The primary endpoint of these trials is invasive DFS and, if met, these studies have the potential to change practice in operable triple-negative breast cancer.

There may be clinical situations that may lead a treating physician to consider adding carboplatin to neoadjuvant chemotherapy, such as a young woman with a germline BRCA mutation and locally advanced disease. However, I would argue that — based upon the differences in study designs of currently reported phase 2 trials, and the fact that these trials were underpowered to determine DFS and OS benefit — the addition of a platinum-based therapy remains a research question. Given the potential added toxicity of platinum therapies, it also will be important to potentially identify molecular subsets that associate with platinum therapy sensitivity, so as to limit overtreatment in this population.

Thus, although the GeparSixto and CALGB 40603 trials demonstrate a pCR benefit, larger studies that are powered to address long-term clinical benefit with platinum therapies are necessary prior to this approach being deemed standard of care for operable triple-negative breast cancer.

References:

Masuda N, et al. N Eng J Med. 2017;doi:10.1056;NEJMoa1612645.

von Minckwitz G, et al. Lancet Oncol. 2014;doi:10.1016/S1470-2045(14)70160-3.

Sikov WM, et al. Abstract S2-05. Presented at: San Antonio Breast Cancer Symposium; Dec. 8-12, 2015; San Antonio.

Kevin Kalinsky, MD, MS, is assistant professor of medicine at NewYork-Presbyterian Hospital/Columbia University Medical Center. He can be reached at kk2693@cumc.columbia.edu. Disclosure: Kalinsky reports no relevant financial disclosures.