Understanding the Role of pCR in Early-Stage TNBC Opens Doors for Tailored Treatment


As ongoing research efforts are shifting further into personalized care, Hope S. Rugo, MD, FASCO discusses how pathologic complete response and the predictive value of residual cancer burden scoring are becoming a pivotal end point for the changing triple-negative breast cancer landscape.

Hope S. Rugo, MD, FASCO

Hope S. Rugo, MD, FASCO

New opportunities to improve the treatment of patients with early-stage triple-negative breast cancer (TNBC) stem from understanding the prognostic link between pathologic complete response (pCR) and survival outcomes, according to Hope S. Rugo, MD, FASCO. The next step on the roadmap of progress in the disease will focus on identifying therapeutic approaches that are directed to biologic subsets.

“We have made some remarkable progress in the treatment for early-stage TNBC…We know that pCR is highly prognostic for longer-term outcomes, [such as] event-free survival [EFS] and distant recurrence–free survival [DRFS],” Rugo said in a presentation during the 21st Annual International Congress on the Future of Breast Cancer® West.1 “…We can use this to capitalize on understanding how tumors respond on an individual basis, and hopefully, try to provide therapy that is appropriate for each patient’s cancer.

In her talk, Rugo, who is a professor of medicine and director of Breast Oncology and Clinical Trials Education at the University of California San Francisco Comprehensive Cancer Center, discussed key lessons learned in the neoadjuvant treatment of TNBC, including optimal chemotherapy backbone, leveraging immunotherapy, and novel combinations under exploration. As ongoing research efforts are shifting further into personalized care, Rugo discussed how pCR and the predictive value of residual cancer burden (RCB) scoring are becoming a pivotal end point for the changing landscape.

pCR: Lessons Learned

Although it was known that pCR is a prognostic biomarker for long-term outcomes, investigators involved with the phase 2 I-SPY2 trial (NCT01042379) set out to understand the strength of this association with EFS and DRFS in subpopulations of patients with high-risk, operable breast cancer who received standard treatment with 1 or more novel therapies.

Three-year outcomes from the trial showed that achievement of a pCR following neoadjuvant therapy was linked with a reduction in recurrence rate of approximately 80%, irrespective of disease subtype and/or treatment regimen.2 Of the 950 patients included in the trial, 34.7% achieved a pCR to treatment; the 3-year EFS and DRFS rates for those who experienced a pCR were 95%. Moreover, the hazard ratios (HRs) for pCR vs non-pCR were 0.19 (95% CI, 0.12-0.31) and 0.21 (95% CI, 0.13-0.34) for EFS and DRFS, respectively.

“Subsequently…published data [looked] at RCB score, [and showed] that the amount of cancer that [the patient] has at the time of surgery—not just having none vs some—has a big impact on DRFS and EFS over time,” Rugo explained. This knowledge can help clinicians to understand how individual tumors respond, and thus, select the optimal therapeutic option for each patient.

Neoadjuvant Platinum: What Do the Data Show?

Leveraging pCR as a marker for clinical benefit, investigators sought to establish the optimal chemotherapy backbones for patients with early-stage disease.

For example, the randomized, double-blind, placebo-controlled, phase 3 BrighTNess trial (NCT02032277) paved the way for the regimen of paclitaxel and carboplatin regimen to be used in future studies of neoadjuvant chemotherapy including the evaluation of the addition of immunotherapy.

“[BrighTNess] the largest trial to look specifically at what the addition of platinum does for pCR,” Rugo said. Of the 634 patients with TNBC who were enrolled, 316 received paclitaxel plus carboplatin and the PARP inhibitor veliparib (ABT-888), 160 received paclitaxel and carboplatin, and 158 were given paclitaxel alone.

Data showed that those who received paclitaxel and carboplatin alone experienced the highest pCR, at 58% vs 53% with paclitaxel/carboplatin and veliparib (P = .357) and 31% with paclitaxel alone (P < .0001).3 Among patients who were RBC class 0 or 1, the pCRs achieved in those who received paclitaxel plus carboplatin (n = 140) were 70% vs 68% in those who received paclitaxel/carboplatin and the PARP inhibitor (n = 268; P = .739) and 47% in those who received paclitaxel alone (n = 125; P < .0001).

“We saw that the addition of platinum to standard weekly paclitaxel, with all patients receiving AC [adriamycin/cyclophosphamide] after the combination chemotherapy and then going to surgery, resulted in a markedly higher pCR rate,” Rugo noted. “The addition of veliparib did not improve pCR further than the addition of carboplatin.”

Rugo added that an important component of the trial was understanding how to manage the toxicity of adding carboplatin to paclitaxel. Giving carboplatin on a weekly cadence improved the completion rate of anthracycline-based therapy following treatment with the doublet.

A post-hoc analysis of the trial, which looked at EFS with paclitaxel plus carboplatin vs paclitaxel alone, showed that the HR was 0.57 (95% CI, 0.36-0.91; P = .02).4

“These are the best data that we have, suggesting that adding carboplatin to a paclitaxel-based backbone not only improved pCR, but [had] an improvement in EFS with a long 4.5-year follow-up; this is more than adequate for TNBC,” Rugo said. “It led to the idea that adding platinum would improve outcomes for the majority of patients with who had at least stage III TNBC in the neoadjuvant setting.”

Moreover, several trials have examined whether the addition of a platinum agent to a taxane-based backbone could serve as an alternative for anthracyclines. The WSG-ADAPT-TN trial (NCT01815242) evaluated neoadjuvant nab-paclitaxel (Abraxane) plus carboplatin (n = 146) vs nab-paclitaxel plus gemcitabine (n = 178) in patients with TNBC; the pCR rates with these regimens were 45.9% and 28.7%, respectively (P < .001).5

“[The trial] clearly demonstrated that nab-paclitaxel and carboplatin was the optimal chemotherapy regimen if you eliminated anthracyclines in the neoadjuvant setting, with pCR as the end point,” Rugo noted.

Using pCR/RCB to Leverage Checkpoint Inhibitors

Checkpoint inhibition has become a part of standard care for patients who have at least stage II early-stage TNBC, according to Rugo. The rationale for combining checkpoint inhibitors with chemotherapy is based on the idea that chemotherapy results in tumor lysis and antigen shedding, which enhances host immune response and upregulates PD-L1 expression.

The phase 3 KEYNOTE-522 trial (NCT03036488) enrolled patients with newly diagnosed, stage II or III TNBC (n = 1174) and randomly assigned them 2:1 to receive neoadjuvant treatment with 4 cycles of pembrolizumab (Keytruda) at 200 mg every 3 weeks plus paclitaxel and carboplatin (n = 784) or placebo every 3 weeks plus paclitaxel/carboplatin (n = 390).

The primary end point was pCR at the time of surgery and EFS in the intention-to-treat population. “I think this is a model for future neoadjuvant-style trials, as the trial was powered for both a pCR end point, as well as an EFS end point, so you would not have to do a subsequent trial to understand the outcome on EFS,” Rugo noted.

Data from the first interim analysis showed that among the first 602 patients who were randomized, 64.8% (95% CI, 59.9%-69.5%) of those who received pembrolizumab plus chemotherapy achieved a pCR vs 51.2% (95% CI, 44.1%-58.3%) with chemotherapy alone (P < .001).6 The EFS rate in the pembrolizumab and chemotherapy-alone arms were 91.3% (95% CI, 88.8%-93.3%) and 85.3% (95% CI, 80.3%-89.1%), respectively (HR, 0.63; 95% CI, 0.43-0.93).

The phase 3 IMpassion031 trial (NCT03197935) also enrolled those with previously untreated, stage II to III TNBC. Participants were randomly assigned 1:1 to receive chemotherapy plus atezolizumab (Tecentriq) at 840 mg (n = 165) or placebo (n = 168) every 2 weeks prior to surgery. Patients then continued to receive 1 year of atezolizumab and this portion of the trial was unblinded.

At a median follow-up of 20.6 months (interquartile range [IQR], 8.7-24.9) in the chemoimmunotherapy arm, and 19.8 months (IQR, 8.1-24.5) in the chemotherapy-alone arm, pCR rates were 57.6% and 41.1%, respectively (P = .0044).7

“We learned something from these trials about the impact of immune markers on response. The benefit from immunotherapy, comparing the control arm with the arm receiving pembrolizumab or atezolizumab, was independent of PD-L1 status on the tumor,” Rugo said.

Moreover, a higher pCR rate was observed with the immunotherapy agents in those with PD-L1–positive disease vs those with negative status; as such, PD-L1 was found to be predictive of response to chemotherapy.

“We know that tumor-infiltrating lymphocytes and PD-L1 not only predict response to chemotherapy, but also, overall outcome,” Rugo said. “We might be able to use [available] data in the future to try and individualize therapy for patients with early-stage TNBC.”

Taking a Closer Look at KEYNOTE-522

Updated data from the KEYNOTE-522 trial, recently published in the New England Journal of Medicine, showed a statistically significant improvement in EFS (HR, 0.63; 95% CI, 0.48-0.82; P = .00031) and DRFS (HR, 0.61; 95% CI, 0.46-0.82) in those who received pembrolizumab and chemotherapy vs chemotherapy alone.8

“Remember that patients received 1 year of treatment with a checkpoint inhibitor, and those on placebo received 6 months of chemotherapy,” Rugo said. “The curve separated at about 12 months and stayed separated over time; this is highly statistically significant and very exciting data.

Data from the trial supported the July 2021 FDA approval of pembrolizumab in patients with high-risk, early-stage TNBC in combination with chemotherapy as neoadjuvant treatment and then continued as a single agent as adjuvant therapy after surgery.9

Subgroup analyses revealed that patients who had node-positive or node-negative disease, and those who had stage II or III disease, all derived benefit from the addition of pembrolizumab to chemotherapy. “However, the amount of disease that you start therapy with determines the pCR rate, even outside of whether they receive a checkpoint inhibitor not,” Rugo said.

Specifically, those with node-positive disease who received pembrolizumab/chemotherapy or chemotherapy alone had lower pCR rates (80.7% vs 71.5%, respectively) than those with node-negative disease (88.6% vs 82.2%, respectively).10,11 The same was true for disease stage; those with stage III disease who received pembrolizumab/chemotherapy or chemotherapy alone experienced lower pCR rates than those with stage II disease, at 71.8% and 62%, respectively, vs 88.6% and 81.7%, respectively.10,11

“Interestingly, [this observation] did not translate into a difference by node status or stage in terms of benefit of pembrolizumab; you see benefit regardless of stage,” Rugo said. “In some ways, you could argue that the patients who have the higher-stage disease with the worst outcome benefit the most, but we can cure even more patients with lower-stage, better-risk disease by adding the checkpoint inhibitor.”

When looking at EFS by pCR status, it was found that patients who achieved a pCR, irrespective of whether they received pembrolizumab or not, experienced an “excellent” outcome, according to Rugo. Those who did not achieve a pCR did not experience a large benefit with the immunotherapy. “This brought up the question of whether we could create a frameshift in the amount of residual disease,” Rugo noted.

To this end, investigators leveraged data from the first 600 patients included in KEYNOTE-522 to examine RCB in terms of EFS benefit.12 Data showed that those with a RCB score of 0 experienced a good outcome, irrespective of whether they received pembrolizumab. Those with a RCB score of 1 had outcomes that “were a little worse, but still overall good for this patient population,” according to Rugo. Those with a RCB score of 3 had very poor outcomes, irrespective of whether they received the immunotherapy.

Several additional trials are examining checkpoint inhibitors in the neoadjuvant setting including the phase 3 NeoTrip trial (NCT02620280) of atezolizumab and the phase 2 GeparNuevo trial (NCT02685059) of durvalumab (Imfinzi).

Notable studies examining immunotherapies in the adjuvant setting include the phase 3 IMpassion030 trial (NCT03498716) comparing atezolizumab in combination with adjuvant anthracycline/taxane-based chemotherapy vs chemotherapy alone in operable TNBC; the phase 3 A-Brave trial (NCT02926196) examining adjuvant avelumab (Bavencio) in high-risk TNBC; and the phase 3 SWOG S1418/NRG BR006 trial (NCT02954874) examining adjuvant pembrolizumab.

According to Rugo, efforts are being made to address key questions regarding which patients need checkpoint inhibitors which takes factors such as benefit-risk ratio into account, the optimal chemotherapy backbone for immunotherapy combinations, the optimal duration of a checkpoint inhibitor if a pCR is achieved, and the optimal post-neoadjuvant therapy.

Alternative Neoadjuvant Approaches

In addition to immunotherapy, approaches using different classes of agents, such as antibody-drug conjugates (ADC), have begun to gain traction in early-stage TNBC.

The phase 2 NeoSTAR trial (NCT04230109) is examining neoadjuvant treatment with sacituzumab govitecan-hziy (Trodelvy) in patients with localized TNBC.13 Of the 50 patients enrolled to the trial, 12 had stage I disease, 26 had stage II disease, and 11 had stage III disease. Moreover, 62% of patients were node negative, and 9 patients had germline BRCA positivity.

Study participants received sacituzumab govitecan at a starting dose of 10 mg/kg for 4 cycles on days 1 and 8 of each 21-day treatment cycle. Following those 4 cycles, patients with residual disease confirmed via biopsy had the option to receive additional neoadjuvant therapy per physician discretion.

Data from the trial, presented during the 2022 ASCO Annual Meeting, showed that the pCR rate achieved in the overall population was 30%. In those with stage I, II, and III disease, these rates were 50%, 27%, and 18%, respectively. Moreover, the pCR rate with the ADC in those with BRCA-positive disease was 75%.

“They are now studying the same regimen in combination with pembrolizumab,” Rugo said. “There are a lot of data to suggest that giving ADCs with pembrolizumab may enhance the effect of the checkpoint inhibitors, so we will be interested to see those data, as well as others that are looking at ADCs in combination with checkpoint inhibitors in the neoadjuvant setting.”

Investigators of the single-arm phase 2 NeoPACT trial (NCT03639948) took another look at the efficacy of chemoimmunotherapy and employed a biomarker analysis to identify potential prognostic factors of pCR. The trial examined pembrolizumab in combination with docetaxel and carboplatin for 6 cycles in 109 evaluable patients with TNBC; notably, 88% of patients had stage II or III disease, Rugo said.

Data showed that the pCR achieved with this approach in those with stage III disease was 43%, “which is very good,” Rugo said.14 Those with stage I disease achieved a pCR rate of 69% and those with stage II disease experienced a pCR rate of 59%. Those who achieved a pCR experienced a 2-year EFS rate of 98%.

In the biomarker analysis, patients who had a high rate of stromal tumor-infiltrating lymphocytes of 30% or higher experienced a higher pCR than those with a lower rate below 30%, at 76% and 41%, respectively (odds ratio [OR], 4.66; 95% CI, 2.02-10.78; P < .001). Moreover, those with a high DNA damage immune response signature had a higher pCR than those who did not, at 71% and 46%, respectively (OR, 2.90; 95% CI, 1.20-7.00; P = .018).

Looking to the Future

An evolution of the I-SPY 2 trial, I-SPY 2.2, seeks to identify treatments that will further improve subtype-specific response. With the trial, investigators hope to enable the testing of emerging targeted drugs and combinations to offer less toxic chemotherapy regimens or to replace chemotherapy entirely with effective, safer options for patients.

“[We have seen] that patients who had immune-positive signature had a marked benefit from the addition of a checkpoint inhibitor. [We also see] this with [other markers,] and we can really use these to individualize therapy,” Rugo concluded. “[The trial] is now open and enrolling patients to novel therapies in block A.”


  1. Rugo HS. Optimal treatment for early stage triple negative breast cancer. Presented at: 21st Annual International Congress on the Future of Breast Cancer® West; July 29-30, 2022; San Diego, CA.
  2. Yee D, DeMichele AM, Yau C, et al. Association of event-free and distant recurrence-free survival with individual-level pathologic complete response in neoadjuvant treatment of stages 2 and 3 breast cancer: three-year follow-up analysis for the I-SPY2 adaptively randomized clinical trial. JAMA Oncol. 2020;6(9):1355-1362. doi:10.1001/jamaoncol.2020.2535
  3. Loibl S, O’Shaughnessy J, Untch M, et al. Addition of PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial. Lancet Oncol. 2018;19(4):497-509. doi:10.1016/S1470-2045(18)30111-6
  4. Loibl S, Sikov W, Huober J, et al. Event-free survival (EFS), overall survival (OS), and safety of adding veliparib (V) plus carboplatin (Cb) or carboplatin alone to neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) after ≥4 years of follow-up: BrighTNess, a randomized phase III trial. Ann Oncol. 2021;32(suppl 5):S408. doi:10.1016/j.annonc.2021.08.400
  5. Gluz O, Nitz U, Liedtke C, et al. Comparison of neoadjuvant nab-paclitaxel + carboplatin vs nab-paclitaxel + gemcitabine in triple-negative breast cancer: randomized WSG-ADAPT-TN trial results. J Natl Cancer Inst. 2018;110(6):628-637. doi:10.1093/jnci/djx258
  6. Schmid P, Cortes J, Pusztai L, et al; KEYNOTE-522 Investigators. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020;382(9):810-821. doi:10.1056/NEJMoa1910549
  7. Mittendorf EA, Zhang H, Barrios CH, et al. Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. Lancet. 2020;396(10257):1090-1100. doi:10.1016/S0140-6736(20)31953-X
  8. Schmid P, Cortes J, Dent R, et al; KEYNOTE-522 Investigators. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med. 2022;386(6):556-567. doi:10.1056/NEJMoa2112651
  9. FDA approves Keytruda (pembrolizumab) for treatment of patients with high-risk early-stage triple-negative breast cancer in combination with chemotherapy as neoadjuvant treatment, then continued as single agent as adjuvant treatment after surgery. News release. Merck. July 27, 2021. Accessed July 30, 2022. https://bit.ly/3rAtLtP
  10. Schmid P, Park YH, Ferreira M, et al. KEYNOTE-522: phase 3 study of neoadjuvant pembrolizumab + chemotherapy versus placebo + chemotherapy, followed by adjuvant pembrolizumab versus placebo for early triple-negative breast cancer: pathologic complete response in key subgroups and by treatment exposure and residual cancer burden. Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Accessed July 30, 2022. https://bit.ly/3oIgu1C
  11. Schmid P, Cortés J, Dent R, et al. KEYNOTE-522 study of neoadjuvant pembrolizumab + chemotherapy vs placebo + chemotherapy, followed by adjuvant pembrolizumab vs placebo for early-stage TNBC: event-free survival sensitivity and subgroup analyses. Cancer Res. 2022;82(suppl 4):GS1-01. doi:10.1158/1538-7445.SABCS21-GS1-01
  12. Pusztai L, Denkert C, O’Shaughnessy J, et al. Event-free survival by residual cancer burden after neoadjuvant pembrolizumab + chemotherapy versus placebo + chemotherapy for early TNBC: exploratory analysis from KEYNOTE-522. J Clin Oncol. 2022;40(suppl 16):503. doi:10.1200/JCO.2022.40.16_suppl.503
  13. Spring L, Tolaney SM, Desai NV, et al. Phase 2 study of response-guided neoadjuvant sacituzumab govitecan (IMMU-132) in patients with localized triple-negative breast cancer: results from the NeoSTAR trial. J Clin Oncol. 2022;40(suppl 16):512. doi:10.1200/JCO.2022.40.16_suppl.512
  14. Sharma P, Stecklein SR, Yoder R, et al. Clinical and biomarker results of neoadjuvant phase II study of pembrolizumab and carboplatin plus docetaxel in triple-negative breast cancer (TNBC) (NeoPACT). J Clin Oncol. 2022;40(suppl 16):513. doi:10.1200/JCO.2022.40.16_suppl.513
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