NCCN Refines Guidelines for Breast Cancer Care

Although there were no major changes to the 2016 update to the National Comprehensive Cancer Network (NCCN) Breast Cancer Guidelines, there were some “tweaks,” according to William J. Gradishar.

Neoadjuvant Endocrine Therapy

At the 2016 NCCN Annual Conference, Gradishar, a professor of Breast Oncology at the Feinberg School of Medicine at Northwestern University, discussed updates to the NCCN Breast Cancer Guideline and the latest research developments in the field.

“We made [guideline] modifications suggesting that endocrine therapy can be used selectively in the preoperative setting for patients with ER-positive disease,” said Gradishar.

The most suitable patients for neoadjuvant endocrine therapy are patients with ER rich cancers who are older (postmenopausal), or if they are younger, those who have significant morbidities that make them poor candidates for chemotherapy.

The multicenter, open-label phase 3 ACOSOG Z1031 study randomized women with stage 2 or 3 ER-rich (Allred score six through eight) breast cancer to 16 weeks of neoadjuvant treatment with Aromasin (exemestane), Femara (letrozole), or Arimidex (anastrozole).¹ The clinical response rate ranged between 60 percent and 72 percent among the three treatment arms.

“These data were primarily in postmenopausal women, but if you were to treat a premenopausal woman with an aromatase inhibitor [AI], you would obviously have to render her postmenopausal with ovarian suppression ablation before doing so,” said Gradishar.

Gradishar also noted that neoadjuvant chemotherapy with or without anti-HER2 therapy is increasingly successful in producing pathologic complete responses (pCRs), but only in ER-negative/HER2-positive cancers.

He cited the pivotal phase 2 NeoSphere trial,² which showed that Perjeta (pertuzumab), combined with Herceptin (trastuzumab) and Taxotere (docetaxel), significantly improved pCR when compared with three other neoadjuvant regimens (Herceptin plus Taxotere, Perjeta plus Herceptin, or Perjeta plus Taxotere) in newly diagnosed patients with HER2-positive, early-stage breast cancer, leading to the FDA approval of the Perjeta regimen.

In each of the four cohorts in the NeoSphere trial, pCR was higher among patients who were HR-negative. Gradishar stressed, however, that pCR in ER-positive patients may not be as critical in predicting outcomes.

Adjuvant Endocrine Therapy in Pre- and Postmenopausal Women

In a study by Ring et al³ of 435 patients who received neoadjuvant chemotherapy for operable breast cancer, overall survival (OS) outcomes were improved in patients who achieved a pCR compared with those who did not. This correlation held up in ER-negative patients, but pCR did not have prognostic significance in ER-positive patients. The NCCN guidelines stipulate that for premenopausal women at diagnosis, the optimal adjuvant endocrine therapy is Nolvadex (tamoxifen) for five years with or without ovarian function suppression (OFS) or an AI for five years with OFS.

If a patient becomes postmenopausal after five years, physicians should consider Nolvadex for an additional five years or switch to an AI for five years. If a patient remains premenopausal, physicians should consider Nolvadex for an additional five years or no further endocrine therapy.

“In postmenopausal women [at diagnosis] we have several different options, that include Nolvadex to start, switching over [to an AI] at some point, or, really what we view as the standard for most women, is to start with an AI," said Gradishar. "And, again, the data for an AI beyond five years is really limited at this point…as it stands at this point we would say that five years of an AI is the optimal duration.”

Gradishar cited a combined analysis⁴ of the ATLAS and aTTom trials, which examined the long-term impact of Nolvadex in women with early-stage ER-positive great cancer.

The combined data showed that in years five through nine, the impact of Nolvadex was not evident, with an HR for breast cancer mortality of 0.97 and an HR for OS of 0.99. However, in years 10 and beyond, Nolvadex was associated with a 25 percent reduction in the risk of breast cancer mortality and a 16 percent improvement in OS.

“So we have justification for using longer durations of therapy based on this data set,” said Gradishar.

There have also been efforts made by the NCCN guideline panelists to consider the appropriate use of OFS in premenopausal women with ER-positive and/or PR-positive breast cancer.

Gradishar said physicians should consider use of OFS plus Nolvadex or OFS plus an AI in patients aged under 35 years who need chemotherapy (ie, greater risk of recurrence), who remain premenopausal and who have larger, higher-grade tumors with multiple positive nodes. He added that the optimal duration of OFS-based therapy is uncertain, but suggested a trial period of three to five years.

The recommendations are based on outcomes from the SOFT and TEXT trials. The SOFT trial included 3,047 premenopausal women with early HR-positive breast cancer randomized to five years of Nolvadex or OFS added to either Nolvadex (tamoxifen) or Aromasin. The TEXT trial randomized 2,672 premenopausal women with HR+ breast cancer to Nolvadex plus OFS for five years or Aromasin plus OFS for five years.

A joint analysis⁵ of the TEXT and SOFT trials showed that Aromasin plus OFS improved outcomes versus Nolvadex plus OFS in terms of disease-free survival, breast cancer-free interval and distant disease-free interval. However, OS was the same between the two regimens.

Despite the benefit, several grade 3 and 4 AEs were higher with the Aromasin versus the Nolvadex regimen, including musculoskeletal events (11 percent vs 5.2 percent) and dyspareunia (2.3 percent vs 1.4 percent). Aromasin was also associated with a higher incidence of vaginal dryness, loss of sexual interest, difficulty with arousal and bone/joint pain.

Neoadjuvant HER2 Therapy

For additional clarity, “long-term follow-up of the pivotal [TEXT and SOFT] trials for adherence, toxicity, and benefit is critical,” said Gradishar.Gradishar said the ongoing critical question with neoadjuvant HER2-positive treatment in breast cancer remains, “Does increasing pCR improve outcomes?”

The answer to this question remains unclear, Gradishar noted.

Findings from the NeoALTTO study,⁶ showed that patients who achieved a pCR after receiving Tykerb (lapatinib) and Herceptin as neoadjuvant therapy displayed a significantly higher rate of three-year event-free survival, raising hopes that the adjuvant ALTTO⁷ trial would confirm those results.

However, in the ALTTO trial, use of the Tykerb/Herceptin regimen in the adjuvant setting for HER2-positive early breast cancer failed to demonstrate a significant improvement in disease-free survival over standard therapy with Herceptin alone.

As mentioned above, a neoadjuvant Perjeta regimen was given an accelerated FDA approval in HER2-positive, early-stage breast cancer based on pCR findings from the phase 2 NeoSphere trial. The approval is contingent on the confirmatory phase 3 APHINITY trial, which is comparing Perjeta, Herceptin, and chemotherapy with Herceptin and chemotherapy in the adjuvant setting for patients with HER2-positive early-stage breast cancer.

“If the adjuvant APHINITY trial proves not to be positive and does not represent what we’ve seen in the preoperative setting, the guidelines may change, but based on the data that we have available at this point, we feel that it’s a reasonable and prudent thing to offer [the neoadjuvant Perjeta regimen] to patients.”

New Combinations With Endocrine Therapy in Metastatic Disease

Gradishar said updated NeoSphere data⁸ presented at the 2015 ASCO Annual Meeting offered hope that the pCR benefit in the NeoSphere trial would accurately project a positive outcome with Perjeta in APHINITY trial. The findings presented at ASCO showed that patients who received Perjeta plus Herceptin/Taxotere appeared to have the best improvement in progression-free survival (PFS) compared with the other arms, which was consistent with the Perjeta triplet having the highest pCR in the initial analysis.

“If you look at the guidelines over the last few years, the striking thing that changes is instead of having a series of monotherapy choice options, we start to see the introduction of targeted therapy in combination with endocrine therapy as a standard, whether it’s Afinitor (everolimus), Ibrance (palbociclib), or even combinations of endocrine therapy.”

In February 2015, the FDA granted an accelerated approval to the CDK 4/6 inhibitor Ibrance as a frontline treatment for postmenopausal women with ER-positive, HER2-negative metastatic breast cancer, based on findings from the phase 2 PALOMA-1 trial.⁹

In the open-label phase 2 study, treatment with Ibrance plus Femara reduced the risk of disease progression by 51 percent compared with Femara alone. The median PFS with Ibrance was 20.2 versus 10.2 months for Femara alone (HR, 0.488; P = .0004).

Ibrance was approved by the FDA in February 2016 for use in combination with fulvestrant in pretreated patients with HR-positive, HER2-negative metastatic breast cancer.

The approval was based on findings from the phase 3 PALOMA-3 trial,¹⁰ in which adding Ibrance to standard Faslodex more than doubled PFS in pretreated patients with HR-positive, HER2-negative breast cancer. Median PFS was 9.5 months with the Ibrance combination versus 4.6 months in the placebo arm.

Gradishar said this information is now included in the guidelines.

“We now have a series of different treatments. We have to, again, judge whether a patient is appropriate for combining endocrine therapy with these different kinds of agents, like Ibrance and Afinitor, but I think that as we go forward, we are going to see more of this.”

References:

1. Olsen JA, et al. Presented at: 2010 Breast Cancer Symposium; October 1-3, 2010; Washington, DC. Abstract 91.
2. Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13(1):25-32.
3. Ring AE, Smith IE, Ashley S, et al. Oestrogen receptor status, pathological complete response and prognosis in patients receiving neoadjuvant chemotherapy for early breast cancer. Br J Cancer. 2004;91(12):2012-2017.
4. Gray RG, Rea D, Handley K, et al. aTTom: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years in 6,953 women with early breast cancer. J Clin Oncol 31, 2013 (suppl; abstr 5).
5. Pagani O, Regan MM, Walley BA, et al. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med. 2014;371:107-118.
6. Piccart-Gebhart M, Holmes AP, de Azambuja E, et al. The association between event-free survival and pathological complete response to neoadjuvant lapatinib, trastuzumab, or their combination in HER2-positive breast cancer. Survival follow-up analysis of the NeoALTTO study. Presented at: the 36th Annual San Antonio Breast Cancer Symposium; December 10-14, 2013; San Antonio, TX. Abstract S1-01.
7. Piccart-Gebhart M, Holmes AP, Baselga J, et al. First results from the phase III ALTTO trial (BIG 2-06; NCCTG [Alliance] N063D) comparing one year of anti-HER2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T→L), or their combination (T+L) in the adjuvant treatment of HER2-positive early breast cancer (EBC). Presented at: 2014 ASCO Annual Meeting Press Briefing; June 1, 2014; Chicago, IL. Abstract LBA4.
8. Gianni L, Pienkowski T, Im Y-H et al. Five-year analysis of the phase II NeoSphere trial evaluating four cycles of neoadjuvant docetaxel (D) and/or trastuzumab (T) and/or pertuzumab (P). J Clin Oncol 33, 2015 (suppl; abstr 505).
9. Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015;16(1):25-35.
10. Cristofanilli M, Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016. pii: S1470-2045(15)00613-0.